Benzobicyclic compounds and their manufacturing methods and applications

Abstract

The present invention discloses a benzobicyclo-based compound and its preparation method and application. Specifically, the present invention provides a compound, such as a compound of formula (X), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma-ceutically acceptable salt or prodrug of the compound of formula (X). [Case 1] TIFF2025508097000118.tif43170

Description

[Technical Field]

[0001] This application is It claims priority from CN202210219469.9, filed on March 8, 2022.

[0002] The present invention relates to the field of chemical medicine technology, and more particularly to benzobicyclo-based compounds and their preparation methods and applications. [Background technology]

[0003] Diabetes mellitus is a multi-etiological metabolic disease characterized by chronic hyperglycemia accompanied by impaired glucose, lipid, and protein metabolism due to defective insulin secretion or action. Diabetes is a very old disease characterized by an absolute or relative deficiency of insulin in the human body, which leads to elevated blood glucose levels and excessive excretion of sugar in the urine, resulting in symptoms such as polydipsia, polyuria, polyphagia, and weight loss.

[0004] Based on the mechanism of diabetes onset, diabetes can generally be divided into type I diabetes and type II diabetes. Type I diabetes is caused by the loss of insulin secretion function due to the autoimmune system attacking pancreatic islet β cells. Type II diabetes begins with abnormal insulin resistance or cells that do not respond to insulin, and obesity is one of the main causes of insulin resistance, so obesity can be said to be a major risk factor for type II diabetes. Since type II diabetes patients account for approximately 90% of all diabetes patients, this disease has become a major public health issue in developed countries where obesity is a serious problem, and in China, where the number of obese people is constantly increasing.

[0005] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its effects by binding to specific receptors present in a wide range of tissues. Currently, GLP-1 receptors are clearly present in pancreatic islets, gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and cardiovascular system, and may also be present in liver, adipose tissue, and skeletal muscle. GLP-1 not only stimulates insulin secretion by acting on β cells, but also inhibits glucagon secretion by acting on α cells. Serum GLP-1 levels are generally not significantly different in patients with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. However, after a meal, β cell responses to GLP-1 are impaired, and under certain conditions, continuous infusion of GLP-1 significantly enhances this response. The duration of action of the human body's own GLP-1 is very short (t1 / 2<1.5 minutes after intravenous injection), so the human body's own GLP-1 is not suitable for clinical treatment of diabetes.

[0006] Peptide-based GLP-1 receptor agonists (e.g., liraglutide, exenatide, etc.) have the effect of lowering fasting and postprandial blood glucose and improving blood glucose levels in patients with type 2 diabetes. However, due to the poor oral bioavailability and inconvenient administration of peptide-based GLP-1, there is an urgent need in clinical practice for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0007] Currently, scientific researchers have conducted several studies in hopes of finding therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications WO 2018109607, WO 2019239319, WO 2019239371, WO 2020103815, WO 2020207474, WO 2020263695, WO 2021154796, WO 2021112538, WO 2021096304, WO 2021096284, WO 2021081207, WO 2021018023, and WO 2021254470 disclose many small molecule compounds that act as GLP-1 receptor agonists to prevent or treat diabetes. However, there is still an urgent need for more and better GLP-1 receptor agonists in the clinic. Summary of the Invention

[0008] The present invention provides a compound that can be an agonist of the GLP-1 receptor, or a pharmaceutical composition thereof. The present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a drug, which treats a disease and / or condition by stimulating the GLP-1 receptor with the compound. The present invention also further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0009] In a first aspect, the present invention provides a compound, which is a compound as shown in formula (X) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (X), [ka] Here, ring A1 is a 5- to 6-membered heteroaryl group, a phenyl group, a 5- to 6-membered heterocyclyl group, and C 5-6 cycloalkyl groups, Ring C is a 5- to 6-membered heteroaryl group; Z is O, S, N(R z ) and C(Rz )2, Each R c , R2 and R3 are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C 1-6 alkyl group, 1-6 the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R4, R5, R6, R7, and R9 each independently represent H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C 1-6 alkyl group, 1-6 the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Each R a are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 Cycloalkyl groups, -C(=O)NHS(=O)2 phenyl groups, 5- to 6-membered heteroaryl groups, and [ka] wherein said —C(═O)NHC(═O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 the cycloalkyl group, -C(=O)NHS(=O)2 phenyl group, or 5- to 6-membered heteroaryl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; Each R zare independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; Each R b are independently H, F, Cl, Br, I, oxo, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; R8 is H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R 10 and C 1-6 Alkylene C(R S RM R N ) wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R 10 and C 1-6 Alkylene C(R S R M R N ) optionally contains 1, 2 or 3 R 8a is replaced by Each R 8a are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclyl groups, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has one, two, or three R 8b is replaced by Each R 8b are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups; R 10 is C 3-6 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, wherein said C 3-6 The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxy, amino, cyano, nitro, C1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group or C 1-6 may be substituted with an alkylamino group, R S , R M , R N are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or R S , R M are concatenated into C 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group, [ka] represents a single bond or a double bond, m is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0010] In some aspects of the invention, the compound of formula (X), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (X), is as shown in formula (Ia) or (Ib) or (Ic): [ka] Here, ring A1 is a 5- to 6-membered heteroaryl group, a phenyl group, a 5- to 6-membered heterocyclyl group, and C 5-6 cycloalkyl groups, X5, X6, X7, and X9 are each independently C(R c ) and N; X4 and X8 are O, S, C(R c )2 and N(R c ) and Y is independently C(R Y ) and N; Z is independently O, S, or N(Rz ) and C(R z )2 is selected, Each R c , R1, R2 and R3 are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group and C 1-6 alkyl group, 1-6 the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R4, R6, and R7 each independently represent H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C 1-6 alkyl group, 1-6 the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Each R a are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 Cycloalkyl groups, -C(=O)NHS(=O)2 phenyl groups, 5- to 6-membered heteroaryl groups, and [ka] wherein said —C(═O)NHC(═O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 the cycloalkyl group, -C(=O)NHS(=O)2 phenyl group, or 5- to 6-membered heteroaryl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; R Y and each R z are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; Each R b are independently H, F, Cl, Br, I, oxo, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; R8 is H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R 10 and C 1-6 Alkylene C(R S R M R N) wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R 10 and C 1-6 Alkylene C(R S R M R N ) optionally contains 1, 2 or 3 R 8a is replaced by Each R 8a are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclyl groups, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has one, two, or three R 8b is replaced by Each R 8b are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups; R 10 is C 3-6 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, wherein said C 3-6 The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxy, amino, cyano, nitro, C 1-6 Alkyl group, C 1-6Alkoxy group, C 1-6 Alkylthio group or C 1-6 may be substituted with an alkylamino group, R S , R M , R N are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or R S , R M are concatenated into C 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group, [ka] represents a single bond or a double bond, m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0011] In some aspects of the invention, the compound of formula (X), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (X), is as shown in formula (II-a) or (II-b) or (II-c) or (II-d) or (II-e) or (II-f) or (II-g) or (II-h) or (II-i): [ka] [ka] where X1, X2, and X3 each independently represent C(R a ) and N; X5, X6, X7, X9, Y1, and Y4 each independently represent C(R c ) and N; X4, X8, Y2, Y3 are O, S, C(R c )2 and N(R c ) and Y is C(R Y ) and N; Z is O, S, N(R z ) and C(R z )2 is selected, Each R a are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 Cycloalkyl groups, -C(=O)NHS(=O)2 phenyl groups, 5- to 6-membered heteroaryl groups, and [ka] wherein said —C(═O)NHC(═O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-6 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-6 Alkyl group, -C(=O)NHS(=O)2C 3-6 the cycloalkyl group, -C(=O)NHS(=O)2 phenyl group, or 5- to 6-membered heteroaryl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; Each R c , R1, R2 and R3 are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group and C 1-6 alkyl group, 1-6 the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R4, R6, and R7 each independently represent H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C 1-6 alkyl group, 1-6the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R Y and each R z are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; Each R b are independently H, F, Cl, Br, I, oxo, hydroxy group, cyano group, nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, carboxyl group, -C(=O)OC 1-6 Alkyl group or -C 1-6 AlkyleneC(=O)OC 1-6 alkyl groups, wherein said -C(=O)OC 1-6 Alkyl groups and -C 1-6 AlkyleneC(=O)OC 1-6 the alkyl group is independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups; R8 is H, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R10 and C 1-6 Alkylene C(R S R M R N ) wherein C is selected from 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups, -C 1-6 Alkylene-R 10 and C 1-6 Alkylene C(R S R M R N ) optionally contains 1, 2 or 3 R 8a is replaced by Each R 8a are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 cycloalkyl groups and 3- to 6-membered heterocyclyl groups, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has one, two, or three R 8b is replaced by Each R 8b are independently D, F, Cl, Br, I, CN, and C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Alkylamino group, C 3-6 selected from cycloalkyl groups and 3- to 6-membered heterocyclyl groups; R 10 is C 3-6 cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, wherein said C 3-6The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxy, amino, cyano, nitro, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group or C 1-6 may be substituted with an alkylamino group, R S , R M , R N are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or R S , R M are concatenated into C 3-6 forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group, [ka] represents a single bond or a double bond.

[0012] In some embodiments of the present invention, R8 is selected from the group consisting of H, C, 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclyl groups and -C 1-3 Alkylene-R 10 wherein C is selected from 1-3 Alkyl group, C 2-3 Alkenyl group, C 2-3 Alkynyl group, C 3-6 a cycloalkyl group, a 3- to 6-membered heterocyclyl group, or -C 1-3 Alkylene-R 10 optionally 1, 2 or 3 R 8a and other variables are as defined herein.

[0013] In some embodiments of the present invention, the R 8a are D, F, Cl, Br, I, CN, and C 1-3 Alkyl group, C 1-3Alkoxy group, C 1-3 Alkylthio group, C 1-3 Alkylamino group, C 4-6 cycloalkyl groups and 5- to 6-membered heterocyclyl groups, 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Alkylamino group, C 4-6 The cycloalkyl group or the 5- to 6-membered heterocyclyl group may optionally contain one, two, or three R 8b and other variables are as defined herein.

[0014] In some embodiments of the present invention, the R 8b are D, F, Cl, Br, I, CN, and C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Alkylamino group, C 5-6 It is selected from a cycloalkyl group and a 5- to 6-membered heterocyclyl group, and the other variables are as defined in the present invention.

[0015] In some embodiments of the present invention, the R 10 is C 5-6 It is selected from a cycloalkyl group, a 5- to 6-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group, and the other variables are as defined herein.

[0016] In some embodiments of the present invention, the R 10 represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, [ka] and the other variables are as defined herein.

[0017] In some embodiments of the present invention, R8 is H, [ka] and the other variables are as defined herein.

[0018] In some embodiments of the present invention, R1, R2, and R3 are each independently selected from H, D, F, Cl, Br, and I, and the other variables are as defined herein.

[0019] In some embodiments of the present invention, R4, R6, and R7 are each independently selected from H, D, F, Cl, Br, and I, and the other variables are as defined herein.

[0020] In some embodiments of the present invention, each R a are independently -C(=O)OH, -C(=O)NHC(=O)C 1-3 Alkyl group, -C(=O)NHS(=O)2C 1-3 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-3 Alkyl group, -C(=O)NHS(=O)2C 3-6 Cycloalkyl groups, -C(=O)NHS(=O)2 phenyl groups, 5- to 6-membered heteroaryl groups, and [ka] wherein said —C(═O)NHC(═O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-3 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-3 Alkyl group, -C(=O)NHS(=O)2C 3-6 The cycloalkyl group, -C(=O)NHS(=O)2 phenyl group, or 5-6 membered heteroaryl group may be independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups, and all other variables are as defined herein.

[0021] In some embodiments of the present invention, each R a independently [ka] and the other variables are as defined herein.

[0022] In some embodiments of the present invention, each R a are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C 1-3 Alkyl group, -C(=O)NHS(=O)2C 1-3 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-3 Alkyl group, -C(=O)NHS(=O)2C 3-6 Cycloalkyl groups, -C(=O)NHS(=O)2 phenyl groups, 5- to 6-membered heteroaryl groups, and [ka] wherein said —C(═O)NHC(═O)C 1-6 Alkyl group, -C(=O)NHS(=O)2C 1-3 Alkyl group, -C(=O)NHS(=O)2NH2, -C(=O)NHS(=O)2NH C 1-3 Alkyl group, -C(=O)NHS(=O)2C 3-6 The cycloalkyl group, -C(=O)NHS(=O)2 phenyl group, or 5-6 membered heteroaryl group may be independently optionally substituted with 1, 2, 3, 4, or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, or cyano groups, and all other variables are as defined herein.

[0023] In some embodiments of the present invention, each R a are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, [ka] and the other variables are as defined herein.

[0024] The compound of formula (X), or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound of formula (X), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from one of the following structures:

[0025] In a further aspect, the present invention further provides a pharmaceutical composition, which, according to an embodiment of the present invention, comprises a compound as described above, a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

[0026] In some forms of the invention, the composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

[0027] In a further aspect, the present invention further provides the use of the compounds as hereinbefore described, their stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs or the pharmaceutical compositions as hereinbefore described in a medicament for preventing, treating or alleviating a GLP-1 receptor agonist mediated disease in a patient.

[0028] In a further aspect, the present invention further provides the use of the above-described compounds, stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof or the above-described pharmaceutical compositions in the manufacture of a medicament for the prevention and / or treatment of diseases and / or conditions associated with the GLP-1 receptor downstream signaling pathway.

[0029] In some embodiments of the present invention, the disease and / or condition associated with the GLP-1 receptor downstream signaling pathway is selected from diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia and diabetic infection, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular problems, epilepsy, atherosclerosis, Parkinson's disease, and Alzheimer's disease.

[0030] In a further aspect, the present invention further provides an application of the above-described compounds, their stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the above-described pharmaceutical compositions in the manufacture of a drug that stimulates insulin secretion or lowers blood glucose.

[0031] In a further aspect, the present invention further provides the use of the above-described compounds, their stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs or the above-described pharmaceutical compositions in the manufacture of a medicament for preventing and / or treating diabetes.

[0032] In some embodiments of the invention, the diabetes is type 1 diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of adolescence, malnutrition-related diabetes, or latent autoimmune diabetes of adults.

[0033] Definitions and General Terms The present invention specifically recites references corresponding to the content of the identified embodiments, and all examples are accompanied by structural and chemical formula diagrams. The present invention is intended to cover all alternatives, modifications, and equivalents, which may fall within the prior art of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which may be applied to the practice of the present invention. The present invention is in no way limited to the description of the methods and materials. Many references and similar materials are distinct from or contradict the present application, including, but not limited to, definitions of terms, usage of terms, techniques described, or scope controlled by the present application.

[0034] Unless otherwise indicated, the present invention applies the following definitions. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and The Chemical Manual, 75, th Ed., 1994. General principles of organic chemistry are also described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all contents of which are incorporated by reference.

[0035] The term "comprises" is an open expression and includes the content explicitly meant by the present invention, but does not exclude the content of other aspects.

[0036] Compounds as described herein, for example, compounds of the general formula of the present invention, or specific examples, subclasses, and compounds included in the examples, may be optionally substituted with one or more substituents. It should be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted." Generally, whether the term "optionally" precedes the term "substituted," it means that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise indicated, an optional substituent may have one substituent at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents selected from a specified group, the substituents can be the same or different at each position. The substituents, as used herein, include hydrogen, F, Cl, Br, I, nitro, cyano, oxo, and the like. (=O), hydroxy group, alkyl group, hydroxyalkyl group, alkylamino group, aminoalkyl group, halogenated alkoxy group, cycloalkyl group, amino group, aryl group, heterocyclyl group, heteroaryl group, alkenyl group, alkynyl group, cycloalkyloxy group, alkoxy group, alkoxyalkyl group, halogenated alkyl group, -COOH, -alkylene-C(=O)O-alkyl group, -alkylene-S(=O)2-alkyl group, -alkylene-S(=O)2-amino group, -S(=O)2-alkyl group, -S(=O)2-amino group, -S(=O)2OH, -O-alkylene-C(=O)O-alkyl group, -O-alkylene -S(=O)2-alkyl group, -O-alkylene-S(=O)2-amino group, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl group, -C(=O)N(alkyl)-alkyl group, -C(=O)NHS(=O)2-alkyl group, -C(=O)NHS(=O)2-amino group, -C(=O)NHS(=O)2OH, -N(halogenated alkyl)-alkyl group, -N(alkyl)-S(=O)2-alkyl group, -NHS(=O)2-alkyl group, -NHS(=O)2-halogenated alkyl group, -N(alkyl)S(=O)2-halogenated alkyl group, -N(alkyl)S(=O)2-alkylamino group,-NHC(=O)-alkyl group, -NHC(=O)-halogenated alkyl group, -N(alkyl)C(=O)-halogenated alkyl group, -N(alkyl)C(=O)-alkylamino group, -N(alkyl)C(=O)O-alkyl group, -NHC(=O)O-alkyl group, -NHC(=O)O-halogenated alkyl group, -N(alkyl)C(=O)O-halogenated alkyl group, -N(alkyl)C(=O)O-aminoalkyl group, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(halogenated alkyl group), -NHC(=O)N(alkyl)-alkyl group, -OC(=O)-alkyl group, -OC(=O)-amino group, -OC(=O)-alkylamino group, -OC(=O )-aminoalkyl group, -OC(=O)-alkoxy group, -C(=O)N(alkyl)S(=O)2-alkyl group, -C(=O)N(alkyl)S(=O)2-amino group, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl group, -C(=NH)N(alkyl)-alkyl group, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl group, -C(=O)N(alkyl)C(=O)O-alkyl group, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl group.

[0037] As used herein, the term "alkyl group" includes saturated linear or branched monovalent hydrocarbon groups containing 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, where alkyl groups may be independently and optionally substituted with one or more substituents described herein. Further examples of alkyl groups are methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH (CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3) Examples of alkyl groups include, but are not limited to, 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)), n-heptyl, and n-octyl. The term "alkyl group" and its prefix "alkyl," as used herein, are inclusive of both straight and branched saturated carbon chains.The terms "alkylene" or "alkylene group," as used herein, refer to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight- or branched-chain saturated hydrocarbon; examples of such groups include, but are not limited to, methylene, ethylene, and isopropylidene.

[0038] The term "alkenyl group" refers to a straight or branched chain hydrocarbon group containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one position is unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group may be independently and optionally substituted with one or more substituents described herein, including groups having "trans," "cis," or "E," "Z" orientations, wherein specific examples of alkenyl groups include, but are not limited to, vinyl groups (-CH=CH), allyl groups (-CHCH=CH), and the like.

[0039] The term "alkynyl group" refers to a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp triple bond, and wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein, wherein specific examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CHC≡CH), and the like.

[0040] The term "heteroatom" refers to one or more of O, S, N, P, and Si, including any oxidation state of C, N, S, and P, primary, secondary, and tertiary amines and quaternary ammonium salts, or a heterocyclic ring in which a hydrogen atom on a nitrogen atom is substituted, for example, N (N in a 3,4-dihydro-2H-pyrrolyl group), NH (NH in a pyrrolidinyl group), or NR (NR in an N-substituted pyrrolidinyl group), or a -CH- in the heterocyclic ring is oxidized to form -C(=O)-.

[0041] The term "halogen" refers to F, Cl, Br or I.

[0042] The term "deuterium" refers to heavy hydrogen, D.

[0043] The term "unsaturated" as used herein means partially containing one or more degrees of unsaturation.

[0044] The term "alkoxy group" or "alkyloxy group" as used herein refers to an alkyl group, as defined herein, that is linked to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups, examples of which include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups, may be independently unsubstituted or substituted with one or more substituents according to the present invention.

[0045] As used herein, the term "alkylthio group" or "alkylthio group" refers to an alkyl group, as defined herein, that is linked to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 alkylthio groups, examples of which include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio groups, and the alkylthio groups may be independently unsubstituted or substituted with one or more substituents according to the present invention.

[0046] The term "alkylamino group" or "alkylamino group" as used herein refers to an alkyl group, as defined herein, linked to the rest of the compound molecule via an N atom. In some embodiments, the alkylamino group is C 1-4 alkylamino groups, examples of which include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups, which may be independently unsubstituted or substituted with one or more substituents according to the present invention.

[0047] The term "cycloalkyl group" or "cycloalkane" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic carbocyclic ring system containing 3 to 12 carbon atoms, either saturated or containing one or more unsaturated bonds, but never aromatic. In one embodiment, a cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, a cycloalkyl group contains 3 to 8 carbon atoms; and in another embodiment, a cycloalkyl group contains 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0048] The terms "heterocyclyl group" and "heterocycle", which may be used interchangeably herein, refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, and in no case including an aromatic ring, in which at least one ring atom is a heteroatom. In one embodiment, a "heterocyclyl group" or "heterocycle" contains 3 to 10 ring atoms, in one embodiment, a "heterocyclyl group" or "heterocycle" contains 3 to 8 ring atoms, in another embodiment, a "heterocyclyl group" or "heterocycle" contains 5 to 8 ring atoms, in yet another embodiment, a "heterocyclyl group" or "heterocycle" contains 3 to 6 ring atoms, in another embodiment, a "heterocyclyl group" or "heterocycle" contains 5 to 6 ring atoms, and in yet another embodiment, a "heterocyclyl group" or "heterocycle" contains 4 to 6 ring atoms, and unless otherwise specified, a heterocyclyl group may be a carbon or nitrogen group, and the heteroatoms have the meanings described herein. Examples of heterocyclyl groups include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, and dihydropyranyl. Examples of heterocyclyl groups include, but are not limited to, pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxane, dithianyl, thioxane, homopiperazinyl, homopiperidinyl, oxepanyl, thiepane, oxazepinyl, diazepinyl, thiazepinyl, and 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of heterocyclyl groups in which -CH-yl is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl, and pyrimidinedione.Examples of heterocyclyl groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl groups, which may be optionally substituted with one or more substituents according to the present invention.

[0049] The term "aryl group" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, where at least one ring is aromatic, and where each ring contains 3 to 7 ring atoms and has one or more attachment points connected to the remainder of the molecule. The term "aryl group" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl groups may be independently and optionally substituted with one or more substituents described herein.

[0050] The term "heteroaryl group" refers to a monocyclic, bicyclic, or tricyclic ring system containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, where at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, where each ring contains 5 to 7 atoms and has one or more points of attachment to the remainder of the molecule. The term "heteroaryl group" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5 to 10 atoms contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, where the nitrogen atom may be further oxidized.

[0051] Examples of heteroaryl groups include furyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl), pyridyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, and 5-pyrimidinyl), pyridyl, and pyrimidinyl groups. ridazinyl group, thiazolyl group (e.g., 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group), tetrazolyl group (e.g., 5-tetrazolyl group), triazolyl group, thienyl group (e.g., 2-thienyl group, 3-thienyl group), pyrazolyl group, isothiazolyl group, 1,2,3-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,3-triazolyl group, 1,2,3-thiodiazolyl group, 1,3,4-thiodiazolyl group Examples of quinolyl groups include, but are not limited to, benzoyl, 1,2,5-thiodiazolyl, pyrazinyl, and 1,3,5-triazinyl groups, as well as benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, and 4-quinolyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, indoline, and isoquinolinyl (e.g., 1-isoquinolinyl). Bicycles such as, but not limited to, pyrazolo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and [1,2,4]triazolo[1,5-a]pyridyl.

[0052] As described herein, a ring system formed by connecting one bond of a substituent to a ring indicates that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent R can be mono- or polysubstituted at any substitutable position on the pyridine ring. [ka]

[0053] As described herein, a ring system formed by connecting a single bond to a ring (e.g., as shown in formula b) represents that the bond can be connected to the remainder of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be connected to the remainder of the molecule. [ka]

[0054] It should also be explained that unless clearly indicated otherwise, the descriptive methods "each and independently," "and each independently," and "and each independently" used throughout this specification are interchangeable and should be understood in a broad sense, which may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other.

[0055] Unless otherwise indicated, the structural formulae depicted in the present invention encompass all isomeric forms (e.g., enantiomers, diastereomers, geometric or conformational isomers), such as the R, S configuration containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, any single stereochemical isomer of a compound of the present invention or a mixture of its enantiomers, diastereomers, geometric or conformational isomers is within the scope of the present invention.

[0056] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, single stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the invention are also within the scope of the invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0057] A "metabolite" is a product obtained by metabolism in the body of a specific compound described in this invention or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits activity similar to that of the compound of formula (X) in vivo or in vitro. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by testing methods as described in this invention. Such products can be obtained by treating the administered compound with methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, or enzymatic cleavage. Accordingly, the present invention includes metabolites of compounds, including those produced by sufficient contact of a compound of this invention with a mammal for a period of time.

[0058] In the present invention, the definitions and conventions of stereochemistry generally refer to the following publications: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers, and therefore, different stereoisomers exist. All stereoisomeric forms of the compounds of the present invention include, but are not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, including, but not limited to, racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. When describing an optically active compound, the prefixes D, L, or R, S are intended to denote the absolute configuration of the chiral centers of the molecule. The prefixes d, l, (+), and (-) designate the sign of a compound's plane-polarized light rotation; (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure but differ in their configuration. A particular stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemic, which can result in a lack of stereoselectivity or stereodirection in a chemical reaction process. The terms "racemic mixture" and "racemic" refer to an equimolar mixture of two diastereomers, lacking optical activity.

[0059] The term "tautomer" or "tautomeric form" refers to isomers of different energy structures that can be interconverted via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers due to proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include tautomers due to rearrangement of bond electrons.

[0060] As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., "Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977." Salts formed with pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with an amino group, such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate, and organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, and malonate, or by other methods, such as ion exchange methods, as described in the literature. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, boronate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, glucarate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, and the like. Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium and N-type salts. + (C 1-4The present invention also contemplates quaternary ammonium salts of compounds containing N groups. Water-soluble or oil-soluble or dispersible products can be obtained by quaternary ammonium salt formation. Alkali metals or alkaline earth metals that form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts include suitable non-toxic ammonium and quaternary ammonium salts and amine cations composed of anti-equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Further included are sulfonates and aromatic sulfonates.

[0061] The term "hydrate" as used herein refers to an association of solvent molecules with water.

[0062] The term "solvate" as used herein refers to an association formed by one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0063] The term "ester" as used herein refers to an ester formed by a compound of formula (X) containing a hydroxy group that can be hydrolyzed in vivo. Such esters are, for example, pharmaceutically acceptable esters that can be hydrolyzed in the human or animal body to produce the parent alcohol. Examples of ester groups that can be hydrolyzed in vivo by a compound of formula (X) containing a hydroxy group include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl.

[0064] The term "nitrogen oxide" as used herein means that, when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen atoms of nitrogen heterocycles. The corresponding amines can be treated with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1977-1987). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, by reacting an amino compound with m-chloroperbenzoic acid (MCPBA) in an inert solvent (e.g., dichloromethane).

[0065] The term "prodrug" as used herein means that a compound is converted in the body to a compound of formula (X). Such conversion may be effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compounds of the present invention may be esters, and those useful as prodrugs in prior inventions include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonate esters, carbamates, and amino acid esters. For example, if a compound of the present invention contains a hydroxy group, it can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, for example, these phosphate ester compounds can be obtained by phosphorylating the parent hydroxy group. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0066] As used herein, the terms "a," "one," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) may be construed to include both the singular and the plural, unless otherwise stated or the context clearly dictates otherwise.

[0067] As used herein, the term "GLP-1 receptor agonist" refers to a substance that can stimulate the activity of the GLP-1 receptor.

[0068] General Synthesis Process In order to describe the present invention, examples are listed below, but it should be understood that the present invention is not limited to these examples, which only provide a method for practicing the present invention.

[0069] In general, the compounds of the present invention can be prepared by the methods described herein, and unless otherwise specified, the definitions of the substituents are as described herein. The following reaction schemes and examples are intended to further illustrate the subject matter of the present invention.

[0070] As will be appreciated by those skilled in the art, the chemical reactions described in this invention can be used to appropriately prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of these non-exemplified compounds according to the invention can be successfully achieved by those skilled in the art through modified methods, such as by appropriate protection of interfering groups, the use of other known reagents in addition to those of the invention, or some conventional modifications of reaction conditions. It is also recognized that the reactions disclosed in this invention or known reaction conditions are widely applicable to the preparation of other compounds of the invention.

[0071] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commodity suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Miner Chemical Technology Co., Ltd., and Shanghai McLin Biochemical Technology Co., Ltd., and were not further purified when used. Unless otherwise indicated, common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Haiyang Chemical Factory.

[0072] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, toluene, and acetonitrile were obtained by molecular sieve drying. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, methanol, and isopropanol were used as analytical reagents.

[0073] For the following reactions, reactions were generally carried out under a positive pressure of nitrogen or argon gas or anhydrous solvents with a drying tube (unless otherwise noted), reaction flasks were capped with appropriate rubber stoppers, and substrates were syringed in. All glassware was dried.

[0074] The silica gel column was a flash silica gel column purchased from Tianjin Bona Eljier Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

[0075] H NMR spectra were recorded using a Bruker 500 MHz nuclear magnetic resonance spectrometer. H NMR spectra were recorded in CDC13, DMSO-d6, CD3OD, or acetone-d6 as solvents (in ppm) and referenced to TMS (0 ppm) or chloroform (7.26 ppm). When multiple peaks occur, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0076] Low-resolution mass spectrometry (MS) data was collected using an Agilent G6125C quaternary rod HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 microns, 6 min, flow rate: 1 mL / min). The mobile phase was 0% to 95% (CH3CN) in a 90:10 mixture of HO containing 0.1% formic acid and CH3CN. Electrospray ionization (ESI) was performed at 210 nm / 254 nm using a DAD.

[0077] The compounds were purified using Tianjin Bona Ajier Technology Co., Ltd. Cheetah Pro medium pressure high speed purification preparative chromatography, and detected by UV detection at 210 nm / 254 nm.

[0078] The following abbreviations are used throughout the present invention:

[0079] [Table 1-1]

[0080] The following reaction schemes below describe the steps for preparing the compounds of the present invention. Unless otherwise indicated, each R a , R b , R c , R4, R5, R6, R7, R8, R9, m, n, k have the definitions described in the present invention.

[0081] Reaction Scheme 1 [ka] The compound represented by formula (6) can be produced by Reaction Scheme 1. The compound represented by formula (1) and the compound represented by formula (2) are reacted under the action of anhydrous potassium carbonate to obtain the compound represented by formula (3). The compound represented by formula (3) is reacted under the action of palladium carbon and hydrogen gas to obtain the compound represented by formula (4). The compound represented by formula (4) and the compound represented by formula (5) are reacted under the action of p-toluenesulfonic acid to obtain the compound represented by formula (6).

[0082] Reaction Scheme 2 [ka] The compound represented by formula (15) can be produced by Reaction Scheme 2. The compound represented by formula (7) and the compound represented by formula (8) are reacted under the action of potassium carbonate to obtain the compound represented by formula (9). The compound represented by formula (9) is reacted under the action of polyphosphoric acid to obtain the compound represented by formula (10). The compound represented by formula (10) is reacted under the action of azodiisobutyronitrile and N-bromosuccinimide to obtain the compound represented by formula (11). The compound represented by formula (11) and the compound represented by formula (12) are reacted under the action of potassium carbonate to obtain the compound represented by formula (13). The compound represented by formula (13) and the compound represented by formula (14) are reacted under the action of lithium diisopropylamide to obtain the compound represented by formula (15).

[0083] Reaction Scheme 3 [ka] The compound represented by formula (19) can be produced by Reaction Scheme 3. The compound represented by formula (16) and the compound represented by formula (17) are reacted under the action of LiHMDS to obtain the compound represented by formula (18). The compound represented by formula (18) is reacted under the action of bis(pinacolato)diboron, tetrakistriphenylphosphinepalladium, and potassium acetate to obtain the compound represented by formula (19).

[0084] Reaction Scheme 4 [ka] The compound represented by formula (25) can be prepared by Reaction Scheme 4. The compound represented by formula (19) and the compound represented by formula (20) are reacted with [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex and potassium carbonate to obtain the compound represented by formula (21). The compound represented by formula (21) is reacted with lithium hydroxide monohydrate to obtain the compound represented by formula (22). The compound represented by formula (22) and the compound represented by formula (4) are reacted with HATU, DIPEA, and DMF to obtain the compound represented by formula (23). The compound represented by formula (23) is reacted with glacial acetic acid to obtain the compound represented by formula (24). The compound represented by formula (24) is reacted with lithium hydroxide monohydrate to obtain the compound represented by formula (25).

[0085] Reaction Scheme 5 [ka] The compound represented by formula (34) can be prepared by Reaction Scheme 5. The compound represented by formula (26) is reduced by palladium carbon dioxide to obtain the compound represented by formula (27). The compound represented by formula (27) is reacted under acidic conditions to obtain the compound represented by formula (28). The compound represented by formula (28) is reacted with the compound represented by formula (29) to obtain the compound represented by formula (30). The compound represented by formula (30) is reacted under alkaline conditions to obtain the compound represented by formula (31). The compound represented by formula (31) is reacted with the compound represented by formula (4) to obtain the compound represented by formula (32). The compound represented by formula (32) is subjected to a ring-closure reaction to obtain the compound represented by formula (33). The compound represented by formula (33) is reacted under alkaline conditions to obtain the compound represented by formula (34). DETAILED DESCRIPTION OF THE INVENTION

[0086] The present invention will be described and illustrated below with reference to specific examples, which are merely illustrative and do not limit the present invention in any way.

[0087] Example 1 Synthesis of 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1) [ka]

[0088] Step 1: Synthesis of ethyl 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (191 mg, 0.65 mmol), 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (200 mg, 0.59 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (22 mg, 0.03 mmol), and potassium carbonate (163 The resulting mixture (mg, 1.18 mmol) was added to 1,4-dioxane (15 mL) and water (4 mL) and reacted at 85°C for 6 h under nitrogen gas protection. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 15:1) to give 200 mg of a yellow viscous product in a 79.5% yield.

[0089] 1H NMR (500MHz,DMSO-d6) δ 8.15 (dd,J=2.4,1.0Hz,1H),7.68 - 7.61 (m,1H),7.41 (d,J=8.0Hz,1H),7.33 (dd,J=8.0,1.1Hz,1H),7.07 - 7.02 (m,2H),6.70 (d,J=8.1Hz,2H),5.64 (s,2H),4.08 (qd,J=7.2,1.2Hz,2H),2.54 - 2.50 (m,1H),2.37 - 2.28 (m,4H),2.01-1.96 (m,1H),1.94 - 1.82 (m,2H),1.41 - 1.31 (m,1H),1.20 (td, J = 7.1, 1.2 Hz, 3 H). LC-MS (ESI): [M+H] + =426.2.

[0090] Step 2: Synthesis of 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid The compound 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (1.18 g, 2.77 mmol) was dissolved in 1,4-dioxane (20 mL) and water (6 mL), and lithium hydroxide monohydrate (350 mg, 8.31 mmol) was added. The mixture was reacted at 45°C for 2 hours, cooled in an ice bath, and diluted hydrochloric acid was added to adjust the pH to 2. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 3:1) to obtain 1.03 g of an oily yellow viscous product, with a yield of 93.4%.

[0091] 1H NMR (500MHz,DMSO-d6) δ 12.04 (s,1H),8.16 (d,J=2.2Hz,1H),7.65 (t,J=7.8Hz,1H),7.42 (d,J=8.0Hz,1H),7.34 (d,J=7.9Hz,1H),7.06 (d,J=7.1Hz,2H),6.70 (d,J=8.0Hz,2H),5.65 (s,2H),2.53 (d,J=5.1Hz,1H),2.39 - 2.30 (m,2H),2.23 (d,J=6.8Hz,2H),2.01 - 1.95 (m,1H),1.92 - 1.83 (m,2H),1.46 - 1.32 (m,1H). LC-MS (ESI): [M+H] = 398.2.

[0092] Step 3: Synthesis of methyl 4-(2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid (525 mg, 1.32 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (327 mg, 1.39 mmol) were added to dichloromethane (25 mL), HATU (752 mg, 1.98 mmol) and DIPEA (341 mg, 2.64 mmol) were added, and the mixture was allowed to react at room temperature for 6 hours. The solvent was removed under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 3:2) to give 380 mg of a pale yellow viscous product in 46.7% yield.

[0093] LC-MS (ESI): [M+H] + =616.5.

[0094] Step 4: Synthesis of methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound methyl 4-(2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (380 mg, 0.62 mmol) was added to glacial acetic acid (15 mL) and reacted at 70 °C for 6 h. The solvent was removed under reduced pressure, water (60 mL) was added, and the pH of the system was adjusted to 8 with sodium bicarbonate solution (2 M). Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 1:1) to give 210 mg of a white solid, 56.9% yield.

[0095] 1 H NMR (500MHz,DMSO-d6) δ 8.23 ​​(d,J=1.6Hz,1H),8.15 (d,J=2.2Hz,1H),7.81 (dd,J=8.4,1.6Hz,1H),7.66 (dt,J=7.9,3.6Hz,2H),7.42 (d,J=7.9Hz,1H),7.34 (d,J=8.0Hz,1H),7.09 - 7.01 (m,2H),6.72 (dd,J=11.9,6.2Hz,2H),5.65 (s,2H),5.06 - 4.99 (m,1H),4.65 (dd,J=15.6,7.1Hz,1H),4.53 (dt,J=15.3,2.3Hz,1H),4.45 (td,J=8.0,5.8Hz,1H),4.29 (dt,J=9.1,5.9Hz,1H),3.87 (s,3H),3.04- 2.93 (m,2H),2.74 - 2.65 (m,1H),2.57 (d,J=17.6Hz,1H),2.47 - 2.30 (m,4H),2.10 - 2.01 (m,1H),2.00 - 1.95 (m,1H),1.54- 1.46 (m ,1H). LC-MS (ESI): [M+H] + =598.4.

[0096] Step 5: Synthesis of 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (145 mg, 0.24 mmol) and lithium hydroxide monohydrate (31 mg, 0.73 mmol) were added to 1,4-dioxane (10 mL) and water (3 mL) and reacted at 40° C. for 2 h. Stirring was stopped and the mixture was cooled to room temperature. The mixture was diluted with water (20 mL), adjusted to pH 5 with hydrochloric acid (2 M), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 85 mg of the title compound, with a yield of 60%.

[0097] 1H NMR (500MHz,DMSO-d6) δ 12.66 (s,1H),8.21 (d,J=1.5Hz,1H),8.15 (d,J=2.3Hz,1H),7.80 (dd,J=8.3,1.6Hz,1H),7.64 (q,J=8.2Hz,2H),7.42 (d,J=8.0Hz,1H),7.34 (d,J=8.0Hz,1H),7.12 - 7.01 (m,2H),6.72 (dd,J=13.0,6.3Hz,2H),5.65 (s,2H),5.05 -5.0 (m,1H),4.63 (dd,J=15.6,7.2Hz,1H),4.57 - 4.42 (m,2H),4.30 (dt,J=9.1,5.9Hz,1H),3.05 - 2.91 (m,2H),2.72 -2.65 (m,1H),2.57 (d,J=17.7Hz,1H),2.48 - 2.28 (m,4H),2.09 -2.01 (m,1H),2.00-1.95 (m,1H),1.53 -1.45 (m,1H). LC-MS (ESI): [M+H] + =584.4.

[0098] Example 2 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 2) [ka]

[0099] Step 1: Synthesis of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate The compound methyl 3-fluoro-4-nitrobenzoate (500 mg, 2.51 mmol), anhydrous potassium carbonate (521 mg, 3.77 mmol) was added to anhydrous tetrahydrofuran (6 mL), and (S)-oxetane-2-methylamine (241 mg, 2.76 mmol) was added and reacted at room temperature for 15 h. Water (25 mL) and ethyl acetate (10 mL) were added, and after stirring, the organic phase was separated. The aqueous phase was extracted with ethyl acetate (5 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate for 20 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:4) to give 522 mg of a reddish-brown solid in 78.1% yield.

[0100] 1 HNMR (500MHz,DMSO-d6) δ 8.32 (t,J=5.8Hz,1H),8.17 (d,J=8.9Hz,1H),7.67 (d,J=1.7Hz,1H),7.16 (dd,J=8.9,1.8Hz,1H),5.03 - 4.96 (m,1H),4.58 - 4.54 (m,1H),4.46 - 4.42 (m,1H),3.88 (s,3H),3.71 - 3.61 (m,2H),2.71 - 2.64 (m,1H),2.56 - 2.50 (m,1H). LC-MS (ESI): [M+H] + =267.1.

[0101] Step 2: Synthesis of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (3.6 g, 13.52 mmol) was dissolved in methanol (30 mL) and tetrahydrofuran (15 mL), and 10% palladium carbon (water content 60%, 1.43 g) was added. The mixture was purged with hydrogen gas three times and reacted overnight at room temperature and atmospheric pressure with hydrogen gas. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 3.18 g of a pale yellow liquid product, with a yield of 99.5%.

[0102] 1HNMR (500MHz,DMSO-d6) δ 7.17 (dd,J=8.1,1.9Hz,1H),7.04 (d,J=1.9Hz,1H),6.56 (d,J=8.1Hz,1H),5.44 (s,2H),4.95 - 4.90 (m,1H),4.67 (t,J=5.7Hz,1H),4.56 - 4.52 (m,1H),4.50 - 4.46 (m,1H),3.73 (s,3H),3.37 - 3.25 (m,2H),2.70 - 2.63 (m,1H),2.48 - 2.43 (m,1H). LC-MS (ESI): [M+H] + =237.1.

[0103] Step 3: Synthesis of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The compound (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (1.0 g, 4.23 mmol), trimethylchloroethyl orthoacetate (790 mg, 5.08 mmol), and p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL), stirred at 45 °C for 5 h, cooled, concentrated under reduced pressure to remove the solvent, dissolved in dichloromethane (6 mL), and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:2) to give 1.1 g of a white solid product in 88.2% yield.

[0104] 1 HNMR (500MHz,DMSO-d6) δ 8.35 (s,1H),7.87 (dd,J=8.5,1.6Hz,1H),7.74 (d,J=8.5Hz,1H),5.20 - 5.08 (m,2H),5.09 - 5.04 (m,1H),4.78 - 4.74 (m,1H),4.66 - 4.63 (m,1H),4.50 - 4.45 (m,1H),4.35 - 4.30 (m,1H),3.89 (s,3H),2.73 - 2.66 (m,1H),2.41 - 2.34 (m,1H). LC-MS (ESI): [M+H] + =295.2.

[0105] Step 4: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene 5-Chloro-2-methylphenol (15 g, 105.2 mmol), 2-bromo-1,1-diethoxyethane (25 g, 126.9 mmol), and potassium carbonate (29.1 g, 210.4 mmol) were added to N,N-dimethylformamide (50 mL) and reacted at 120 °C for 11 h under nitrogen gas protection. After cooling to room temperature, water (100 mL) was added and extracted with ethyl acetate (35 mL × 3). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 1% EtOAc:PE (v / v)) to give 21.1 g of a light brown liquid product in 77.5% yield.

[0106] 1 HNMR (500MHz,CDCl3) δ 7.03 (d,J=7.9Hz,1H),6.84 (dd,J=7.9,2.0Hz,1H),6.81 (d,J=2.0Hz,1H),4.84 (t,J=5.2Hz,1H),3.98 (d,J=5.2Hz,2H),3.81 - 3.74 (m,2H),3.68 - 3.62 (m,2H),2.18 (s,3H),1.25 (t,J=7.0Hz,6H).

[0107] Step 5: Synthesis of 4-chloro-7-methylbenzofuran The compound 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (23-1) (21 g, 81.2 mmol) and polyphosphoric acid (16.6 g, 202.9 mmol) were added to 1,2-dichloroethane (50 mL) and reacted overnight at 85 °C under nitrogen gas protection. After cooling to room temperature, the solvent was removed under reduced pressure, water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to obtain 9.2 g of a colorless liquid product, with a yield of 68.0%.

[0108] 1 HNMR (500MHz,CDCl3) δ 7.63 (d,J=2.3Hz,1H),7.12 (d,J=7.9Hz,1H),7.00 (d,J=7.9Hz,1H),6.84 (d,J=2.3Hz,1H),2.48 (s,3H).

[0109] Step 6: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran The compound 4-chloro-7-methylbenzofuran (4.1 g, 24.61 mmol), azodiisobutyronitrile (810 mg, 4.92 mmol), and N-bromosuccinimide (5.26 g, 29.53 mmol) were added to 1,2-dichloroethane (30 mL) and reacted overnight at 75 °C under nitrogen gas protection. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to obtain 4.3 g of a colorless liquid product with a yield of 71.2%.

[0110] 1 HNMR (500MHz,CDCl3) δ 7.71 (s,1H),7.24 - 7.20 (m,2H),6.89 (s,1H),4.75 (s,2H).

[0111] Step 7: Synthesis of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine The compound 7-(bromomethyl)-4-chlorobenzofuran (600 mg, 2.44 mmol), 2-bromo-6-pyridine (467 mg, 2.68 mmol), and potassium carbonate (675 mg, 4.88 mmol) were added to DMF (6 mL) and reacted at 60° C. for 1.5 h. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 8%) to give 756 mg of a white solid product in a 91.4% yield.

[0112] 1 HNMR (500MHz,CDCl3) δ 7.68 (s,1H),7.41 (td,J=7.9,2.9Hz,1H),7.36 (dd,J=8.0,2.8Hz,1H),7.27 - 7.21 (m,1H),7.08 (dd,J=7.5,2.9Hz,1H),6.88 (s,1H),6.73 (dd,J=8.2,2.9Hz,1H),6.54 (s,2H).

[0113] Step 8: Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridine The compound 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (600 mg, 1.77 mmol) and N-fluorobisbenzenesulfonamide (670 mg, 2.12 mmol) were added to anhydrous tetrahydrofuran (30 mL) and cooled to -40 °C under nitrogen gas protection. Lithium diisopropylamide (2.0 mol / L THF solution) (1.4 mL, 2.80 mmol) was added and the reaction was allowed to proceed at -40 °C for 3 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 10%) to give 211 mg of a white solid product in 33.4% yield.

[0114] 1HNMR (500MHz,CDCl3) δ 7.43 (t,J=7.8Hz,1H),7.33 (d,J=8.1Hz,1H),7.25 (d,J=8.5Hz,1H),7.09 (d,J=7.5Hz,1H),6.74 (d,J=8.1Hz,1H),6.01 (d,J=6.7Hz,1H),5.57 (s,2H).

[0115] Step 9: Synthesis of ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate The compound ethyl 4-oxocyclohexaneacetate (3.0 g, 16.28 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (6.98 g, 19.54 mmol) were added to anhydrous tetrahydrofuran (30 mL) and cooled to -40 °C under nitrogen gas protection. LiHMDS (1 mol / L THF solution) (21.2 mL, 21.2 mmol) was added and the reaction was allowed to proceed at this temperature for 2 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 2% EtOAc:PE (v / v)) to give 4.1 g of a colorless liquid product in 79.6% yield.

[0116] 1 HNMR (500MHz,CDCl3) δ 5.72 (s,1H),4.15 (q,J=7.1Hz,2H),2.49 - 2.39 (m,1H),2.38 - 2.31 (m,2H),2.30 (d,J=7.1Hz,2H),2.18 - 2.09 (m,1H),1.97 - 1.89 (m,2H),1.57 - 1.48 (m,1H),1.26 (t,J=7.1Hz,3H).

[0117] Step 10: Synthesis of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)ethyl acetate (3.9 g, 12.33 mmol), bis(pinacolato)diboron (3.29 g, 12.95 mmol), tetrakistriphenylphosphinepalladium (710 mg, 0.62 mmol), and potassium acetate (2.42 g, 24.66 mmol) were added to 1,4-dioxane (30 mL) and reacted at 90 °C for 1 h under nitrogen gas protection. The mixture was cooled to room temperature, quenched by adding water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 5%) to obtain 2.0 g of a colorless liquid product, with a yield of 55.1%.

[0118] 1 HNMR (500MHz,CDCl3) δ 6.50 (s,1H),4.15 - 4.10 (m,2H),2.30 - 2.19 (m,4H),2.15 - 2.03 (m,2H),1.84 - 1.73 (m,2H),1.40 - 1.28 (m,1H),1.25 (s,12H),1.28 - 1.23 (m,3H).

[0119] Step 11: Synthesis of ethyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate The compounds 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (799 mg, 2.47 mmol), 2-bromo-6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridine (880 mg, 2.72 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (101 mg, 0.12 mmol), and charcoal Potassium carbonate (682 mg, 4.93 mmol) was added to 1,4-dioxane (12 mL) and water (3 mL) and reacted at 85°C for 6 h under nitrogen gas protection. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 5%) to give 905 mg of a colorless liquid product, with a yield of 82.6%.

[0120] 1 HNMR (500MHz,CDCl3) δ 7.52 (t,J=7.8Hz,1H),7.32 (d,J=8.2Hz,1H),7.23 (d,J=8.2Hz,1H),6.94 (d,J=7.5Hz,1H),6.84 - 6.69 (m,1H),6.64 (d,J=8.1Hz,1H),6.00 (d,J=6.6Hz,1H),5.62 (s,2H),4.16 (q,J=7.0Hz,2H),2.64 - 2.57 (m,1H),2.50 - 2.39 (m,2H),2.34 (d,J=7.1Hz,2H),2.22 - 2.13 (m,1H),2.02 - 1.91 (m,2H),1.51 - 1.42 (m,1H),1.28 (t,J=7.2Hz,3H). LC-MS (ESI): [M+H] + =444.2.

[0121] Step 12: Synthesis of 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid The compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (680 mg, 1.53 mmol) was dissolved in 1,4-dioxane (6 mL) and water (3 mL), and lithium hydroxide monohydrate (322 mg, 7.67 mmol) was added. The mixture was reacted at 40°C for 4 hours, cooled in an ice bath, and diluted hydrochloric acid was added to adjust the pH to 2. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 635 mg of a pale yellow solid product, with a yield of 99.7%.

[0122] 1 HNMR (500MHz,CDCl3) δ 7.49 (t,J=7.8Hz,1H),7.30 (d,J=8.2Hz,1H),7.21 (d,J=8.2Hz,1H),6.90 (d,J=7.5Hz,1H),6.73 (s,1H),6.62 (d,J=8.2Hz,1H),5.98 (d,J=6.6Hz,1H),5.60 (s,2H),2.64 - 2.54 (m,1H),2.50 - 2.41 (m,2H),2.38 (d,J=7.1Hz,2H),2.22 - 2.13 (m,1H),2.05 - 1.93 (m,3H),1.53 - 1.43 (m,1H). LC-MS (ESI): [M- H] - =414.2.

[0123] Step 13: Synthesis of methyl 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid (300 mg, 0.72 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (170 mg, 0.72 mmol) were added to dichloromethane (5 mL) and N,N-dimethylformamide (2 mL), and HATU (411 mg, 1.08 mmol) and DIPEA (233 mg, 1.80 mmol) were added, followed by reaction at 45° C. overnight. The solvent was removed under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:DCM (v / v) = 1:5) to give 402 mg of a white solid product, with a yield of 87.9%.

[0124] 1 HNMR (500MHz,CDCl3) δ 8.01 (s,1H),7.87 - 7.75 (m,2H),7.60 - 7.48 (m,3H),7.32 (d,J=7.8Hz,1H),7.22 (d,J=8.8Hz,1H),6.94 (d,J=7.4Hz,1H),6.75 (s,1H),6.64 (d,J=8.1Hz,1H),5.99 (d,J=6.6Hz,1H),5.62 (s,2H),5.08 - 5.01 (m,1H),4.75 - 4.68 (m,1H),4.62 - 4.55 (m,1H),3.89 (s,3H),3.75 - 3.65 (m,1H),3.50 - 3.37 (m,1H),3.36 - 3.28 (m,1H),3.21 - 3.12 (m,1H),2.77 - 2.68 (m,1H),2.65 - 2.56 (m,1H),2.55 - 2.40 (m,4H),2.34 - 2.24 (m,1H),2.09 - 1.95 (m,2H). LC-MS (ESI): [M+H] + =634.4.

[0125] Step 14: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)methyl benzoate (390 mg, 0.62 mmol) was added to glacial acetic acid (10 mL) and reacted at 80 ° C. for 2 h. The solvent was removed under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 45%) to give 169 mg of a white solid product, with a yield of 44.6%.

[0126] 1 HNMR (500MHz,CDCl3) δ 8.09 (d,J=7.2Hz,1H),7.96 (t,J=7.9Hz,1H),7.74 (t,J=8.2Hz,1H),7.51 (q,J=7.8Hz,1H),7.30 (t,J=8.0Hz,1H),7.21 (t,J=8.1Hz,1H),6.93 (t,J=7.6Hz,1H),6.77 - 6.71 (m,1H),6.63 (t,J=7.9Hz,1H),5.98 (t,J=7.1Hz,1H),5.61 (d,J=7.6Hz,2H),5.21 - 5.13 (m,1H),4.63 - 4.56 (m,1H),4.50 - 4.32 (m,3H),3.94 (d,J=7.6Hz,3H),3.08 - 2.95 (m,2H),2.76 - 2.68 (m,1H),2.66 - 2.58 (m,1H),2.54 - 2.37 (m,4H),2.14 - 1.98 (m,2H),1.65 - 1.54 (m,1H). LC-MS (ESI): [M+H] + =616.40.

[0127] Step 15: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (160 mg, 0.26 mmol) and lithium hydroxide monohydrate (54 mg, 1.29 mmol) were added to 1,4-dioxane (4 mL) and water (1.5 mL) and reacted at 40 °C for 40 min. Part of the solvent was removed under reduced pressure, the mixture was adjusted to pH = 6 with glacial acetic acid, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH: DCM (v / v) = 3%) to give the title compound (91 mg, 51.8% yield).

[0128] 1 HNMR (500MHz,CDCl3) δ 8.27 - 8.15 (m,1H),8.07 (d,J=8.4Hz,1H),7.84 (d,J=8.5Hz,1H),7.60 - 7.46 (m,1H),7.37 - 7.16 (m,2H),6.94 - 6.91 (m,1H),6.81 - 6.71 (m,1H),6.62 (d,J=8.0Hz,1H),6.04 - 5.93 (m,1H),5.60 (s,2H),5.26 - 5.13 (m,1H),4.70 - 4.56 (m,1H),4.54 - 4.29 (m,3H),3.09 (s,2H),2.80 - 2.59 (m,2H),2.57 - 2.35 (m,4H),2.20 - 1.97 (m,2H),1.47 - 1.28 (m,1H). LC-MS (ESI): [M+H] + =602.40.

[0129] Example 3 Synthesis of 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 3) [ka]

[0130] Step 1: Synthesis of methyl (4-chlorobenzofuran-7-yl)acetate The compound 7-(bromomethyl)-4-chlorobenzofuran (2.50 g, 10.18 mmol) was added to DMF (20 mL) and potassium acetate (7.00 g, 71.28 mmol) and reacted at room temperature for 3 h. The reaction was stopped, water (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.0 g of a brown oil in 87.4% yield.

[0131] Step 2: Synthesis of (4-chlorobenzofuran-7-yl)methanol The compound (4-chlorobenzofuran-7-yl)methyl acetate (2.0 g, 8.90 mmol) was added to a mixture of 1,4-dioxane (30 mL) and water (8 mL), and lithium hydroxide monohydrate (1.12 g, 26.71 mmol) was added. The mixture was heated to 42 °C and reacted for 2 h. The reaction was stopped, cooled to room temperature, diluted with water (60 mL), and extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 3:1) to obtain 1.6 g of a white solid in 98.4% yield.

[0132] 1H NMR (500MHz,DMSO-d6) δ 8.10 (d,J=2.2Hz,1H),7.33 (q,J=8.0Hz,2H),6.99 (d,J=2.2Hz,1H),5.36 (d,J=5.3Hz,1H),4.79 (d,J=2.8Hz,2H). LC-MS (ESI): [M-17] - =165.0.

[0133] Step 3: Synthesis of 2-chloro-4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine The compound (4-chlorobenzofuran-7-yl)methanol (850 mg, 4.65 mmol) and 2,4-dichloro-5-fluoropyrimidine (816 mg, 4.89 mmol) were dissolved in acetonitrile (20 mL), and cesium carbonate (2.275 g, 6.98 mmol) was added in an ice bath. The mixture was warmed to room temperature and reacted for 17 h. The reaction was stopped, filtered through diatomaceous earth, and the filtrate was concentrated and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 10:1) to give 1.31 g of a white solid in 89.9% yield.

[0134] 1 H NMR (500MHz,DMSO-d6) δ 8.63 (d,J=2.6Hz,1H),8.18 (d,J=2.3Hz,1H),7.49 (d,J=8.0Hz,1H),7.40 (d,J=8.0Hz,1H),7.07 (d,J=2.2Hz,1H),5.77 (s,2H).

[0135] Step 4: Synthesis of ethyl 2-(4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetate The compounds 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (1.35 g, 4.60 mmol), 2-chloro-4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (1.31 g, 4.18 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (310 mg, 0.42 mmol), and potassium carbonate The residue (1.16 g, 8.37 mmol) was added to 1,4-dioxane (32 mL) and water (8 mL), and the mixture was reacted at 85°C for 11 h under nitrogen gas protection. The mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 10:1) to give 1.24 g of a yellow viscous product, with a yield of 66.6%.

[0136] 1 H NMR (500MHz,DMSO-d6) δ 8.53 (d,J=2.8Hz,1H),8.17 (d,J=2.2Hz,1H),7.46 (d,J=8.0Hz,1H),7.36 (d,J=8.0Hz,1H),7.06 (dd,J=5.8,2.4Hz,2H),5.80 (s,2H),4.08 (q,J=7.1Hz,2H),2.67 - 2.57 (m,1H),2.41 - 2.28 (m,4H),2.02 - 1.90 (m,2H),1.86- 1.81 (m,1H),1.36- 1.29 (m,1H),1.19 (t,J=7.1Hz,3H). LC-MS (ESI): [M+H] + =445.20.

[0137] Step 5: Synthesis of 2-(4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetic acid The compound 2-(4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (1.24 g, 2.79 mmol) was dissolved in 1,4-dioxane (30 mL) and water (10 mL), and lithium hydroxide monohydrate (350 mg, 8.36 mmol) was added. The mixture was reacted at 40 ° C for 2 hours, cooled to room temperature, diluted with water (60 mL), and adjusted to pH = 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.1 g of an oily yellow viscous product, with a yield of 94.7%.

[0138] LC-MS (ESI): [M- H] - =417.2.

[0139] Step 6: Synthesis of methyl 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetic acid (500 mg, 1.2 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (285 mg, 1.2 mmol) were added to dichloromethane (12 mL) and DMF (3 mL), and HATU (684 mg, 1.8 mmol) and DIPEA (310 mg, 2.4 mmol) were added, followed by reaction at 60° C. overnight. The solvent was removed under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 25:1) to give 600 mg of a pale yellow viscous material, with a yield of 78.6%.

[0140] LC-MS (ESI): [M+H] + =636.6.

[0141] Step 7: Synthesis of methyl 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)methyl benzoate (600 mg, 0.94 mmol) was added to glacial acetic acid (20 mL) and reacted at 70 °C for 6 h. The solvent was removed under reduced pressure, water (60 mL) was added, and the pH of the system was adjusted to 8 with sodium bicarbonate solution (2 M). Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent DCM / MeOH (v / v) = 18:1) to give 70 mg of a white solid, 12.0% yield.

[0142] 1H NMR (500MHz,DMSO-d6) δ 8.55 (t,J=2.8Hz,1H),8.24 (d,J=2.4Hz,1H),8.18 (d,J=2.8Hz,1H),7.85 - 7.78 (m,1H),7.66 (dd,J=8.5,2.5Hz,1H),7.48 (dd,J=8.0,2.4Hz,1H),7.39 (dd,J=8.0,2.4Hz,1H),7.11 (s,1H),7.09 - 7.03 (m,1H),5.82 (d,J=2.5Hz,2H),5.03 (q,J=7.5Hz,1H),4.66 (dd,J=15.6,7.1Hz,1H),4.53 (d,J=15.4Hz,1H),4.46 (q,J=7.5Hz,1H),4.34 - 4.26 (m,1H),3.88 (d,J=2.4Hz,3H),3.08 - 2.93 (m,2H),2.70 (q,J=8.0Hz,2H),2.49 - 2.29 (m,4H),2.11 (t,J=13.5Hz,1H),2.00 - 1.95 (m,1H),1.48 (s,1H). LC-MS (ESI): [M+H] + =617.4.

[0143] Step 8: Synthesis of 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.08 mmol) and lithium hydroxide monohydrate (11 mg, 0.24 mmol) were added to 1,4-dioxane (10 mL) and water (3 mL) and reacted at 40 °C for 2 h. The reaction was stopped and cooled to room temperature. The mixture was diluted with water (15 mL), the pH of the system was adjusted to 5 with dilute hydrochloric acid (2 M), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (eluent DCM / MeOH (v / v)=10:1) gave 10 mg of the title compound, with a yield of 20.5%.

[0144] 1 H NMR (500MHz,DMSO-d6) δ 12.65 (s,1H),8.55 (d,J=2.7Hz,1H),8.24 - 8.16 (m,2H),7.79 (d,J=8.4Hz,1H),7.62 (d,J=8.4Hz,1H),7.48 (d,J=8.0Hz,1H),7.38 (d,J=8.2Hz,1H),7.11 (s,1H),7.06 (d,J=2.3Hz,1H),5.82 (s,2H),5.05- 5.00 (m,1H),4.64 (dd,J=15.5,7.1Hz,1H),4.51 (d,J=15.4Hz,1H),4.45 (t,J=7.2Hz,1H),4.30 (dt,J=9.1,5.8Hz,1H),3.04 - 2.93 (m,2H),2.69 (d,J=16.0Hz,2H),2.36 (dd,J=18.9,9.1Hz,4H),2.15 - 2.05 (m,1H),2.02 - 1.93 (m,1H),1.51 - 1.45 (m,1H). LC-MS (ESI): [M+H] + =603.50.

[0145] Example 4 Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4) [ka]

[0146] Step 1: Synthesis of methyl 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohexyl)acetate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl acetate (500 mg, 1.61 mmol) was added to ethyl acetate (5 mL), 10% palladium carbon (50 mg) was added, the atmosphere was purged with hydrogen gas three times, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through diatomaceous earth and washed with dichloromethane (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to give 350 mg of a colorless oil, with a yield of 69.5%.

[0147] LC-MS (ESI): [M+H] + =313.3.

[0148] Step 2: Synthesis of methyl 2-(4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohexyl)acetate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohexyl)methyl acetate (350 mg, 1.12 mmol) was added to a 4N hydrochloric acid (5 mL) methanol solution and stirred at 50° C. for 2 hours. Concentration under reduced pressure gave 260 mg of a colorless oil, a yield of 86.5%, which was used directly in the next step.

[0149] LC-MS (ESI): [M+H] + =269.3.

[0150] Step 3: Synthesis of methyl 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)acetate The compound 2-(4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohexyl)methyl acetate (200 mg, 0.75 mmol) was added to N,N-dimethylformamide (3 mL), potassium carbonate (310 mg, 2.25 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (237 mg, 0.9 mmol) were added, and the mixture was stirred at 60 ° C. for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to give 90 mg of a colorless oil, with a yield of 33.5%.

[0151] LC-MS (ESI): [M+H] + =451.3.

[0152] Step 4: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)acetic acid The compound 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)methyl acetate (90 mg, 0.2 mmol) was added to 1,4-dioxane (0.6 mL) and water (0.6 mL), and lithium hydroxide (42 mg, 1.75 mmol) was added and stirred at 40° C. for 2 hours. Water (3 mL) was added to dilute the mixture, and an aqueous solution of hydrochloric acid (1 N) was slowly added dropwise to adjust the pH to 6. Dichloromethane (5 mL) was added, and the mixture was extracted with methanol (0.5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 110 mg of a colorless oil, which was used directly in the next step.

[0153] LC-MS (ESI): [M+H] + =437.3.

[0154] Step 5: Synthesis of methyl (S)-4-(2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)acetamido)-3-((oxetan-2-methyl)amino)benzoate The compound 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)acetic acid (100 mg, crude) was added to N,N-dimethylformamide (3 mL), 2-(7-azobenzotriazole)-N,N,N,N,-tetramethyluronium hexafluorophosphate (261 mg, 0.69 mmol) was added, N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added, stirred for 5 minutes, and (S)-4-amino-3-((oxetan-2-yl)methyl)aminobenzoate (54 mg, 0.23 mmol) was added, and stirred overnight. The mixture was concentrated under reduced pressure, diluted with water (5 mL), extracted with dichloromethane (5 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:1) to give 72 mg of a light brown oil, with a yield of 48%.

[0155] LC-MS (ESI): [M+H] + =655.5.

[0156] Step 6: Synthesis of methyl (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The compound methyl (S)-4-(2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)acetamido)-3-((oxetan-2-methyl)amino)benzoate (72 mg, 0.12 mmol) was added to acetic acid (3 mL) and stirred at 70° C. for 4 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v)=10:1) to give 50 mg of a pale brown oil, with a yield of 64.3%.

[0157] LC-MS (ESI): [M+H] + =637.0, 1 HNMR (400MHz,DMSO-d6) δ 8.57 (s,1H),8.24 - 8.21 (m,1H),7.81 - 7.78 (m,1H),7.65 - 7.63 (m,1H),7.47 - 7.42 (m,2H),6.56 - 6.53 (m,1H),5.75 - 5.74 (m,2H),5.0 - 4.98 (m,1H),4.97 - 4.24 (m,4H),3.86 (s,3H),2.93 - 2.88 (m,2H),2.68 - 2.64 (m,2H),2.37 - 2.3 (m,2H),2.29 - 2.11 (m,2H),1.87 - 1.31 (m,6H).

[0158] Step 7: Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.08 mmol) was added to 1,4-dioxane (0.8 mL) and water (0.2 mL). Lithium hydroxide (16 mg, 0.38 mmol) was added and the mixture was stirred at 40 °C for 8 hours. The mixture was concentrated under reduced pressure, and the pH was adjusted to 6-7 with the addition of hydrochloric acid (1 N). The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: CHCN:HO (v / v) = 60%) to give 21.9 mg of a white solid, a yield of 46.1%.

[0159] LC-MS (ESI): [M+H] + =623.2, 1 HNMR (400MHz,DMSO-d6) δ 12.69 (s,1H),8.60 - 8.53 (m,1H),8.19 (d,J=8.3Hz,1H),7.81 - 7.76 (m,1H),7.61 (d,J=7.4Hz,1H),7.50 - 7.42 (m,2H),6.55 - 6.53 (m,1H),5.75 (d,J=8.8Hz,2H),4.99 - 4.83 (m,1H),4.61 - 4.25 (m,4H),2.97 - 2.81 (m,3H),2.74 - 2.61 (m,2H),2.40 - 2.25 (m,2H),2.16 - 1.85 (m,2H),1.72 - 1.54 (m,3H),1.45 - 1.18 (m,2H).

[0160] Example 5 Synthesis of 2-(4-(4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 5) [ka]

[0161] Step 1: Synthesis of 6-chloro-5-nitro-2-carboxylic acid pyridine 2-Chloro-6-methyl-3-nitropyridine (8.0 g, 46.36 mmol) was added to concentrated sulfuric acid (40 mL), and potassium dichromate (20.46 g, 69.54 mmol) was slowly added at room temperature. The mixture was stirred overnight at room temperature. Ice water (500 mL) was slowly added under ice bath conditions, and the mixture was extracted with ethyl acetate (150 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 8.26 g of a pale yellow solid (88.0% yield).

[0162] LC-MS (ESI): [M+H] + =203.0.

[0163] Step 2: Synthesis of 6-chloro-5-nitro-2-methylpyridine carboxylate The compound 6-chloro-5-nitro-2-carboxylic acid pyridine (200 mg, 0.99 mmol) was dissolved in methanol (15 mL), concentrated sulfuric acid (0.5 mL, 0.99 mmol) was added, and the mixture was heated to 68 °C and reacted overnight. The mixture was concentrated under reduced pressure, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:1) to give 185 mg of a white solid, with a yield of 86.5%.

[0164] LC-MS (ESI): [M+ H] + =217.1, 1 H NMR (500MHz,CDCl3) δ 8.31 (dd,J=8.3,0.8Hz,1H),8.22 (dd,J=8.2,0.8Hz,1H),4.04 (d,J=0.9Hz,3H).

[0165] Step 3: Synthesis of methyl (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate The compound 6-chloro-5-nitro-2-methylpyridine carboxylate (1.3 g, 6.0 mmol) and (S)-oxetane-2-methylamine (0.58 g, 6.6 mmol) were dissolved in tetrahydrofuran (20 mL), and potassium carbonate (1.24 g, 9.00 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 2:1) to give 1.09 g of a yellow solid, a yield of 68.0%.

[0166] LC-MS (ESI): [M+ H] + =268.2, 1 H NMR (500MHz,DMSO-d6) δ 8.58 (dd,J=8.4,1.0Hz,1H),8.51 (t,J=5.8Hz,1H),7.31 (dd,J=8.4,1.0Hz,1H),5.01 - 4.93 (m,1H),4.56 -4.52 (m,1H),4.48 - 4.45 (m,1H),3.96 - 3.87 (m,4H),3.82 (dt,J=13.8,5.2Hz,1H),2.68 - 2.58 (m,1H),2.53 - 2.49 (m,1H).

[0167] Step 4: Synthesis of methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate Under hydrogen gas protection, the compound (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (1.09 g, 4.08 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL). Palladium carbon (10% Pd, containing 40-60% water) (185 mg, 1.74 mmol) was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The product was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 885 mg of an oily yellow viscous product in 91.5% yield.

[0168] LC-MS (ESI): [M+ H] + =238.1, 1 H NMR (500MHz,DMSO-d6) δ 7.23 (d,J=7.8Hz,1H),6.68 (d,J=7.8Hz,1H),5.95 (t,J=5.6Hz,1H),5.61 (s,2H),4.92 - 4.87 (m,1H),4.54 - 4.50 (m,1H),4.45 (dt,J=9.0,5.9Hz,1H),3.72 (s,4H),3.62 (dt,J=13.8,5.2Hz,1H),2.65 - 2.57 (m,1H),2.44 - 2.39 (m,1H).

[0169] Step 5: Synthesis of 2-chloro-5-fluoro-4-(methoxymethoxy)pyrimidine The compound 2-chloro-5-fluoropyrimidin-4-ol (20 g, 127.93 mmol) was added to a mixture of dichloromethane (100 mL) and N,N-dimethylformamide (100 mL) and stirred for 10 minutes under ice-bath conditions. N,N-Diisopropylethylamine (63.9 mL, 386.85 mmol) was slowly added dropwise, and stirring was continued for 10 minutes. Bromomethyl methyl ether (33 g, 250.86 mmol) was added and stirred overnight. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (35 mL × 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 25% EtOAc:PE (v / v)) to give 10 g of a white solid product in 40.6% yield.

[0170] 1 HNMR (400MHz,DMSO-d6) δ 8.08 (d,J=1.6Hz,1H),5.46 (s,2H),3.36 (s,3H).

[0171] Step 6: Synthesis of methyl 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetate Compound 2-chloro-5-fluoro-4-(methoxymethoxypyrimidine) (8 g, 41.54 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl acetate (13.44 g, 45.7 mmol), potassium carbonate (11.48 g, 83.09 mmol) were added to 1,4-dioxane (100 mL) and water (25 mL), and 1,1'-bis(diphenylphosphino)ferrocene dichloride palladium (II) (0.76 g, 1.04 mmol) was added to the reaction solution, and the atmosphere was replaced with nitrogen gas three times and reacted at 85 ° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure, the mixture was diluted with water (80 mL), extracted with ethyl acetate (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 33%) to give 8.1 g of a colorless oily product, the yield was 60.1%.

[0172] LC-MS (ESI): [M+H] + =311.3, 1 HNMR (400MHz,CDCl3) δ 7.83 (d,J=1.6Hz,1H),6.12 (s,1H),5.40 - 5.35 (m,2H),3.70 (s,3H),3.50 (s,3H),2.44 - 2.43 (m,2H),2.43 - 2.34 (m,2H),2.19 - 1.91 (m,4H),1.50 - 1.44 (m,1H).

[0173] Step 7: Synthesis of 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)ethan-1-ol The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl acetate (8.1 g, 26.1 mmol) was dissolved in tetrahydrofuran (250 mL) and stirred at -78 °C for 5 minutes. A solution of diisobutylaluminum hydride in n-hexane (1 mol / L, 78.3 mL) was added dropwise to the reaction system, and the reaction was allowed to proceed for 4 hours. Saturated ammonium chloride solution (300 mL) was added to quench the reaction, and dichloromethane (200 mL) was added and extracted. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 75%) to obtain 5 g of a pale yellow oily product in 68.8% yield.

[0174] LC-MS (ESI): [M+H] + =283.5.

[0175] Step 8: Synthesis of 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)ethan-1-ol (5 g, 17.73 mmol) was added to dichloromethane (200 mL) and completely dissolved. After that, Dess-Martin oxidant (22.56 g, 53.19 mmol) was added and stirred at room temperature overnight. The precipitate was filtered through diatomaceous earth, and the organic layer was concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 50%) to give 3 g of a colorless oily product in 60.4% yield.

[0176] LC-MS (ESI): [M+H] + =281.4.

[0177] Step 9: Synthesis of methyl 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate) The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (101 mg, 0.43 mmol) and (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (102 mg, 0.43 mmol) were added to acetic acid (1.5 mL) and reacted at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 3%) to obtain 84 mg of a pale yellow oily product, with a yield of 47.3%.

[0178] LC-MS (ESI): [M+H] + =498.5, 1 HNMR (400MHz,DMSO-d6) δ 8.14 (d,J=8.4Hz,1H),8.09 (d,J=2.4Hz,1H),8.0 (d,J=8.4Hz,1H),6.07 (s,1H),5.29 (s,2H),5.12 - 5.09 (m,1H),4.68 - 4.31 (m,4H),3.90 (s,3H),3.35 (s,3H),3.10 - 3.02 (m,2H),2.75 - 2.66 (m,1H),2.44 - 2.36 (m,5H),2.06 - 1.91 (m,2H),1.54 - 1.46 (m,1H).

[0179] Step 10: Synthesis of methyl 2-(4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound methyl 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate (80 mg, 0.16 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2.4 mL) was slowly added dropwise, and the mixture was stirred at -50 ° C. for 12 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 5%) to obtain 63 mg of a pale yellow solid product, with a yield of 86.4%.

[0180] LC-MS (ESI): [M+H] + =454.6.

[0181] Step 11: Synthesis of methyl 2-(4-(4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-(4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (63 mg, 0.14 mmol) was added to N,N-dimethylformamide (2.7 mL). After complete dissolution, potassium carbonate (58 mg, 0.42 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (44 mg, 0.17 mmol) were added, and the mixture was reacted at 60 °C for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 50%) to obtain 67 mg of a pale yellow solid product in a 75.8% yield.

[0182] LC-MS (ESI): [M+H] + =636.6.

[0183] Step 12: Synthesis of 2-(4-(4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound methyl 2-(4-(4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (67 mg, 0.11 mmol) was added to a mixture of dioxane (0.8 mL) and water (0.2 mL). After complete dissolution, lithium hydroxide (13 mg, 0.54 mmol) was added and the mixture was reacted at 40 °C for 2 h. The pH was adjusted to 6 with acetic acid (0.2 mL), concentrated under reduced pressure, and purified by pre-HPLC (eluent CHCN: HO (v / v) = 60%) to give 12.5 mg of a white solid product, with a yield of 19.1% and an HPLC purity of 98.13%.

[0184] LC-MS (ESI): [M+H] + =622.5, 1 HNMR (400MHz,DMSO-d6) δ 12.81 (s,1H),8.58 (s,1H),8.12 (d,J=8.4Hz,1H),7.99 (d,J=8.4Hz,1H),7.49 - 7.43 (m,2H),7.11 (s,1H),6.55 (d,J=6.4Hz,1H),5.77 (s,2H),5.12 (m,1H),4.68 - 4.30 (m,4H),3.11 - 3.06 (m,2H),2.71 - 2.67 (m,2H),2.43 - 2.34 (m,4H),2.33 - 2.32 (m,2H),1.99 - 1.87 (m,1H).

[0185] Example 6 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 6) [ka]

[0186] Step 1: Synthesis of methyl 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)acetaldehyde (300 mg, 1.15 mmol) (for synthesis see Step 7 in Example 8) and (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (286 mg, 1.21 mmol) (for synthesis see Step 4 in Example 5) were added to acetic acid (10 mL) and stirred at 60° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to give 160 mg of a light brown solid product, with a yield of 47.6%.

[0187] LC-MS (ESI): [M+H] + =435.4 1H NMR (400MHz,DMSO-d6) δ 11.27 (s,1H),8.14 (d,J=8.2Hz,1H),8.00 (d,J=8.2Hz,1H),7.39 (dd,J=9.0,7.1Hz,1H),6.46 (s,1H),6.21 (t,J=7.3Hz,2H),5.09 (d,J=6.2Hz,1H),4.65 (dd,J=15.0,6.6Hz,1H),4.49 (m,2H),4.36 - 4.27 (m,1H),3.90 (s,3H),3.07 (dd,J=11.4,7.0Hz,2H),2.75 - 2.65 (m,1H),2.47 - 2.28 (m,5H),2.09 - 1.93 (m,2H),1.48 (m,1H).

[0188] Step 2: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate methyl (200 mg, 0.46 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (182 mg, 0.69 mmol) was added to N,N-dimethylformamide (10 mL), potassium carbonate (190 mg, 1.38 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 200 mg of a pale yellow solid product, with a yield of 70.3%.

[0189] LC-MS (ESI): [M+H] + =617.6.

[0190] Step 3: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.32 mmol) was dissolved in dioxane (16 mL) and water (4 mL). Lithium hydroxide (31 mg, 1.3 mmol) was added and stirred at room temperature for 4 hours. The pH was adjusted to 6-7 with 0.5 N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: acetonitrile:water (v / v)=50%) to give 66.2 mg of a white solid product, the yield was 33.9%.

[0191] LC-MS (ESI): [M+H] + =603.6, 1HNMR (400MHz,DMSO-d6) δ 12.80 (s,1H),8.11 (d,J=8.2Hz,1H),7.99 (d,J=8.2Hz,1H),7.67 (t,J=7.8Hz,1H),7.41 (q,J=8.2Hz,2H),7.07 (d,J=7.5Hz,1H),6.72 (d,J=8.2Hz,2H),6.52 (dd,J=6.4,2.7Hz,1H),5.59 (s,2H),5.16 - 5.07 (m,1H),4.66 (dd,J=15.0,6.6Hz,1H),4.54 (dd,J=15.0,3.6Hz,1H),4.46 (dd,J=13.7,7.6Hz,1H),4.36 - 4.27 (m,1H),3.15 - 3.01 (m,2H),2.75 - 2.65 (m,1H),2.57 (d,J=17.3Hz,1H),2.47 - 2.31 (m,4H),2.13 - 1.94 (m,2H),1.57 - 1.42 (m,1H).

[0192] Example 7 Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7) [ka]

[0193] Step 1: Synthesis of methyl (S)-4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetamido)-3-((oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetic acid (700 mg, 1.68 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (400 mg, 1.68 mmol) were added to N,N-dimethylformamide (10 mL), and HOAT (300 mg, 2.18 mmol), EDCI (480 mg, 2.51 mmol) and N,N-diisopropylethylamine (DIPEA) (430 mg, 3.35 mmol) were added, and the mixture was reacted at 40° C. overnight. The solvent was removed under reduced pressure, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 45%) to give 700 mg of a white solid, with a yield of 65.7%.

[0194] LC-MS (ESI): [M+H] + =636.4.

[0195] Step 2: Synthesis of methyl (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound (S)-4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetamido)-3-((oxetan-2-yl)methyl)amino)benzoate (700 mg, 1.10 mmol) was added to glacial acetic acid (20 mL) and reacted at 80 °C for 4 h. The solvent was removed under reduced pressure, and the mixture was adjusted to pH = 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 2:3) to give 600 mg of a pale yellow solid product in 88.2% yield.

[0196] 1 HNMR (500MHz,CDCl3) δ 8.09-8.07 (m,1H),7.97 - 7.94 (m,1H),7.75 - 7.72 (m,1H),7.53 - 7.46 (m,1H),7.32 (d,J=8.7Hz,1H),7.24 - 7.21 (m,1H),6.82 - 6.70 (m,1H),6.62 - 6.58 (m,1H),6.00 - 5.98 (m,1H),5.60 (d,J=14.9Hz,2H),5.20 - 5.13 (m,1H),4.65 - 4.55 (m,1H),4.45 - 4.30 (m,3H),3.94 - 3.93 (m,3H),3.01 - 2.94 (m,2H),2.82 - 2.60 (m,2H),2.57 - 2.35 (m,2H),1.99 - 1.89 (m,2H),21.63 - 1.58 (m,6H).

[0197] LC-MS (ESI): [M+H] + =618.4.

[0198] Step 3: Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (600 mg, 0.97 mmol) and lithium hydroxide monohydrate (200 mg, 4.85 mmol) were added to isopropanol (18 mL) and water (3 mL), and the mixture was reacted at 50° C. for 2 hours. The mixture was adjusted to pH 4 with 2 M diluted hydrochloric acid in an ice bath, diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH: DCM (v / v) = 5%) to obtain 200 mg of a pale yellow solid product, with a yield of 31.9%.

[0199] 1 HNMR (500MHz,CDCl3) δ 8.19 - 8.17 (m,1H),8.07 - 8.04 (m,1H),7.83 - 7.81 (m,1H),7.51 - 7.45 (m,1H),7.33 - 7.30 (m,1H),7.23 - 7.20 (m,1H),6.82 - 6.69 (m,1H),6.61 - 6.57 (m,1H),6.00 - 5.98 (m,1H),5.00 - 5.57 (m,2H),5.23 - 5.14 (m,1H),4.66 - 4.57 (m,1H),4.51 - 4.32 (m,3H),3.06 - 2.98 (m,2H),2.81 - 2.55 (m,2H),2.48 - 2.39 (m,1H),2.16 - 1.93 (m,4H),1.80 - 1.58 (m,3H),1.44 - 1.24 (m,3H). LC-MS (ESI): [M+H] + =604.5.

[0200] Example 8 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 8) [ka]

[0201] Step 1: Synthesis of methyl 4-bromo-5-nitrothiophene-2-carboxylate The compound methyl 4-bromothiophene-2-carboxylate (6 g, 27.1 mmol) was added to concentrated sulfuric acid (20 mL), and the solution was cooled to -5°C. Nitric acid (4 mL) was added to concentrated sulfuric acid (12 mL), and the mixture was slowly added dropwise to the reaction system and stirred for 30 minutes. Ice water (50 mL) was added, and a large amount of solid precipitated. The mixture was filtered under suction, and the filter cake was washed with water (50 mL x 3). The filter cake was further concentrated under reduced pressure to give 6.7 g of a pale yellow solid product, with a yield of 90.9%.

[0202] LC-MS: [M+H] + =267.1, 1 HNMR (400MHz, CDCl3) δ 7.71 (s,1H),3.96 (s,3H).

[0203] Step 2: Synthesis of methyl (S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate The compound methyl 4-bromo-5-nitrothiophene-2-carboxylate (6.35 g, 23.9 mmol) and (S)-oxetan-2-ylmethylamine (2.50 g, 28.6 mmol) were added to 1,4-dioxane (120 mL), triethylamine (10.0 mL, 71.6 mmol), and the mixture was heated to 110 °C under nitrogen gas protection and stirred overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:2) to give 3.5 g of a yellow solid product in 53.9% yield.

[0204] LC-MS: [M+H] + =273.3, 1 HNMR (400MHz,CDCl3) δ 8.02 (s,1H),7.29 (s,1H),4.99 (s,1H),4.63 (dd,J=14.3,7.4Hz,1H),4.48 (dd,J=14.8,6.1Hz,1H),3.86 (s,3H),3.56 (t,J=9.7Hz,2H),2.78 - 2.63 (m,1H),2.56 - 2.41 (m,1H).

[0205] Step 3: Synthesis of methyl (S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate The compound (S)-methyl 5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (150 mg, 0.55 mmol) was added to acetic acid (5 mL), and zinc powder (360 mg, 5.5 mmol) was added in an ice bath. The mixture was stirred at room temperature for 5 minutes. The reaction mixture was filtered through diatomaceous earth, and the solid was concentrated under reduced pressure. The solid was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 80 mg of a dark brown solid product in 59.9% yield.

[0206] LC-MS: [M+H] + =243.4, 1 HNMR(400MHz,DMSO-d6) δ 7.15 (s,1H),5.92 (s,2H),4.84 - 4.75 (m,1H),4.51 (dd,J=13.8,7.6Hz,1H),4.43 (dt,J=9.1,5.9Hz,1H),4.24 (s,1H),3.66 (s,3H),3.18 (qd,J=13.4,4.9Hz,2H),2.65 - 2.55 (m,1H),2.46 - 2.34 (m,1H).

[0207] Step 4: Synthesis of 2-bromo-6-((methoxymethyl)oxy)pyridine The compound 6-bromopyridin-2-ol (16 g, 92.0 mmol) was added to dichloromethane (160 mL), triethylamine (63.9 mL, 459.5 mmol) was added, and the mixture was stirred in an ice bath for 10 minutes. Bromo(methoxy)methane (23 g, 184.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (30 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:20) to give 5.2 g of a colorless oily product in 25.9% yield.

[0208] 1 HNMR (400MHz,DMSO-d6) δ 7.72 (d,J=7.8Hz,1H),7.28 (d,J=7.3Hz,1H),6.93 (d,J=7.9Hz,1H),5.42 (s,2H),3.42 (s,3H).

[0209] Step 5: Synthesis of methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-bromo-6-((methoxymethyl)oxy)pyridine (5.2 g, 23.8 mmol) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate (7.68 g, 27.4 mmol) were added to 1,4-dioxane (60 mL) and water (15 mL). Potassium carbonate (6.59 g, 47.7 mmol) was added, and the mixture was purged with nitrogen gas three times. Pd(dppf)Cl2 (0.52 g, 0.72 mmol) was added, and the mixture was purged with nitrogen gas three times. The mixture was heated to 85 °C and stirred overnight. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:15) to give 4.0 g of a colorless oily product in 57.6% yield.

[0210] 1 HNMR (400MHz,CDCl3) δ 7.48 (t,J=7.8Hz,1H),6.90 (d,J=7.5Hz,1H),6.68 (dd,J=3.1,1.9Hz,1H),6.57 (d,J=8.1Hz,1H),5.49 (s,2H),3.62 (s,3H),3.45 (d,J=3.2Hz,3H),2.53 (dd,J=16.5,3.0Hz,1H),2.46 - 2.31 (m,2H),2.28 (d,J=7.2Hz,2H),2.17 - 2.03 (m,1H),1.96 - 1.84 (m,2H),1.38 (m,1H).

[0211] Step 6: Synthesis of 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)ethyl-1-ol The compound (4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)methyl acetate (1.5 g, 5.2 mmol) was added to tetrahydrofuran (30 mL) and stirred at -20 °C for 5 minutes. Lithium tetrahydroaluminum (0.39 g, 10.3 mmol) was added and stirred at 0 °C for 2 hours. Water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to obtain 1.3 g of a colorless oily product in a 95.9% yield.

[0212] LC-MS (ESI): [M+H] + =264.3.

[0213] Step 7: Synthesis of 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)acetaldehyde The compound 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)ethyl-1-ol (600 mg, 2.2 mmol) was added to dichloromethane (20 mL), Dess-Martin reagent (1.45 g, 3.4 mmol) was added, and the mixture was stirred in an ice bath for 3 hours, resulting in the precipitation of a large amount of solid. Water (4 mL) was added, and the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to give 260 mg of a colorless oily product in 43.7% yield.

[0214] LC-MS (ESI): [M+H] + =262.1.

[0215] Step 8: Synthesis of methyl 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-enyl)methyl)-1-(((2S)-oxetan-2-yl)methyl)thieno[3,2-d]imidazole-5-carboxylate The compound 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)acetaldehyde (200 mg, 0.76 mmol) and (S) methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (280 mg, 1.1 mmol) were added to acetic acid (5 mL), heated to 60° C., and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to obtain 160 mg of a light brown solid product in a yield of 47.6%.

[0216] LC-MS (ESI): [M+H] + =440.6.

[0217] Step 9: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-enyl)methyl)-1-(((2S)-oxetan-2-yl)methyl)thieno[3,2-d]imidazole-5-carboxylate (150 mg, 0.34 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (117 mg, 0.44 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (118 mg, 0.85 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. The mixture was diluted with water (5 mL), extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 10:1) to obtain 85 mg of a white solid product in a 40.0% yield.

[0218] LC-MS (ESI): [M+H] + =622.2.

[0219] Step 10: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (75 mg, 0.12 mmol) was dissolved in dioxane (8 mL) and water (2 mL). Lithium hydroxide (12 mg, 0.50 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N), extracted with ethyl acetate (5 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by prep-HPLC (eluent acetonitrile:water (v / v) = 50%) to give 9.8 mg of a white solid product in 13.4% yield.

[0220] LC-MS (ESI): [M+H] + =608.5, 1 HNMR (400MHz,DMSO-d6) δ 12.87 (s,1H),7.79 (s,1H),7.66 (t,J=7.8Hz,1H),7.46 - 7.36 (m,2H),7.06 (d,J=7.5Hz,1H),6.72 (d,J=8.1Hz,2H),6.52 (d,J=6.4Hz,1H),5.59 (s,2H),5.00 (d,J=7.1Hz,1H),4.58 - 4.37 (m,4H),2.97 - 2.86 (m,2H),2.76 - 2.62 (m,1H),2.57 - 2.52 (m,1H),2.42 - 2.28 (m,3H),2.24 - 2.19 (m,1H),2.10 - 1.89 (m,2H),1.46 - 1.38 (m,1H).

[0221] Example 9 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo(d)imidazole-6-carboxylic acid (Compound 9) [ka]

[0222] Step 1: Synthesis of methyl 3-(2-methoxyethyl)amino)-4-nitrobenzoate The compound methyl 3-fluoro-4-nitrobenzoate (2 g, 10.04 mmol), 2-methoxyethan-1-amine (1.2 g, 15.98 mmol), and N,N-diisopropylethylamine (2.6 g, 10.04 mmol) were added to tetrahydrofuran (30 mL), heated to 50 ° C, and stirred for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to obtain 2.4 g of a pale yellow solid product in a 98% yield.

[0223] 1 H NMR (400MHz,DMSO-d6) δ 8.17 (d,J=8.8Hz,2H),7.57 (s,1H),7.16 (d,J=8.9Hz,1H),3.89 (s,3H),3.69 - 3.50 (m,4H),3.32 (s,3H).

[0224] Step 2: Synthesis of methyl 4-amino-3-((2-methoxyethyl)amino)benzoate The compound methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (2.4 g, 9.44 mmol) and 10% Pd / C (240 mg, 2.26 mmol) were added to MeOH (20 mL) and reacted under H protection at room temperature for 2 hours. After completion of the reaction, the mixture was filtered through diatomaceous earth to remove palladium carbon, and concentrated to give 2.1 g of a gray solid product in 99.2% yield.

[0225] LC-MS (ESI): [M+H] + =225.2.

[0226] Step 3: Synthesis of methyl 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (200 mg, 0.71 mmol) and methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (160 mg, 0.71 mmol) were added to acetic acid (10 mL), heated to 60 ° C under nitrogen gas protection, and reacted for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to obtain 280 mg of a yellow oily product, with a yield of 81.0%.

[0227] LC-MS (ESI): [M+H] + =485.1, 1 H NMR (400MHz,DMSO-d6) δ 8.18 (d,J=1.1Hz,1H),8.09 (d,J=2.2Hz,1H),7.80 (dd,J=8.4,1.5Hz,1H),7.65 (d,J=8.4Hz,1H),6.07 (s,1H),5.29 (s,2H),4.50 (t,J=5.0Hz,2H),3.88 (s,3H),3.65 (t,J=5.0Hz,2H),3.35 (s,3H),3.18 (d,J=2.9Hz,3H),2.95 (d,J=6.3Hz,2H),2.36 (s,3H),2.05 - 1.88 (m,2H),1.56 - 1.43 (m,1H),1.23 (s,1H).

[0228] Step 4: Synthesis of methyl 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (260 mg, 0.54 mmol) was added to DCM (13 mL) and the mixture was cooled to -10 °C. TFA (6.5 mL, 87.51 mmol) was added, and the mixture was maintained at -10 °C and reacted overnight. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:20) to give 230 mg of a brown oily product in 97.3% yield.

[0229] LC-MS (ESI): [M+H] + =441.4, 1 H NMR (400MHz,DMSO-d6) δ 12.67 (s,1H),8.17 (s,1H),8.03 (s,1H),7.84-7.77 (m,1H),7.65 (d,J=8.2Hz,1H),6.78 (s,1H),4.49 (s,2H),3.88 (s,3H),3.63 (d,J=5.1Hz,2H),3.17 (d,J=4.7Hz,3H),2.93 (d,J=7.1Hz,2H),2.33 (s,3H),1.99 (d,J=70.6Hz,2H),1.44 (s,1H),1.19 (d,J=35.1Hz,1H).

[0230] Step 5: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (210 mg, 0.48 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (253 mg, 0.96 mmol) were added to DMF (15 mL) and stirred to dissolve. Potassium carbonate (198 mg, 1.43 mmol) was added, and the reaction mixture was heated to 60 ° C. under nitrogen gas protection and reacted for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to obtain 220 mg of an off-white solid product, with a yield of 74.1%.

[0231] LC-MS (ESI): [M+H] + =624.0.

[0232] Step 6: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (220 mg, 0.35 mmol) was added to 1,4-dioxane (5 mL), and lithium hydroxide (74 mg, 1.76 mmol) dissolved in water (2 mL) was added to the system. The reaction mixture was heated to 40 °C under nitrogen gas protection and reacted for 2 hours. The reaction mixture was cooled to room temperature, adjusted to a pH of about 4 with acetic acid, concentrated under reduced pressure, and purified by prep-HPLC (eluent acetonitrile:water (v / v) = 50%) to obtain 22.1 mg of a white solid product in a 10.3% yield.

[0233] LC-MS (ESI): [M+H] + =609.6, 1 H NMR (400MHz,DMSO-d6) δ 12.74 (s,1H),8.57 (d,J=2.9Hz,1H),8.15 (d,J=0.9Hz,1H),7.80 (dd,J=8.4,1.4Hz,1H),7.62 (d,J=8.4Hz,1H),7.49 - 7.42 (m,2H),7.12 (s,1H),6.55 (d,J=6.4Hz,1H),5.76 (s,2H),4.48 (t,J=4.9Hz,2H),3.65 (t,J=5.0Hz,2H),3.18 (s,3H),2.93 (t,J=11.5Hz,2H),2.68 (d,J=17.7Hz,1H),2.49 - 2.46 (m,1H),2.33 (s,2H),2.18 - 1.90 (m,2H),1.54 - 1.39 (m,1H).

[0234] Example 10 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 10) [ka]

[0235] Step 1: Synthesis of 6-chloro-5-nitro-2-carboxylic acid pyridine The compound 2-chloro-6-methyl-3-nitropyridine (8.0 g, 46.36 mmol) was added to concentrated sulfuric acid (40 mL), and potassium dichromate (20.46 g, 69.54 mmol) was slowly added at room temperature. The reaction was stirred overnight at room temperature. Ice water (500 mL) was slowly added under ice bath conditions, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.26 g of a pale yellow solid (88.0% yield).

[0236] LC-MS (ESI): [M+H] + =203.0.

[0237] Step 2: Synthesis of 6-chloro-5-nitro-2-methylpyridine carboxylate The compound 6-chloro-5-nitro-2-pyridine carboxylate (200 mg, 0.99 mmol) was dissolved in methanol (15 mL), concentrated sulfuric acid (0.5 mL, 0.99 mmol) was added, and the mixture was heated to 68 °C and reacted overnight. The solvent was concentrated, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:1) to give 185 mg of a white solid, with a yield of 86.5%.

[0238] LC-MS (ESI): [M+ H] + =217.1, 1 H NMR (500MHz, CDCl3) δ 8.31 (dd,J=8.3,0.8Hz,1H),8.22 (dd,J=8.2,0.8Hz,1H),4.04 (d,J=0.9Hz,3H).

[0239] Step 3: Synthesis of tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate The compound (1-(aminomethyl)cyclopropyl)methanol (2.5 g, 24.72 mmol) and di-tert-butyl dicarbonate (2.5 g, 24.72 mmol) were dissolved in DCM (50 mL), and diisopropylethylamine (8.2 mL, 49.43 mmol) was added. The mixture was stirred at room temperature for 3 h. Stirring was stopped, and the mixture was diluted with water (40 mL). The mixture was extracted three times with dichloromethane (15 mL × 3). The combined organic phases were washed twice with dilute hydrochloric acid (1 M), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 3:2) to give 4.24 g of a pale yellow viscous material in 85.2% yield.

[0240] 1H NMR (500MHz, CDCl3) δ 4.98 (s,1H),3.37 (d,J=6.5Hz,2H),3.25 (s,1H),3.10 (d,J=6.4Hz,2H),1.44 (d,J=5.8Hz,9H),0.45-0.40 (m,4H).

[0241] Step 4: Synthesis of (1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl methanesulfonate The compound ((1-(hydroxymethyl)cyclopropyl)methyl) tert-butyl carbamate (1.81 g, 8.99 mmol) was dissolved in DCM (40 mL) and triethylamine (2.5 mL, 17.99 mmol) was added. Methanesulfonyl chloride (0.8 mL, 10.79 mmol) was slowly added at 0 °C, and the reaction was continued with stirring for 2 h. Stirring was stopped, and the reaction was quenched by adding water (50 mL). The mixture was extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give 2.0 g of a pale yellow viscous material, with a yield of 79.6%.

[0242] Step 5: Synthesis of tert-butyl ((1-(cyanomethyl)cyclopropyl)methyl)carbamate The compound (1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl methanesulfonate (2.0 g, 7.16 mmol) and cyanotrimethylsilane (1.9 mL, 14.32 mmol) were dissolved in acetonitrile (30 mL). Tetrabutylammonium fluoride (4.2 mL, 14.32 mmol) was added, and the mixture was heated to 80 °C and reacted for 2 h. Heating was stopped and the mixture was cooled to room temperature. The solvent was concentrated, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 10:1) to obtain 850 mg of a pale yellow solid in 56.5% yield.

[0243] 1 H NMR (500MHz, CDCl3) δ 4.75 (s,1H),3.13 (d,J=6.4Hz,2H),2.48 (s,2H),1.44 (s,9H),0.61 (d,J=3.7Hz,4H).

[0244] Step 6: Synthesis of 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride The compound ((1-(cyanomethyl)cyclopropyl)methyl) tert-butyl carbamate (700 mg, 3.33 mmol) was dissolved in DCM (10 mL) and then a solution of hydrochloric acid in 1,4-dioxane (1 mL) was added. The mixture was stirred at room temperature for 4 h. The stirring was stopped, and the solvent was concentrated to give 400 mg of a white solid, with a yield of 81.9%.

[0245] LC-MS (ESI): [M-HCl+ H] + =111.2.

[0246] Step 7: Synthesis of methyl 6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropyridinecarboxylate The compound 6-chloro-5-nitro-2-methylpyridine carboxylate (500 mg, 2.31 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride (1.02 g, 6.93 mmol) were dissolved in tetrahydrofuran (5 mL), N,N-diisopropylethylamine (1.49 g, 11.55 mmol) was added, and the mixture was stirred at room temperature overnight. The filtrate was concentrated and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:1) to give 560 mg of a yellow solid, the yield was 83.6%.

[0247] LC-MS (ESI): [M+ H] + =291.3 Step 8: Synthesis of methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)pyridinecarboxylate Under hydrogen gas protection, the compound methyl 6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-5-nitropyridinecarboxylate (160 mg, 0.55 mmol) was dissolved in a mixture of ethyl acetate (20 mL) and palladium on carbon (10% Pd, containing 40-60% water) (80 mg) was added. The reaction was stirred at room temperature for 2 hours, and the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to obtain 120 mg of an oily yellow viscous product in 83.6% yield.

[0248] LC-MS (ESI): [M+ H] + =261.13.

[0249] Step 9: Synthesis of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-(4-(5-fluoro-4-((methoxymethyl)oxy)pyrimidin-2-yl)cyclohex-3-enyl)acetaldehyde (130 mg, 0.46 mmol) and methyl 5-amino-6-(((1-(cyanomethyl)cyclopropyl)methyl)amino)pyridinecarboxylate (120 mg, 0.46 mmol) were added to acetic acid (3 mL) and stirred at 60 ° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 200 mg of a yellow solid product, with a yield of 82.8%.

[0250] LC-MS (ESI): [M+H] + =521.1.

[0251] Step 10: Synthesis of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.38 mmol) was added to dichloromethane (10 mL), the solution was stirred at −10° C. for 5 minutes, trifluoroacetic acid (5 mL, 67.31 mmol) was added dropwise, and the mixture was stirred at −10° C. overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 10:1) to give 95 mg of a pale yellow solid product, with a yield of 51.9%.

[0252] LC-MS (ESI): [M+1] + =477.2.

[0253] Step 11: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (95 mg, 0.20 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (105 mg, 0.40 mmol), potassium carbonate (82 mg, 0.59 mmol) was added to N,N-dimethylformamide (5 mL) and stirred at 60 ° C. for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:3) to obtain 75 mg of a pale yellow solid product, with a yield of 57.1%.

[0254] LC-MS (ESI): [M+H] + =659.2.

[0255] Step 12: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (75 mg, 0.11 mmol), lithium hydroxide (14 mg, 0.58 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and reacted at 40 °C for 2 hours. The pH was adjusted to 5 by dropwise addition of acetic acid, concentrated under reduced pressure, and purified by prep-HPLC (eluent acetonitrile:water (v / v) = 0% to 60%) to obtain 20.5 mg of a white solid product in 27.9% yield.

[0256] LC-MS (ESI): [M+H] + =645.2, 1 HNMR (400MHz,DMSO-d6) δ 12.99 (s,1H),8.60 - 8.55 (m,1H),8.09 (d,J=8.0Hz,1H),7.97 (d,J=8.0Hz,1H),7.51 - 7.41 (m,2H),7.12 (s,1H),6.55 (d,J=8.0Hz,1H),5.77 (s,2H),4.40 (s,2H) ,3.08 - 2.97 (m,2H),2.76 - 2.63 (m,3H),2.60 - 2.53 (m,1H),2.46 - 2.30 (m,2H),2.20 - 1.95 (m,2H),1.59 - 1.44 (m,1H),1.03 - 0.94 (m,2H),0.67 - 0.60 (m,2H).

[0257] Example 11 Synthesis of 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 11) [ka]

[0258] Step 1: Synthesis of methyl 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (550 mg, 1.96 mmol) (see Step 8 of Example 5 for the synthesis method) and (S)-methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (571 mg, 2.36 mmol) (see Step 3 of Example 8 for the synthesis method) were added to acetic acid (20 mL) and stirred at 60 ° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 300 mg of a light brown solid product, the yield was 30.4%.

[0259] LC-MS (ESI): [M+H] + =503.4.

[0260] Step 2: Synthesis of methyl 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate methyl (300 mg, 0.6 mmol) was added to anhydrous dichloromethane (16 mL), cooled to -10 ° C, trifluoroacetic acid (8 mL) was added dropwise, and the mixture was maintained at -10 ° C and reacted overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 10:1) to obtain 200 mg of a white solid product, with a yield of 73.3%.

[0261] LC-MS (ESI): [M+H] + =459.4.

[0262] Step 3: Synthesis of methyl 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate methyl (100 mg, 0.22 mmol), 7-(bromomethyl)-4-chlorobenzofuran (80 mg, 0.33 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (91 mg, 0.66 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 103 mg of a white solid product, with a yield of 75.7%.

[0263] LC-MS (ESI): [M+H] + =623.4.

[0264] Step 4: Synthesis of 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (103 mg, 0.17 mmol) was dissolved in dioxane (12 mL) and water (3 mL). Lithium hydroxide (16 mg, 0.68 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with acetic acid, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: acetonitrile:water (v / v) = 60%) to give 40.7 mg of a white solid product in 40.5% yield.

[0265] LC-MS (ESI): [M+H] + =609.6, 1 H NMR (400MHz,DMSO-d6) δ 12.85 (s,1H),8.56 (d,J=2.8Hz,1H),8.20 (d,J=2.1Hz,1H),7.83 (s,1H),7.48 (d,J=8.0Hz,1H),7.39 (d,J=8.0Hz,1H),7.15 - 7.04 (m,2H),5.82 (s,2H),5.01 (d,J=6.9Hz,1H),4.52 - 4.44 (m,3H),4.36 - 4.30 (m,1H),2.95 - 2.81 (m,2H),2.73 - 2.66 (m,2H),2.47 - 2.27 (m,3H),2.29 - 2.18 (m,1H),2.12 - 2.06 (m,1H),2.03 - 1.91 (m,1H),1.47 - 1.39 (m,1H).

[0266] Example 12 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 12) [ka]

[0267] Step 1: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate methyl (100 mg, 0.22 mmol) (see Step 2 of Example 11 for the synthesis method), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (86 mg, 0.33 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (91 mg, 0.66 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 111 mg of a white solid product, with a yield of 67.5%.

[0268] LC-MS (ESI): [M+H] + =641.4.

[0269] Step 2: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (111 mg, 0.17 mmol) was dissolved in dioxane (12 mL) and water (3 mL). Lithium hydroxide (16 mg, 0.68 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with acetic acid, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: acetonitrile:water (v / v)=50%) to give 21.7 mg of a white solid product, the yield was 23.5%.

[0270] LC-MS (ESI): [M+H] + =627.5, 1 HNMR (400MHz,DMSO-d6) δ 12.85 (s,1H),8.57 (s,1H),7.82 (s,1H),7.46 (dd,J=16.9,8.1Hz,2H),7.11 (s,1H),6.55 (d,J=6.3Hz,1H),5.76 (s,2H),5.01 (d,J=4.7Hz,1H),4.63 - 4.26 (m,4H),2.89 (s,2H),2.75 - 2.66 (m,2H),2.40 - 2.36 (m,3H),2.24 - 1.90 (m,3H),1.49 - 1.38 (m,1H).

[0271] Example 13 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 13) [ka]

[0272] Step 1: Synthesis of 6-chloro-5-nitropyridine acid The compound 2-chloro-6-methyl-3-nitropyridine (20 g, 115.89 mmol) was dissolved in concentrated sulfuric acid (100 mL) and cooled to 0 °C in an ice bath. Chromium oxide (45 g, 173.84 mmol) was slowly added, and the mixture was warmed to room temperature and reacted for 12 h. The reaction mixture was slowly added to ice water (500 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with ice water (50 mL x 2). The filter cake was collected, concentrated under reduced pressure, and dried to give 12.5 g of an off-white solid product, with a yield of 53.2%.

[0273] Step 2: Synthesis of methyl 6-chloro-5-nitropyridinecarboxylate The compound 4-bromo-5-nitrothiophene-2-carboxylic acid (6 g, 23.81 mmol) was added to thionyl dichloride (30 mL), DMF (0.2 mL, 2.05 mmol) was added, and the mixture was heated to 60 °C and reacted for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and methanol (50 mL) was added in an ice bath, resulting in the precipitation of a large amount of white solid. Filtration afforded 2.25 g of a white solid product, a yield of 35%.

[0274] 1 H NMR (400MHz, CDCl3) δ 8.32 (d,J=8.2Hz,1H),8.24 (d,J=8.2Hz,1H),4.06 (s,3H).

[0275] Step 3: Synthesis of methyl 6-((2-methoxyethyl)amino)-5-nitropyridinecarboxylate The compound methyl 6-chloro-5-nitropyridine-2-carboxylate (500 mg, 2.31 mmol) and 2-methoxyethan-1-amine (0.2 mL, 2.31 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (957.73 mg, 6.93 mmol) was added, and the mixture was stirred overnight at room temperature under N protection. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to give 583 mg of a yellow solid product in 98.8% yield.

[0276] LC-MS (ESI): [M+H] + =256.2.

[0277] Step 4: Synthesis of methyl 5-amino-6-(2-methoxyethyl)aminopyridinecarboxylate The compound methyl 6-((2-methoxyethyl)amino)-5-nitropyridine-2-carboxylate (583 mg, 2.28 mmol) and 10% Pd / C (58 mg, 0.55 mmol) were added to ethyl acetate (10 mL) and reacted at room temperature for 16 hours under hydrogen gas protection. The mixture was filtered through diatomaceous earth to remove palladium carbon, and the filter cake was washed with ethyl acetate (10 mL). The combined filtrate was concentrated under reduced pressure to give 452 mg of a colorless oily product in 87.8% yield.

[0278] 1 H NMR (400MHz,DMSO-d6) δ 7.23 (d,J=7.8Hz,1H),6.67 (d,J=7.8Hz,1H),5.97 (t,J=5.4Hz,1H),5.64 (s,2H),4.56 - 4.51 (m,2H),3.72 (s,3H),3.32 (s,3H),2.47 - 2.34 (m,2H).

[0279] Step 5: Synthesis of methyl 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-(4-(5-fluoro-4-((methoxymethyl)oxy)pyrimidin-2-yl)cyclohex-3-enyl)acetaldehyde (260.5 mg, 0.93 mmol) (see Step 8 of Example 5 for the synthesis method) and methyl 5-amino-6-(2-methoxyethyl)aminopyridinecarboxylate (210 mg, 0.93 mmol) were added to acetic acid (5 mL), and the mixture was heated to 60 ° C under nitrogen gas protection and reacted for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to obtain 286.6 mg of a brown oily product, with a yield of 63.5%.

[0280] 1 H NMR (400MHz,DMSO-d6) δ 8.10 (dd,J=10.2,5.2Hz,2H),8.00 (d,J=8.2Hz,1H),6.08 (s,1H),5.28 (d,J=10.7Hz,2H),4.49 (t,J=5.2Hz,2H),3.91 (s,3H),3.73 (t,J=5.2Hz,3H),3.58 - 3.48 (m,1H),3.33 - 3.24 (m,2H),3.21 (s,3H),3.02 (d,J=6.4Hz,2H),2.40 (d,J=30.0Hz,5H),2.07 - 1.85 (m,2H),1.51 (s,1H).

[0281] Step 6: Synthesis of methyl 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo(4,5-b)pyridine-5-carboxylate methyl ester (286 mg, 0.59 mmol) was added to dichloromethane (29 mL) and cooled to -10 ° C under nitrogen gas protection. Trifluoroacetic acid (5.5 mL, 74.04 mmol) was slowly added dropwise, and the mixture was maintained at -10 ° C. and reacted overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:10) to obtain 160 mg of a yellow oily product, with a yield of 61.5%.

[0282] LC-MS (ESI): [M+H] + =442.7.

[0283] Step 7: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (160 mg, 0.36 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (143 mg, 0.54 mmol) were added to DMF (12 mL). Potassium carbonate (250 mg, 1.81 mmol) was added, and the mixture was heated to 60 °C under nitrogen gas protection and reacted for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to obtain 113 mg of a pale yellow solid product, with a yield of 50.0%.

[0284] LC-MS (ESI): [M+H] + =624.6.

[0285] Step 8: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (113 mg, 0.18 mmol) was added to dioxane (1.6 mL), and lithium hydroxide (22 mg, 0.52 mmol) dissolved in water (0.4 mL) was added to the reaction system. The reaction mixture was heated to 40 °C under nitrogen gas protection and reacted for two hours. The pH of the reaction mixture was adjusted to 4 with acetic acid. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: acetonitrile:water (v / v) = 50%) to obtain 64.8 mg of a white solid product in 56.8% yield.

[0286] LC-MS (ESI): [M+H] + =610.6, 1 H NMR (400MHz,DMSO-d6) δ 12.96 (s,1H),8.57 (d,J=4.0Hz,1H),8.10 (d,J=8.0Hz,1H),7.98 (d,J=8.0Hz,1H),7.49 - 7.43 (m,2H),7.12 (s,1H),6.55 (d,J=4.0Hz,1H),5.77 (s,2H),4.51 - 4.49 (m,2H),3.74 - 3.71 (m,2H),3.20 (s,3H),3.03 - 3.01 (m,2H),2.71 - 2.66 (m,1H),2.53 - 2.50 (m,1H),2.37 - 2.32 (m,2H),2.14 - 2.08 (m,1H),1.99 - 1.95 (m,1H),1.52 - 1.47 (m,1H).

[0287] Example 14 Synthesis of 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 14) [ka]

[0288] Step 1: Synthesis of methyl 2-(4-oxocyclohexylene)acetate The compound cyclohexane-1,4-dione (20 g, 178.36 mmol) and carbamoylmethylenetriphenylphosphine (29.8 g, 89.22 mmol) were added to toluene (300 mL) and reacted overnight at 110° C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 25%) to obtain 12 g of a white solid product, with a yield of 40.0%.

[0289] 1 HNMR (400MHz, CDCl3) δ 5.86 (s,1H),3.72 (s,3H),3.21 (t,J=7.2Hz,2H),2.67 (t,J=6.8Hz,2H),2.52 - 2.47 (m,4H).

[0290] Step 2: Synthesis of methyl 2-(4,4-dimethoxycyclohexyl)acetate The compound methyl 2-(4-oxocyclohexylene)acetate (12.0 g, 71.43 mmol) was added to methanol (700 ml), the mixture was purged with nitrogen gas three times, palladium carbon (10% palladium, 40-60% water) (1.2 g) was added, the mixture was purged with hydrogen gas three times, and the mixture was allowed to react at room temperature overnight. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give 13.57 g of a colorless oily liquid, with a yield of 88.5%.

[0291] 1HNMR (400MHz,CDCl3) δ 3.67 (s,3H),3.19 (s,3H),3.14 (s,3H),2.23 (d,J=7.2Hz,2H),2.01 - 1.96 (m,2H),1.90 - 1.78 (m,1H),1.70 - 1.59 (m,2H),1.41 - 1.30 (m,2H),1.22 - 1.16 (m,2H).

[0292] Step 3: Synthesis of methyl 2-(4-oxocyclohexyl)acetate The compound 2-(4,4-dimethoxycyclohexyl)methyl acetate (10.5 g, 48.55 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.1 g, 4.85 mmol) were added to acetonitrile (218 mL) and water (25 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:MTBE (v / v) = 10:3) to give 7.5 g of a colorless oily liquid in 90.8% yield.

[0293] 1 HNMR (400MHz,DMSO-d6) δ 3.70 (s,3H),2.41 - 2.21 (m,7H),2.18 - 2.02 (m,2H),1.48 - 1.40 (m,2H).

[0294] Step 4: Synthesis of methyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate Methyl 2-(4-oxocyclohexyl)acetate (6.4 g, 37.60 mmol) was added to tetrahydrofuran (120 mL) and lithium bistrimethylsilylamide (1 mol / L, 45 mL) was added dropwise at -40 °C. The mixture was stirred for 30 minutes, and then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (14.77 g, 41.36 mmol) was added dropwise and stirred overnight. The mixture was quenched by the dropwise addition of saturated ammonium chloride solution (50 mL) in an ice bath, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:MTBE (v / v) = 5:1) to give 8.5 g of a pale yellow solid in 74.8% yield.

[0295] 1 HNMR (400MHz,DMSO-d6) δ 5.86 - 5.85 (m,1H),3.60 (s,3H),2.43 - 2.21 (m,5H),2.02 - 1.79 (m,3H),1.45 - 1.40 (m,1H).

[0296] Step 5: Synthesis of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)methyl acetate (8.5 g, 28.12 mmol), bis(pinacolato)diboron (7.86 g, 30.93 mmol), tetrakistriphenylphosphinepalladium (3.25 g, 2.81 mmol), and potassium acetate (5.52 g, 56.24 mmol) were added to dioxane (150 mL) and stirred at 90 °C for 30 minutes. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:MTBE (v / v) = 10:1) to give 5.6 g of a colorless oily liquid in a 49.8% yield.

[0297] LC-MS (ESI): [M+H] + =281.2.

[0298] 1 HNMR (400MHz,DMSO-d6) δ 6.39 (s,1H),3.58 (s,3H),2.45 - 1.55 (m,9H),1.18 (s,12H).

[0299] Step 6: Synthesis of 4-bromo-2-((4-methoxybenzyl)oxy)thiazole The compound 2,4-dibromothiazole (5.0 g, 20.58 mmol) was added to tetrahydrofuran (50 mL), and sodium hydride (1.23 g, 30.87 mmol) was slowly added at room temperature and stirred for 30 minutes. 4-Methoxybenzyl alcohol (2.84 g, 20.58 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE:EA (v / v) = 10:1) to obtain 4.5 g of a white solid product, with a yield of 72.8%.

[0300] LC-MS (ESI): [M+H] + =300.2, 1 HNMR (400MHz, CDCl3) δ 7.37 (d,J=8.4Hz,2H),6.91 (d,J=8.8Hz,2H),6.58 (s,1H),5.38 (s,2H),3.82 (s,3H).

[0301] Step 7: Synthesis of methyl 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)acetate The compound 4-bromo-2-((4-methoxybenzyl)oxy)thiazole (4.5 g, 14.99 mmol), methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxobenzoate-2-yl)cyclohex-3-en-1-yl)acetate (6.6 g, 22.43 mmol), bis(tri-tert-butylphosphine)palladium (0.76 g, 1.50 mmol) and potassium carbonate (4.2 g, 30.39 mmol) were added to 1,4-dioxane (60 mL) and water (15 mL) and stirred overnight at 95° C. under nitrogen gas protection. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 90%) to give 2.5 g of a pale yellow solid product, with a yield of 43.0%.

[0302] LC-MS (ESI): [M+H] + =374.2.

[0303] Step 8: Synthesis of 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)ethan-1-ol The compound 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl acetate (2.5 g, 6.45 mmol) was added to tetrahydrofuran (70 mL), and lithium aluminum hydride powder (0.61 g, 16.13 mmol) was slowly added under ice bath conditions. The mixture was allowed to react for 3 hours under ice bath conditions. Water (10 mL) was slowly added dropwise under ice bath conditions. The mixture was filtered through diatomaceous earth, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 3:2) to obtain 2.0 g of a yellow solid product in 89.7% yield.

[0304] LC-MS (ESI): [M+H] + =346.2.

[0305] Step 9: Synthesis of 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)acetaldehyde The compound 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)ethan-1-ol (2.0 g, 5.80 mmol) was added to dimethyl sulfoxide (60 mL), and 2-iodoacylbenzoic acid (3.25 g, 11.59 mmol) was added in an ice bath and stirred at room temperature for 2 hours. The mixture was diluted with water (180 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 90%) to give 942 mg of a pale yellow solid product in 47.4% yield.

[0306] LC-MS (ESI): [M+H] + =344.2.

[0307] Step 10: Synthesis of methyl 2-((4-(2-hydroxythiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)acetaldehyde (942 mg, 2.75 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (652 mg, 2.75 mmol) were added to acetic acid (8 mL) and reacted at 60° C. for 2 hours. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to obtain 417 mg of a pale yellow solid product, with a yield of 34.5%.

[0308] LC-MS (ESI): [M+H] + =440.1.

[0309] Step 11: Synthesis of methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((4-(2-hydroxythiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (417 mg, 0.95 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250 mg, 0.95 mmol), and potassium carbonate (262 mg, 1.9 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, and extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:1) to obtain 120 mg of a pale yellow solid product in a 20.3% yield.

[0310] LC-MS (ESI): [M+1] + =622.1.

[0311] Step 12: Synthesis of 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-1-(S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 0.19 mmol) and lithium hydroxide (22.8 mg, 0.95 mmol) were added to 1,4-dioxane (8 mL) and water (2 mL) and reacted at 40 °C for 1 hour. The mixture was cooled in an ice bath, adjusted to pH = 6 with acetic acid, concentrated under reduced pressure, and purified by pre-HPLC (eluent acetonitrile:water (v / v) = 80%) to give 25 mg of a white solid product, with a yield of 26.1%.

[0312] LC-MS (ESI): [M+H] + =608.1, 1 HNMR (400MHz,DMSO-d6) δ 12.70 (s,1H),8.23 (s,1H),7.81 (d,J=8.4Hz,1H),7.64 (d,J=8.8Hz,1H),7.47 - 7.43 (m,2H),6.80 (s,1H),6.56 - 6.51 (m,2H) ,5.66 (s,2H),5.03 - 5.01 (m,1H),4.69 - 4.63 (m,1H),4.55 - 4.45 (m,2H),4.32 - 4.30 (m,1H),2.99 - 2.98 (m,2H),2.73 - 2.67 (m,1H),2.50 - 2.25 (m,5H),2.05 - 1.92 (m,2H),1.48 - 1.45 (m,1H).

[0313] Example 15 Synthesis of 2-((4-(6-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 15) [ka]

[0314] Step 1: Synthesis of methyl 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-(4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate The compound 2-(4-(6-(methoxymethoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (170 mg, 0.65 mmol) and methyl 5-amino-6(((-1-(cyanomethyl)cyclopropyl)methyl)amino)pyridinecarboxylate (169 mg, 0.65 mmol) (see Example 10, Step 8 for synthesis) were added to acetic acid (5 mL) and reacted at 60° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to obtain 175 mg of a pale yellow solid product, with a yield of 58.8%.

[0315] LC-MS (ESI): [M+H] + =458.5, 1 HNMR (400MHz,DMSO-d6) δ 11.21 (s,1H),8.13 (d,J=8.0Hz,1H),8.00 (d,J=8.0Hz,1H),7.42 - 7.36 (m,1H),6.47 (s,1H),6.25 - 6.17 (m,2H),4.38 (s,2H),3.92 (s,3H),3.06 - 2.99 (m,2H) ,2.67 (m,2H),2.49 - 2.27 (m,4H),2.11 - 1.92 (m,2H),1.57 - 1.45 (m,1H),1.04 - 0.96 (m,2H),0.70 - 0.61 (m,2H).

[0316] Step 2: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 3-((1-(cyanomethyl)cyclopropyl)methyl)-2-(4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate (175 mg, 0.39 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (208 mg, 0.79 mmol), and potassium carbonate (163 mg, 1.2 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at 60 °C for 3 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:1) to give 100 mg of a pale yellow solid product in 35.6% yield.

[0317] LC-MS (ESI): [M+H] + =640.5.

[0318] Step 3: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate) (100 mg, 0.16 mmol) and lithium hydroxide (18 mg, 0.75 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and reacted at 40 °C for 1 hour. The mixture was cooled in an ice bath and the pH was adjusted to 6-7 with acetic acid. The mixture was concentrated under reduced pressure and purified by pre-HPLC (eluent: acetonitrile:water (v / v) = 80%) to give 18.3 mg of a white solid product in 18.7% yield.

[0319] LC-MS (ESI): [M+H]+ =626.2, 1 HNMR (400MHz,DMSO-d6) δ 12.91 (s,1H),8.15 - 8.08 (m,1H),7.99 (d,J=4.0Hz,1H),7.67 (t,J=8.0Hz,1H),7.45 - 7.36 (m,2H),7.08 (d,J=4.0Hz,1H),6.77 - 6.69 (m,2H),6.54 - 6.48 (m,1H) ,5.60 (s,2H),4.40 (s,2H),3.08 - 2.98 (m,2H),2.70 (s,2H),2.65 - 2.53 (m,1H),2.48 - 2.31 (m,3H),2.17 - 1.96 (m,2H),1.59 - 1.46 (m,1H),1.03 - 0.94 (m,2H),0.69 - 0.60 (m,2H).

[0320] Example 16 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 16) [ka]

[0321] Step 1: Synthesis of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate The compound methyl 3-fluoro-4-nitrobenzoate (500 mg, 2.51 mmol), (3-ethylimidazol-4-yl)formamide (500 mg, 3.99 mmol) was added to tetrahydrofuran (10 mL), N,N-diisopropylethylamine (2.9 mL, 17.59 mmol) was added, and the reaction mixture was heated to 60 ° C. and reacted for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:15) to obtain 638 mg of a yellow solid product, with a yield of 83.4%.

[0322] LC-MS (ESI): [M+H] + =305.5.

[0323] Step 2: Synthesis of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate The compound methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (638 mg, 2.10 mmol) was added to ethyl acetate (16 mL), stirred, and dissolved. 10% Pd / C (65 mg, 0.61 mmol) was added, and the mixture was heated to 40°C under a hydrogen gas atmosphere and reacted overnight. The mixture was filtered through diatomaceous earth to remove palladium carbon, and the filtrate was concentrated under reduced pressure to give 558 mg of a colorless oily product, with a yield of 96.9%.

[0324] 1 H NMR (400MHz,DMSO-d6) δ 7.78 (s,1H),7.18 (dd,J=8.1,1.8Hz,1H),7.12 (d,J=1.8Hz,1H),6.93 (s,1H),6.55 (d,J=8.1Hz,1H),5.50 (s,2H),4.94 (s,1H),4.26 (d,J=4.3Hz,2H),4.03 (q,J=7.3Hz,2H),3.73 (s,3H),1.35 (t,J=7.3Hz,3H).

[0325] Step 3: Synthesis of methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(5-fluoro-4-((methoxymethyl)oxy)pyrimidin-2-yl)cyclohex-3-enyl)acetaldehyde (170 mg, 0.61 mmol), methyl 4-amino-3-(((1-ethylimidazol-5-yl)methyl)amino)benzoate (166.4 mg, 0.61 mmol) was added to acetic acid (11 mL), stirred at 60 °C for 1.5 hours, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 270 mg of a yellow oily product, the yield was 83.3%.

[0326] LC-MS (ESI): [M+H] + =536.0.

[0327] Step 4: Synthesis of methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (270 mg, 0.51 mmol) was added to dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred overnight at −10° C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 15:1) to obtain 191 mg of a yellow solid product, with a yield of 77.1%.

[0328] LC-MS (ESI): [M+H] + =491.5.

[0329] 1HNMR (400MHz,DMSO-d6) δ 12.58 (s,1H),8.16 (s,1H),7.99 (d,J=3.3Hz,1H),7.82 (dd,J=8.4,1.5Hz,1H),7.72-7.62 (m,2H),6.73 (s,1H),6.42 (s,1H),5.65 (s,2H),3.94 (q,J=7.3Hz,2H),3.85 (s,3H),3.12 - 2.86 (m,2H),2.50 - 2.33 (m,6H),1.39 - 1.21 (m,1H),1.12 (t,J=7.2Hz,3H).

[0330] Step 5: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (190 mg, 0.39 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (153.1 mg, 0.58 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (161 mg, 1.16 mmol) was added, and the mixture was stirred at 60 ° C. for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:1) to give 170 mg of a yellow solid product, with a yield of 65.2%.

[0331] LC-MS (ESI): [M+H] + =673.5.

[0332] 1HNMR (400MHz,DMSO-d6) δ 8.56 (d,J=2.8Hz,1H),8.16 (d,J=0.9Hz,1H),7.83 (dd,J=8.5,1.5Hz,1H),7.70 (d,J=8.7Hz,2H),7.51-7.39 (m,2H),7.08 (s,1H),6.55 (d,J=6.4Hz,1H),6.43 (s,1H),5.77 (d,J=12.1Hz,2H),5.66 (s,2H),3.95 (q,J=7.2Hz,2H),3.85 (s,3H),2.96 - 2.92 (m,2H),2.64 (d,J=19.2Hz,1H),2.50 - 1.88 (m,6H),1.12 (t,J=7.2Hz,3H).

[0333] Step 6: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.15 mmol) was added to dioxane (2 mL), and lithium hydroxide (19 mg, 0.45 mmol) was dissolved in water (0.5 mL) and added to the reaction system, followed by stirring at 40 °C for 3 hours. The reaction solution was adjusted to pH 6 with acetic acid. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: CHCN:HO (v / v) = 50%) to give 44.8 mg of a white solid product, with a yield of 45.8%.

[0334] LC-MS (ESI): [M+H] + =659.3, 1HNMR (400MHz,DMSO-d6) δ 12.58(s,1H),8.56 (d,J=2.9Hz,1H),8.13 (s,1H),7.81 (dd,J=8.4,1.4Hz,1H),7.67 (d,J=8.3Hz,2H),7.46 (q,J=8.2Hz,2H),7.08 (s,1H),6.55 (d,J=6.4Hz,1H),6.44 (s,1H),5.76 (s,2H),5.64 (s,2H),3.94 (q,J=7.2Hz,2H),2.94 (t,J=6.4Hz,2H),2.65 (d,J=19.1Hz,1H),2.49 - 2.43 (m,2H),2.39 - 1.88 (m,3H),1.46 - 1.39 (m,1H),1.12 (t,J=7.2Hz,3H).

[0335] Example 17 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid (Compound 17) [ka]

[0336] Step 1: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-4-((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate The compound methyl 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylate (1.0 g, 3.67 mmol) and 2-(1-ethyl-1H-imidazol-5-yl)acetaldehyde (608 mg, 4.4 mmol) were added to ethanol (10 mL), acetic acid (0.1 mL) was added, and the mixture was stirred at room temperature for 10 minutes. Sodium cyanoborohydride (461.2 mg, 7.34 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 50%) to give 1.2 g of a pale yellow solid product in 86% yield.

[0337] LC-MS (ESI): [M+H] + =381.1, 1 HNMR (400MHz,DMSO-d6) δ 8.5 (s,1H),7.58 (s,1H),7.37 (s,1H),6.79 (s,1H),4.11 (s,2H),3.99 - 3.94 (m,2H),3.77 (s,3H),1,49 - 1.38 (m,12H).

[0338] Step 2: Synthesis of methyl 5-amino-4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate The compound methyl 5-((tert-butoxycarbonyl)amino)-4-((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate (1.2 g, 3.15 mmol) was dissolved in dichloromethane (5 mL). A 4N solution of hydrochloric acid in methanol was added, and the mixture was stirred at room temperature for 4 hours. Concentration under reduced pressure gave 440 mg of a pale yellow solid product, which was used directly in the next step.

[0339] LC-MS (ESI): [M+H] + =281.1.

[0340] Step 3: Synthesis of methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thiophene[2,3-d]imidazole-4-carboxylate The compound methyl 5-amino-4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate (220 mg, 0.786 mmol) and 2-(4-(6-(methoxymethoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (205.4 mg, 0.786 mmol) were added to acetic acid (2 mL), purged with oxygen gas three times, and reacted at 60 °C for 6 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 85%) to give 55 mg of a pale yellow solid in 14.7% yield.

[0341] LC-MS (ESI): [M+H] + =478.3, 1 HNMR (400MHz,DMSO-d6) δ 11.3 (s,1H),7.73 (s,1H),7.4 - 7.36 (m,2H),6.92 (s,1H),6.44 (s,1H),6.22 (d,J=9.2Hz,2H),5.52 (s,2H),3.82 - 3.79 (m,5H),2.9 - 2.87 (m,2H),2.35 - 2.3 (m,2H),2.03 - 1.97 (m,4H),1.2 - 1.18 (m,1H),1.05 - 0.99 (m,3H).

[0342] Step 4: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thiophene[2,3-d]imidazole-4-carboxylate (55 mg, 0.12 mmol) and potassium carbonate (49.7 mg, 0.36 mmol) were added to N,N-dimethylformamide (3 mL), and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (31.6 mg, 0.12 mmol) was added and reacted at 60 ° C. for 1.5 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 95%) to give 28 mg of a yellow solid, a yield of 36.9%.

[0343] LC-MS (ESI): [M+H] + =660.1.

[0344] Step 5: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (28 mg, 0.0424 mmol) was added to a mixture of dioxane (0.2 mL) and water (0.1 mL). Lithium hydroxide (5.1 mg, 0.212 mmol) was added, and the mixture was reacted at 40 °C for 4 hours. The pH was adjusted to 5-6 with acetic acid (0.1 mL), concentrated under reduced pressure, and purified by pre-HPLC (eluent: CHCN:HO (v / v) = 60%) to give 8.5 mg of a white solid in 31% yield.

[0345] LC-MS (ESI): [M+H] + =646.3, 1 HNMR (400MHz,DMSO-d6) δ 7.73 (s,1H),7.66 (t,J=7.8Hz,1H),7.41 (t,J=2Hz,2H),7.24 (s,1H),7.06 (d,J=7.6Hz,1H),6.92 (s,1H),6.72 (d,J=8Hz,2H),6.52 (d,J=6.4Hz,1H),5.59 (s,2H),5.50 (s,2H),3.83 - 3.81 (m,2H),2.92 - 2.89 (m,2H),2.56 (s,1H),2.38 - 2.27 (m,2H),1.99 - 1.91 (m,3H),1,45 - 1.01 (m,1H),0.99 (t,J=7.2Hz,3H).

[0346] Example 18 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 18) [ka]

[0347] Step 1: Synthesis of methyl 4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-nitrothiophene-2-carboxylate The compound (1-ethyl-1H-imidazol-5-yl)methylamine (800 mg, 6.4 mmol) and methyl 4-bromo-5-nitrothiophene-2-carboxylate (2.04 g, 7.68 mmol) were added to N,N-dimethylformamide (15 mL), potassium carbonate (2.65 g, 19.2 mmol) and stirred overnight at 80 °C. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:1) to give 550 mg of a yellow solid product in 27.7% yield.

[0348] LC-MS (ESI): [M+H] + =311.2.

[0349] Step 2: Synthesis of methyl 5-amino-4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate The compound methyl 4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-nitrothiophene-2-carboxylate (550 mg, 1.77 mmol) was dissolved in acetic acid (10 mL). Zinc powder (1.15 g, 17.7 mmol) was added and stirred at room temperature for 5 minutes. After filtration and concentration, 250 mg of crude product was obtained, with a yield of 50.3%, and the crude product was used directly in the next step.

[0350] LC-MS (ESI): [M+H] + =281.1.

[0351] Step 3: Synthesis of methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 5-amino-4-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophene-2-carboxylate (250 mg, 0.89 mmol), 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (250 mg, 0.89 mmol) was added to acetic acid (10 mL) and stirred at 60 ° C. for 1 hour under oxygen gas protection. After concentration, the mixture was purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 10:1) to obtain 100 mg of a yellow solid product, with a yield of 20.7%.

[0352] LC-MS (ESI): [M+H] + =541.2.

[0353] Step 4: Synthesis of methyl 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate The compound 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (100 mg, 0.19 mmol) was added to dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added while stirring at -10 ° C. and stirred overnight. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 8:1) to obtain 50 mg of a yellow solid product, with a yield of 54.5%.

[0354] LC-MS (ESI): [M+H] + =497.3.

[0355] Step 5: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate Compound 1-((1-ethyl-1H-imidazol-5-yl)methyl)-2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate methyl (50 mg, 0.1 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (86 mg, 0.15 mmol) was added to N,N-dimethylformamide (2 mL), potassium carbonate (40 mg, 0.66 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. After the reaction was completed, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 20 mg of a yellow solid product, with a yield of 29.4%.

[0356] LC-MS (ESI): [M+H] + =679.5.

[0357] Step 6: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (20 mg, 0.03 mmol) was dissolved in dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (4 mg, 0.17 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with acetic acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent CH3CN: H2O (v / v) = 50%) to give 12.2 mg of a white solid product, with a yield of 62.2%.

[0358] LC-MS (ESI): [M+H] + =665.3.

[0359] 1 H NMR (400MHz,DMSO-d6) δ 8.57 (d,J=2.8Hz,1H),7.72 (s,1H),7.46 (q,J=8.2Hz,2H),7.20 (s,1H),7.09 (s,1H),6.92 (s,1H),6.55 (d,J=6.4Hz,1H),5.76 (s,2H),5.49 (s,2H),3.82 (q,J=7.2Hz,2H),2.95 - 2.82 (m,2H),2.66 (d,J=17.2Hz,1H),2.36 (dd,J=36.0,15.1Hz,2H),2.03 (d,J=13.0Hz,2H),1.90 (d,J=11.2Hz,1H),1.39 (d,J=6.9Hz,1H),0.99 (t,J=7.2Hz,3H).

[0360] Example 19 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid (Compound 19) [ka]

[0361] Step 1: Synthesis of methyl 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound methyl 5-amino-4-(2-methoxyethyl)amino)thiophene-2-carboxylate (106 mg, 0.46 mmol) and 2-(4-(6-(methoxymethoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (100 mg, 0.38 mmol) were added to acetic acid (1.5 mL) and reacted at 60° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v)=85%) to give 28 mg of a pale yellow solid, a yield of 17.1%.

[0362] LC-MS (ESI): [M+H] + =428.3.

[0363] Step 2: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (28 mg, 0.066 mmol) and potassium carbonate (27.1 mg, 0.196 mmol) were added to N,N-dimethylformamide (2 mL), and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (18.3 mg, 0.069 mmol) was added and reacted at 60 ° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 95%) to give 14.5 mg of a yellow solid in 36% yield.

[0364] LC-MS (ESI): [M+H] + =610.3.

[0365] Step 3: 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (14.5 mg, 0.0238 mmol) was added to a mixture of dioxane (0.1 mL) and water (0.05 mL). Lithium hydroxide (2.9 mg, 0.119 mmol) was added, and the mixture was incubated at 40 °C for 4 hours. The pH was adjusted to 5-6 with acetic acid (0.1 mL), concentrated under reduced pressure, and purified by pre-HPLC (eluent CHCN:HO (v / v) = 60%) to give 5.7 mg of a white solid in 40.2% yield.

[0366] LC-MS (ESI): [M+H] + =596.2.

[0367] 1HNMR (400MHz,DMSO-d6) δ 12.88 (s,1H),7.79 (s,1H),7.66 (t,J=7.8Hz,1H),7.43 - 7.38 (m,2H),7.06 (d,J=7.6Hz,1H),6.72 (d,J=8.4Hz,2H),6.52 (d,J=6.4Hz,1H),5.59 (s,2H),4.54 - 4.38 (m,2H),3.65 - 3.63 (m,2H),3.21 (s,3H),2.86 - 2.83 (m,2H),2.57 (s,1H),2.03 - 2.02 (m,2H),2.05 - 2.03 (m,1H),2.01 - 1.9 (m,2H), 1.44 - 1.42 (m,1H).

[0368] Example 20 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid (Compound 20) [ka]

[0369] Step 1: Synthesis of methyl 4-(2-methoxyethyl)amino-5-nitrothiophene-2-carboxylate The compound methyl 4-bromo-5-nitrothiophene-2-carboxylate (1 g, 3.76 mmol) and triethylamine (1.6 mL, 11.28 mmol) were added to dioxane (40 mL), and 2-methoxyethan-1-amine (0.4 mL, 4.51 mmol) was added. The mixture was heated to 110 °C under nitrogen gas protection and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:20) to give 800 mg of a yellow solid product in 81.8% yield.

[0370] LC-MS (ESI): [M+H] + =261.2.

[0371] Step 2: Synthesis of methyl 5-amino-4-(2-methoxyethyl)amino)thiophene-2-carboxylate The compound methyl 4-(2-methoxyethyl)amino-5-nitrothiophene-2-carboxylate (500 mg, 1.92 mmol) was added to acetic acid (5 mL), zinc powder (628 mg, 9.61 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (50 mL), and the mixture was concentrated under reduced pressure to give 440 mg of a gray oily product in 98.2% yield.

[0372] LC-MS (ESI): [M+H] + =231.2.

[0373] Step 3: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy))-1-toluene 5-Chloro-2-methylphenol (100 g, 701.36 mmol) was added to N,N-dimethylformamide (1 L), stirred, and dissolved. 2-Bromo-1,1-diethoxyethane (129.6 mL, 841.63 mmol) and potassium carbonate (193.86 g, 1402.72 mmol) were added, and the mixture was heated to 120 °C under nitrogen gas protection and reacted overnight. The reaction mixture was cooled to room temperature, added to ice water (5 L), and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed once with saturated brine (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 147 g of a pale yellow oily product in 81.0% yield.

[0374] Step 4: Synthesis of 4-chloro-7-methylbenzofuran Polyphosphoric acid (121.4 mL, 3049.15 mmol) was dissolved in 1,2-dichloroethane (1 L), 4-chloro-2-(2,2-diethoxyethoxy)-1-toluene (147 g, 568.14 mmol) was added, and the mixture was allowed to react overnight at 85°C. The reaction mixture was cooled to room temperature, poured into ice water (2 L), and extracted with dichloromethane (500 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:20) to give 51 g of a colorless oily product in 53.9% yield.

[0375] 1 H NMR (400MHz,DMSO-d6) δ 8.12 (d,J=2.0Hz,1H),7.24 (d,J=8.0Hz,1H),7.16 (d,J=8.0Hz,1H),6.99 (d,J=2.0Hz,1H),2.47 (s,3H).

[0376] Step 5: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran The compound 4-chloro-7-methylbenzofuran (31 g, 186.07 mmol) was added to 1,2-dichloroethane (300 mL), and N-bromosuccinimide (34.78 g, 195.38 mmol) and azodiisobutyronitrile (6.1 g, 37.21 mmol) were added. The mixture was purged with nitrogen gas and reacted at 75 °C overnight. The reaction mixture was cooled to room temperature, and a white solid precipitated and was filtered. The filter cake was washed with dichloromethane (50 mL × 3), and the filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane) to obtain 27.8 g of a white solid product in 60.9% yield.

[0377] 1 H NMR (400MHz,DMSO-d6) δ 8.23 ​​(d,J=2.0Hz,1H),7.45 (d,J=8.0Hz,1H),7.36 (d,J=8.0Hz,1H),7.07 (d,J=2.0Hz,1H),4.95 (s,2H).

[0378] Step 5: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran The compound 7-(bromomethyl)-4-chlorobenzofuran (5.8 g, 23.63 mmol) and N-fluoro-N-(benzenesulfonyl)benzenesulfonamide (9.0 g, 28.54 mmol) were added to tetrahydrofuran (100 mL) and cooled to -78 °C under nitrogen gas protection. Lithium diisopropylamide (2.0 N) (20 mL, 151.22 mmol) was slowly added and the reaction was allowed to proceed overnight at -78 °C. The reaction was quenched by adding water (20 mL) at -78 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane) to give 9.2 g of a white solid product in 14.8% yield.

[0379] 1 H NMR (400MHz, CDCl3) δ 7.22 (d,J=2.2Hz,2H),6.01 (d,J=6.7Hz,1H),4.65 (s,2H).

[0380] Step 6: Synthesis of methyl 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound 2-(4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (100 mg, 0.36 mmol) and methyl 5-amino-4-(2-methoxyethyl)amino)thiophene-2-carboxylate (100 mg, 0.43 mmol) were added to acetic acid (5 mL), and the reaction mixture was heated to 60 °C and reacted for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to give 66 mg of a brown oily product in 37.7% yield.

[0381] LC-MS (ESI): [M+H] + =491.4.

[0382] Step 7: Synthesis of methyl 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound methyl 2-((4-(5-fluoro-4-(methoxymethoxy)pyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (66 mg, 0.16 mmol) was added to dichloromethane (2 mL), and the reaction mixture was cooled to -10 °C under nitrogen gas protection. Trifluoroacetic acid (1 mL, 13.46 mmol) was added, and the reaction mixture was maintained at -10 °C and reacted overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to give 48 mg of a yellow oily product in 75% yield.

[0383] LC-MS (ESI): [M+H] + =447.3.

[0384] Step 8: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate The compound 2-((4-(5-fluoro-4-hydroxypyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (48 mg, 0.13 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (30 mg, 0.13 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (38 mg, 0.27 mmol) was added, and the mixture was heated to 60 ° C under nitrogen gas protection and reacted for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 1:20) to give 54 mg of a pale yellow solid product in 82.2% yield.

[0385] LC-MS (ESI): [M+H] + =629.4.

[0386] Step 9: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(2-methoxyethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylate (54 mg, 0.09 mmol) was added to dioxane (2 mL). Lithium hydroxide (18.0 mg, 0.43 mmol) was dissolved in water (0.5 mL) and added to the reaction mixture. The mixture was heated to 40 °C under nitrogen gas protection and reacted for 3 hours. The reaction mixture was adjusted to pH 4 with acetic acid, concentrated under reduced pressure, and purified by prep-HPLC (eluent: CHCN:HO (v / v) = 50%) to give 31 mg of a white solid product in 56.0% yield.

[0387] LC-MS (ESI): [M+H] + =615.2, 1H NMR (400MHz,DMSO-d6) δ 12.83 (s,1H),8.57 (d,J=2.8Hz,1H),7.76 (s,1H),7.46 (q,J=8.0Hz,2H),7.11 (s,1H),6.55 (d,J=6.4Hz,1H),5.76 (s,2H),4.36 (t,J=4.8Hz,2H),3.64 (t,J=5.2Hz,2H),3.21 (s,3H),2.89 - 2.79 (m,2H),2.72 - 2.62 (m,1H),2.48 - 2.40 (m,1H),2.38 - 2.27 (m,1H),2.26 - 2.16 (m,1H),2.11 - 1.99 (m,1H),1.96 - 1.89 (m,1H),1.48 - 1.38 (m,1H).

[0388] Example 21 Synthesis of 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 21) [ka]

[0389] Step 1: Synthesis of 5-fluoro-4-thio-3,4-dihydropyrimidin-2(1H)-one The compound 5-fluoropyrimidine-2,4(1H,3H)-dione (10 g, 76.9 mmol) was dissolved in pyridine (100 mL), and Lawesson's reagent (17.1 g, 42.3 mmol) was added. The mixture was purged with argon gas three times, heated to 140 °C, and reacted overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:DCM (v / v) = 1:10) to give 4.8 g of a yellow solid product in a 42.8% yield.

[0390] LC-MS (ESI): [M+H] + =147.2.

[0391] Step 2: Synthesis of 4-chloro-5-fluoropyrimidin-2-ol The compound 5-fluoro-4-thio-3,4-dihydropyrimidin-2(1H)-one (4.0 g, 27.37 mmol) was dissolved in acetonitrile (40 mL). Thionyl chloride (20 mL) was added and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, triturated with dichloromethane (20 mL), and filtered to obtain 4.0 g of a yellow solid product, with a yield of 88.6%.

[0392] LC-MS (ESI): [M+H] + =149.1.

[0393] Step 3: Synthesis of 4-chloro-5-fluoro-2-(methoxymethoxy)pyrimidine The compound 4-chloro-5-fluoropyrimidin-2-ol (4.0 g, 26.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), triethylamine (8.15 g, 80.7 mmol) was added, and the mixture was cooled to 0° C. Bromo(methoxy)methane (4.4 g, 35.0 mmol) was added, and the mixture was stirred at 0° C. for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:4) to obtain 800 mg of a colorless oily product, with a yield of 9.84%.

[0394] 1 HNMR (400MHz, CDCl3) δ 8.30 (s,1H),5.45 (s,2H),3.50 (s,3H).

[0395] Step 4: Synthesis of ethyl 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)acetate The compound 4-chloro-5-fluoro-2-(methoxymethoxy)pyrimidine (0.8 g, 4.15 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (1.59 g, 5.4 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). Potassium carbonate (1.72 g, 12.46 mmol) was added, the mixture was purged with nitrogen gas three times, Pd(dppf)Cl (0.3 g, 0.42 mmol) was added, the mixture was purged with nitrogen gas three times, and the mixture was stirred at 85 °C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:8) to give 900 mg of a colorless oily product in 66.8% yield.

[0396] LC-MS (ESI): [M+H] + =325.3.

[0397] Step 5: Synthesis of 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)ethan-1-ol The compound 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)ethyl acetate (900 mg, 2.77 mmol) was added to tetrahydrofuran (40 mL) and stirred at -78 °C for 5 minutes. DIBAL-H (10 mL, 8.31 mmol) was added and stirred at -78 °C for 1 hour. The mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:3) to obtain 513 mg of a colorless oily product in a 65.5% yield.

[0398] LC-MS (ESI): [M+H] + =283.3.

[0399] Step 6: Synthesis of 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)ethane The compound 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)ethan-1-ol (513 mg, 1.8 mmol) was added to dichloromethane (10 mL), Dess-Martin reagent (1.15 g, 2.7 mmol) was added, and the mixture was stirred in an ice bath for 1 hour, resulting in the precipitation of a large amount of solid. Saturated sodium bicarbonate (10 mL) was added, and the mixture was filtered through diatomaceous earth. The mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:6) to give 200 mg of a colorless oily product in a 40.0% yield.

[0400] LC-MS (ESI): [M+H] + =281.3.

[0401] Step 7: Synthesis of methyl 2-((4-(5-fluoro-2-hydroxypyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(5-fluoro-2-(methoxymethoxy)pyrimidin-4-yl)cyclohex-3-en-1-yl)acetaldehyde (200 mg, 0.71 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (169 mg, 0.71 mmol) were added to acetic acid (5 mL) and stirred at 60° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 198 mg of a light brown solid product, with a yield of 61.3%.

[0402] LC-MS (ESI): [M+H] + =453.5.

[0403] Step 8: Synthesis of methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((4-(5-fluoro-2-hydroxypyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.24 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (77 mg, 0.29 mmol) was added to N,N-dimethylformamide (5 mL), DIPEA (126 mg, 0.97 mmol) was added, and the mixture was stirred at 60 ° C. for 1 hour. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 15 mg of a white solid product, with a yield of 9.7%.

[0404] LC-MS (ESI): [M+H] + =635.4.

[0405] Step 9: Synthesis of 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-4-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (15 mg, 0.02 mmol) was dissolved in dioxane (1 mL) and water (0.25 mL). Lithium hydroxide (0.5 mg, 0.12 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with acetic acid, concentrated under reduced pressure, and purified by prep-HPLC (eluent: CHCN:HO (v / v) = 50%) to give 2.5 mg of a white solid product in a 16.9% yield.

[0406] LC-MS (ESI): [M+H] + =621.3, 1 HNMR (400MHz,DMSO-d6) δ 8.60 (d,J=3.2Hz,1H),8.20 (s,1H),7.79 (d,J=8.3Hz,1H),7.62 (d,J=8.3Hz,1H),7.45 - 7.40 (m,2H),6.84 (s,1H),6.54 (d,J=6.3Hz,1H),5.58 (s,2H),5.07 - 4.97 (m,1H),4.67 - 4.27 (m,4H),3.04 - 2.92 (m,2H),2.75 - 2.53 (m,3H),2.45 - 2.31 (m,3H),2.20 - 1.92 (m,2H),1.55 - 4.13 (m,1H).

[0407] Example 22 Synthesis of 2-((4-(2-((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)-1,3-thiazol-4-yl)cyclohex-3-enyl)methyl)-3-((2S)-oxan-2-yl)methyl)imidazole[4,5-b]pyridine-5-carboxylic acid (Compound 22) [ka]

[0408] Step 1: Synthesis of methyl 2-(4-(2-hydroxythiazol-4-yl)cyclohex-3-en-1-yl)methyl)-3-(S-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate The compound 2-(4-(2-(4-methoxybenzyl)oxy)thiazol-4-yl)cyclohex-3-en-1-yl)acetaldehyde (942 mg, 2.75 mmol) (see Step 9 of Example 14 for synthesis) and (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (652 mg, 2.75 mmol) were added to acetic acid (8 mL) and reacted at 60° C. for 2 hours. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to obtain 417 mg of a pale yellow solid product, with a yield of 34.5%.

[0409] LC-MS (ESI): [M+H] + =441.1.

[0410] Step 2: Synthesis of methyl 2-(4-(2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-3-(S-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate The compound 2-(4-(2-hydroxythiazol-4-yl)cyclohex-3-en-1-yl)methyl)-3-(S-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate (417 mg, 0.95 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250 mg, 0.95 mmol), and potassium carbonate (262 mg, 1.9 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at 60 ° C. for 2 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, and extracted with ethyl acetate (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:1) to give 120 mg of a pale yellow solid product in 20.3% yield.

[0411] LC-MS (ESI): [M+1] + =623.1, 1 HNMR (400MHz,DMSO-d6) δ 8.14 (d,J=4.0Hz,1H),8.00 (d,J=4.0Hz,1H),7.52 - 7.42 (m,2H),6.80 (s,1H),6.57 - 6.50 (m,2H),5.67 (s,2H),5.15 - 5.06 (m,1H) ,4.71 - 4.60 (m,1H),4.57 - 4.42 (m,2H),4.36 - 4.27 (m,1H),3.91 (s,3H),3.14 - 3.03 (m,2H),2.75 - 2.64 (m,1H),2.47 - 1.90 (m,8H).

[0412] Step 3: Synthesis of 2-((4-(2-((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)-1,3-thiazol-4-yl)cyclohex-3-enyl)methyl)-3-((2S)-oxan-2-yl)methyl)imidazole[4,5-b]pyridine-5-carboxylic acid The compound 2-(4-(2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)thiazol-4-yl)cyclohex-3-en-1-yl)methyl)-3-(S-oxetan-2-yl)methyl)-3H-imidazole[4,5-b]pyridine-5-carboxylate (120 mg, 0.19 mmol) and lithium hydroxide (22.8 mg, 0.95 mmol) were added to 1,4-dioxane (8 mL) and water (2 mL) and reacted at 40 ° C. for 1 hour. The mixture was cooled in an ice bath, adjusted to pH = 6 with acetic acid, concentrated under reduced pressure, and purified by pre-HPLC (eluent acetonitrile:water (v / v) = 80%) to give 25 mg of a white solid product, a yield of 26.1%.

[0413] LC-MS (ESI): [M+H] + =609.1, 1 HNMR (400MHz,DMSO-d6) δ 12.96 (s,1H),8.11 (d,J=4.0Hz,1H),7.98 (d,J=4.0Hz,1H),7.50 - 7.43 (m,2H),6.80 (s,1H),6.57 - 6.50 (m,2H),5.67 (s,2H),5.16 - 5.06 (m,1H) ,4.71 - 4.61 (m,1H),4.58 - 4.42 (m,2H),4.36 - 4.28 (m,1H),3.14 - 3.10 (m,2H),2.75 - 2.64 (m,1H),2.48 - 2.20 (m,5H),2.10 - 1.90 (m,2H), 1.57 - 1.41 (m,1H).

[0414] Example 23 Synthesis of 2-((3'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 23) [ka]

[0415] Step 1: Synthesis of 1-bromo-3-(methoxymethoxy)benzene 3-Bromophenol (1.0 g, 5.78 mmol) was added to N,N-dimethylformamide (10 mL) and cooled in an ice bath. Sodium hydride (60%, 350 mg, 14.45 mmol) was added and stirred in an ice bath for 10 minutes. Bromo(methoxy)methane (1.08 g, 8.67 mmol) was added and stirred at room temperature for 1 hour. Water (10 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:20) to give 1.2 g of a colorless oil in 96.0% yield.

[0416] 1 H NMR (400MHz, CDCl3) δ 7.14 (dd,J=2.5,1.3Hz,1H),7.08 - 7.04 (m,2H),6.89 (m,1H),5.08 (s,2H),3.40 (s,3H).

[0417] Step 2: Synthesis of ethyl 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate The compound 1-bromo-3-(methoxymethoxy)benzene (1.2 g, 5.53 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (2.44 g, 8.29 mmol) were added to 1,4-dioxane (20 mL) and water (5 mL). Potassium carbonate (2.29 g, 16.59 mmol) was added, the mixture was purged with nitrogen three times, Pd(PPh3)4 (192 mg, 0.0166 mmol) was added, the mixture was purged with nitrogen three times, and the mixture was stirred at 85 °C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:15) to give 1.03 g of a colorless oily product in 61.4% yield.

[0418] 1HNMR (400MHz,CDCl3) δ 7.15 (t,J=7.9Hz,1H),6.97 (dt,J=8.8,4.7Hz,2H),6.84 (dd,J=8.1,1.6Hz,1H),6.02 - 5.98 (m,1H),5.11 (s,2H),4.09 (q,J=7.1Hz,2H),3.42 (s,3H),2.43 - 2.36 (m,2H),2.36 - 2.24 (m,3H),2.16 - 2.04 (m,1H),1.92 - 1.81 (m,2H),1.43 - 1.36 (m,1H),1.21 (t,J=7.1Hz,3H).

[0419] Step 3: Synthesis of 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethan-1-ol The compound 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethyl acetate (1.03 g, 3.39 mmol) was added to tetrahydrofuran (20 mL) and stirred at 0 °C for 5 minutes. Lithium tetrahydroaluminum (0.64 g, 16.95 mmol) was added and stirred at 0 °C for 2 hours. Water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to obtain 0.57 g of a colorless oily product in 64.2% yield.

[0420] LC-MS (ESI): [M+H] + =263.4.

[0421] Step 4: Synthesis of 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetaldehyde The compound 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethan-1-ol (570 mg, 2.2 mmol) was added to dichloromethane (20 mL), Dess-Martin reagent (1.40 g, 3.3 mmol) was added, and the mixture was stirred in an ice bath for 1 hour. A large amount of solid precipitated. Water (5 mL) was added, and the mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:5) to give 250 mg of a colorless oily product in 44.2% yield.

[0422] LC-MS (ESI): [M+H] + =261.3.

[0423] Step 5: Synthesis of methyl 2-((3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetaldehyde (250 mg, 0.96 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (250 mg, 1.05 mmol) were added to acetic acid (10 mL) and stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:1) to obtain 200 mg of a light brown solid product in a 43.7% yield.

[0424] LC-MS (ESI): [M+H] + =477.6.

[0425] Step 6: Synthesis of methyl 2-((3'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((3'-(methoxymethoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (200 mg, 0.42 mmol) was added to dichloromethane (10 mL) and cooled to -10 °C. Trifluoroacetic acid (10 mL) was added and stirred at -10 °C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to give 50 mg of a light brown solid product, with a yield of 27.6%.

[0426] LC-MS (ESI): [M+H] + =433.4, 1 HNMR (400MHz,DMSO-d6) δ 9.28 (s,1H),8.24 (s,1H),7.81 (d,J=8.4Hz,1H),7.65 (d,J=8.4Hz,1H),7.09 (t,J=7.9Hz,1H),6.83 (d,J=7.8Hz,1H),6.77 (s,1H),6.62 (d,J=8.0Hz,1H),6.06 (s,1H),5.02 (d,J=7.1Hz,1H),4.66 (dd,J=15.5,7.4Hz,1H),4.53 (d,J=13.3Hz,1H),4.46 (dd,J=13.8,7.4Hz,1H),4.34 - 4.26 (m,1H),3.87 (s,3H),3.17 (s,1H),2.98 (dd,J=12.6,6.6Hz,2H),2.70 (dd,J=16.6,7.4Hz,1H),2.38 (d,J=9.8Hz,4H),1.99 (s,2H),1.50 (s,1H).

[0427] Step 7: Synthesis of methyl 2-((3'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((3'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.12 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (46 mg, 0.17 mmol) were added to N,N-dimethylformamide (3 mL), potassium carbonate (50 mg, 0.36 mmol) was added, and the mixture was stirred at 60°C for 1 hour. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 55 mg of an off-white solid product, with a yield of 77.5%.

[0428] LC-MS (ESI): [M+H] + =615.3.

[0429] Step 8: Synthesis of 2-((3'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((3'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (55 mg, 0.09 mmol) was added to dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (11 mg, 0.45 mmol) was added and stirred at room temperature for 4 hours. The pH was adjusted to 6-7 with 0.5 N hydrochloric acid, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent CH3CN: H2O (v / v) = 50%) to give 19.2 mg of a white solid product, with a yield of 35.8%.

[0430] LC-MS (ESI): [M+H] + =601.3, 1 HNMR (400MHz,DMSO-d6) δ 12.75 (s,1H),8.21 (s,1H),7.80 (dd,J=8.4,1.3Hz,1H),7.62 (d,J=8.4Hz,1H),7.45 (q,J=8.2Hz,2H),7.24 (t,J=7.9Hz,1H),7.10 - 6.99 (m,2H),6.92 (dd,J=8.1,1.9Hz,1H),6.55 (d,J=6.4Hz,1H),6.15 (s,1H),5.35 (s,2H),5.03 (d,J=6.9Hz,1H),4.65 (dd,J=15.5,7.1Hz,1H),4.56 - 4.40 (m,2H),4.31 (dt,J=12.0,5.9Hz,1H),3.07 - 2.91 (m,2H),2.70 (dt,J=16.3,8.0Hz,1H),2.47 - 2.24 (m,5H),2.10 - 1.93 (m,2H),1.52 (s,1H).

[0431] Example 24 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-2-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 24) [ka]

[0432] Step 1: Synthesis of 2-chloro-5-fluoropyridine 1-oxide The compound 2-chloro-5-fluoropyridine (10.0 g, 76.03 mmol) was added to trifluoroacetic acid (75 mL), and hydrogen peroxide (43 mL, 1428.70 mmol) was added dropwise in an ice bath. The reaction mixture was reacted at 70 °C overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and saturated sodium bicarbonate solution was added to adjust the pH to 6-7. The mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7.9 g of a pale yellow product, with a yield of 70.4%.

[0433] LC-MS (ESI): [M+H] + =148.2.

[0434] 1 HNMR (400MHz, CDCl3) δ 8.26 - 8.24 (m,1H),7.43 - 7.39 (m,1H),7.01 - 6.97 (m,1H).

[0435] Step 2: Synthesis of 6-chloro-3-fluoropyridin-2-ol 2-Chloro-5-fluoropyridine 1-oxide (7.9 g, 53.74 mmol) and triethylamine (6.79 mL, 53.53 mmol) were added to tetrahydrofuran (80 mL) and stirred for 0.5 h in an ice bath. Trifluoroacetic anhydride (20.54 mL, 150.42 mmol) was slowly added dropwise and stirred at room temperature overnight. The reaction was quenched by the addition of saturated sodium hydroxide solution, extracted with ethyl acetate (100 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 50%) to give 3.2 g of a pale yellow solid product in 40.0% yield.

[0436] LC-MS (ESI): [M+H] + =148.2, 1 HNMR (400MHz, DMSO-d6) δ 12.43 (s, 1H), 7.65 (t, J=8.0Hz, 1H), 6.94 - 6.86 (m, 1H).

[0437] Step 3: Synthesis of ethyl 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)acetate The compound 6-chloro-3-fluoropyridin-2-ol (1.2 g, 8.13 mmol), ethyl acetate (4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)cyclohex-3-enyl) (2.87 g, 9.76 mmol), bis(tri-tert-butylphosphine)palladium (4 mg, 0.01 mmol), and potassium carbonate (2.25 g, 16.26 mmol) were added to 1,4-dioxane (35 mL) and water (9 mL). The mixture was purged with nitrogen three times and stirred at 85 °C overnight. The mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 1:1) to give 250 mg of a pale yellow solid product in 11.0% yield.

[0438] LC-MS (ESI): [M+H] + =280.2, 1 HNMR (400MHz,DMSO-d6) δ 11.77 (s,1H),7.37 - 7.29 (m,1H),6.39 - 6.32 (m,1H),6.17 - 6.07 (m,1H),4.13 - 4.03 (m,2H),2.38 - 2.23 (m,5H),2.03 - 1.76 (m,3H),1.40 - 1.27 (m,1H),1.19 (t,J=8.0Hz,3H).

[0439] Step 4: Synthesis of 3-fluoro-6-(4-(2-hydroxyethyl)cyclohex-1-en-1-yl)pyridin-2-ol The compound 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (220 mg, 0.79 mmol) was added to tetrahydrofuran (20 mL), and lithium aluminum hydride (150 mg, 3.95 mmol) was added under ice bath conditions and stirred for 2 hours. The reaction was quenched by slow dropwise addition of water, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 140 mg of a pale yellow solid product in a 74.9% yield.

[0440] LC-MS (ESI): [M+H] + =238.1.

[0441] 1 HNMR (400MHz,DMSO-d6) δ 11.74 (s,1H),7.39 - 7.28 (m,1H),6.43 - 6.34 (m,1H),6.17 - 6.04 (m,1H),4.40 - 4.33 (m,1H),3.54 - 3.42 (m,2H),2.38 - 2.19 (m,3H),1.90 - 1.57 (m,3H),1.51 - 1.35 (m,2H),1.28 - 1.23 (m,1H).

[0442] Step 5: Synthesis of 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)acetaldehyde The compound 3-fluoro-6-(4-(2-hydroxyethyl)cyclohex-1-en-1-yl)pyridin-2-ol (120 mg, 0.51 mmol) was added to dimethyl sulfoxide (4 mL), and Dess-Martin oxidant (643 mg, 1.52 mmol) was added in an ice bath and stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 350 mg of a pale yellow crude product.

[0443] LC-MS (ESI): [M+H] + =236.1.

[0444] Step 6: Synthesis of methyl 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(S-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)acetaldehyde (350 mg, crude product) and methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (70 mg, 0.30 mmol) were added to acetic acid (3 mL), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 40 mg of a brown solid product, with a yield of 29.8%.

[0445] LC-MS (ESI): [M+1] + =452.2, 1 HNMR (400MHz,DMSO-d6) δ 11.75 (s,1H),7.91 - 7.84 (m,2H),7.83 - 7.78 (m,1H),7.14 - 7.06 (m,2H),6.15 - 6.09 (m,1H),5.06 - 4.97 (m,1H),4.72 - 4.60 (m,1H),4.59 - 4.40 (m,2H),4.35 - 4.25 (m,1H),3.87 (s,3H),3.01 - 2.92 (m,2H),2.75 - 2.63 (m,1H),2.46 - 2.20 (m,5H),2.08 - 1.88 (m,2H),1.54 - 1.39 (m,1H).

[0446] Step 7: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(5-fluoro-6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(S-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (35 mg, 0.08 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (41 mg, 0.16 mmol), and potassium carbonate (21 mg, 0.15 mmol) were added to N,N-dimethylformamide (3 mL) and stirred at 60 ° C. for 2 hours. The mixture was concentrated under reduced pressure, water (10 mL) was added, extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to obtain 15 mg of a brown solid product in 30.5% yield.

[0447] LC-MS (ESI): [M+H] + =634.2.

[0448] Step 8: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (15 mg, 0.02 mmol) and lithium hydroxide (3 mg, 0.13 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and stirred at 40° C. for 2 hours. Acetic acid was added dropwise until the solution became slightly acidic. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent acetonitrile:water (v / v) = 90%) to give 5 mg of a white solid product, with a yield of 34.1%.

[0449] LC-MS (ESI): [M+H] + =620.2, 1 HNMR (400MHz,DMSO-d6) δ 12.62 (s,1H),8.21 (s,1H),7.82 - 7.76 (m,1H),7.67 - 7.59 (m,2H),7.47 - 7.38 (m,2H),7.11- 7.05 (m,1H),6.66 (s,1H),6.53 (d,J=8.0Hz,1H),5.68 (s,2H),5.08- 4.98 (m,1H),4.70- 4.60 (m,1H),4.57- 4.40 (m,2H),4.35- 4.25 (m,1H),3.05- 2.92 (m,2H),2.75- 2.62 (m,1H),2.44- 2.24 (m,5H),2.11- 1.91 (m,2H),1.56- 1.40 (m,1H).

[0450] Example 25 Synthesis of 2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 25) [ka]

[0451] Step 1: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene 5-Chloro-2-methylphenol (15 g, 105.2 mmol), 2-bromo-1,1-diethoxyethane (25 g, 126.9 mmol), and potassium carbonate (29.1 g, 210.4 mmol) were added to N,N-dimethylformamide (50 mL) and reacted for 11 h at 120 °C under nitrogen gas protection. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (35 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 1% EtOAc:PE (v / v)) to give 21.1 g of a light brown liquid product in 77.5% yield.

[0452] 1 HNMR (500MHz,CDCl3) δ 7.03 (d,J=7.9Hz,1H),6.84 (dd,J=7.9,2.0Hz,1H),6.81 (d,J=2.0Hz,1H),4.84 (t,J=5.2Hz,1H),3.98 (d,J=5.2Hz,2H),3.81 - 3.74 (m,2H),3.68 - 3.62 (m,2H),2.18 (s,3H),1.25 (t,J=7.0Hz,6H).

[0453] Step 2: Synthesis of 4-chloro-7-methylbenzofuran The compound 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (23-1) (21 g, 81.2 mmol) and polyphosphoric acid (16.6 g, 202.9 mmol) were added to 1,2-dichloroethane (50 mL) and reacted overnight at 85 °C under nitrogen gas protection. After cooling to room temperature, the solvent was removed under reduced pressure, water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to obtain 9.2 g of a colorless liquid product, with a yield of 68.0%. 1 HNMR (500MHz, CDCl3) δ 7.63 (d,J=2.3Hz,1H),7.12 (d,J=7.9Hz,1H),7.00 (d,J=7.9Hz,1H),6.84 (d,J=2.3Hz,1H),2.48 (s,3H).

[0454] Step 3: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran Compound 4-chloro-7-methylbenzofuran (23-2) (4.1 g, 24.61 mmol), azodiisobutyronitrile (810 mg, 4.92 mmol), and N-bromosuccinimide (5.26 g, 29.53 mmol) were added to 1,2-dichloroethane (30 mL) and reacted overnight at 75 °C under nitrogen gas protection. After cooling to room temperature, water (50 mL) was added and extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to give 4.3 g of a colorless liquid product in 71.2% yield.

[0455] 1 HNMR (500MHz, CDCl3) δ 7.71 (s,1H),7.24 - 7.20 (m,2H),6.89 (s,1H),4.75 (s,2H).

[0456] Step 4: Synthesis of 7-(bromomethyl)-2,4-dichlorobenzofuran The compound 7-(bromomethyl)-4-chlorobenzofuran (5.8 g, 23.63 mmol) and hexachloroethane (5.59 g, 23.63 mmol) were added to anhydrous tetrahydrofuran (100 mL) and cooled to -50 °C under nitrogen gas protection. A solution of lithium diisopropylamide in tetrahydrofuran (2.0 mol / L, 20 mL, 40 mmol) was added and reacted at this temperature overnight. Water (300 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE(v) = 100%) to obtain 2.0 g of a white solid product, with a yield of 30.2%.

[0457] 1 HNMR (500MHz, CDCl3) δ 7.31 - 7.25 (m,2H),6.76 (s,1H),4.74 (s,2H).

[0458] Step 5: Synthesis of 2-bromo-6-((methoxymethyl)oxy)pyridine The compound 6-bromopyridin-2-ol (16 g, 92.0 mmol) was added to dichloromethane (160 mL), triethylamine (63.9 mL, 459.5 mmol) was added, and the mixture was stirred in an ice bath for 10 minutes. Bromo(methoxy)methane (23 g, 184.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL), extracted with dichloromethane (30 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:20) to give 5.2 g of a colorless oily product in 25.9% yield.

[0459] 1 HNMR (400MHz,DMSO-d6) δ 7.72 (d,J=7.8Hz,1H),7.28 (d,J=7.3Hz,1H),6.93 (d,J=7.9Hz,1H),5.42 (s,2H),3.42 (s,3H).

[0460] Step 6: Synthesis of methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-bromo-6-((methoxymethyl)oxy)pyridine (5.2 g, 23.8 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate (7.68 g, 27.4 mmol) were added to 1,4-dioxane (60 mL) and water (15 mL). Potassium carbonate (6.59 g, 47.7 mmol) was added, the mixture was purged with nitrogen gas three times, Pd(dppf)Cl (0.52 g, 0.72 mmol) was added, the mixture was purged with nitrogen gas three times, and the mixture was stirred at 85 °C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:15) to give 4.0 g of a colorless oily product in 57.6% yield.

[0461] 1HNMR (400MHz,CDCl3) δ 7.48 (t,J=7.8Hz,1H),6.90 (d,J=7.5Hz,1H),6.68 (dd,J=3.1,1.9Hz,1H),6.57 (d,J=8.1Hz,1H),5.49 (s,2H),3.62 (s,3H),3.45 (d,J=3.2Hz,3H),2.53 (dd,J=16.5,3.0Hz,1H),2.46 - 2.31 (m,2H),2.28 (d,J=7.2Hz,2H),2.17 - 2.03 (m,1H),1.96 - 1.84 (m,2H),1.38 (m,1H).

[0462] Step 7: Synthesis of 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)ethyl-1-ol The compound (4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)methyl acetate (1.5 g, 5.2 mmol) was added to tetrahydrofuran (30 mL) and stirred at -20 °C for 5 minutes. Lithium tetrahydroaluminum (0.39 g, 10.3 mmol) was added and stirred at 0 °C for 2 hours. Water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to obtain 1.3 g of a colorless oily product in a 95.9% yield.

[0463] LC-MS (ESI): [M+H] + =264.3.

[0464] Step 8: Synthesis of 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)acetaldehyde The compound 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)ethyl-1-ol (600 mg, 2.2 mmol) was added to dichloromethane (20 mL), Dess-Martin reagent (1.45 g, 3.4 mmol) was added, and the mixture was stirred in an ice bath for 3 hours, resulting in the precipitation of a large amount of solid. Water (4 mL) was added, and the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:5) to give 260 mg of a colorless oily product in 43.7% yield.

[0465] LC-MS (ESI): [M+H] + =262.1.

[0466] Step 9: Synthesis of methyl 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-enyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-(4-(6-((methoxymethyl)oxy)pyridin-2-yl)cyclohex-3-enyl)acetaldehyde (700 mg, 2.68 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methyl benzoate (633 mg, 2.68 mmol) were added to acetic acid (10 mL), stirred at 60° C. for 1 hour, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 20:1) to give 420 mg of a pale green solid product, the yield was 36.2%.

[0467] LC-MS (ESI): [M+H] + =434.6.

[0468] Step 10: Synthesis of methyl 2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.23 mmol) and 7-(bromomethyl)-2,4-dichlorobenzofuran (98 mg, 0.35 mmol) were added to N,N-dimethylformamide (5 mL), potassium carbonate (159 mg, 1.15 mmol) and stirred at 60 °C for 1 hour. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:1) to give 95 mg of a pale yellow solid product in 65.1% yield.

[0469] LC-MS (ESI): [M+H] + =632.5.

[0470] Step 11: Synthesis of 2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound methyl 2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-xanthen-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (95 mg, 0.15 mmol) was added to dioxane (5 mL) and water (1.25 mL). Lithium hydroxide (22 mg, 0.9 mmol) was added and stirred at room temperature for 4 hours. The pH was adjusted to 6-7 with acetic acid (0.2 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent CH3CN: H2O (v / v) = 50%) to give 33.8 mg of a white solid product, with a yield of 36.4%.

[0471] LC-MS (ESI): [M+H] + =618.3.

[0472] 1 HNMR (400MHz,DMSO-d6) δ 12.74 (s,1H),8.21 (d,J=1.6Hz,1H),7.79 (dd,J=8.5,1.6Hz,1H),7.66 (t,J=7.8Hz,1H),7.62 (d,J=8.4Hz,1H),7.47 - 7.36 (m,2H),7.18 (s,1H),7.07 (d,J=7.5Hz,1H),6.72 (d,J=8.2Hz,1H),6.70 (s,1H),5.61 (s,2H),5.05 - 4.99 (m,1H),4.68 - 4.60 (m,1H),4.55 - 4.42 (m,2H),4.32 - 4.27 (m,1H),3.04 - 2.90 (m,2H),2.73 - 2.64 (m,1H),2.58 - 2.51 (m,1H),2.42 - 2.27 (m,4H),2.10 - 1.93 (m,2H),1.54 - 1.42 (m,1H).

[0473] Example 26 Synthesis of 2-((4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxa-2-yl-methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 26) [ka]

[0474] Step 1: Synthesis of 4-bromo-2-(2,2-diethoxyethoxy))-1-toluene The compound 5-bromo-2-methylphenol (25 g, 134.4 mmol), 2-bromo-1,1-diethoxyethane (31.8 g, 162.3 mmol), and potassium carbonate (37.1 g, 268.8 mmol) were added to N,N-dimethylformamide (250 mL) and stirred overnight at 120 °C under nitrogen gas protection. After completion of the reaction, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1%) to obtain 40 g of a light brown liquid product in 98.5% yield.

[0475] Step 2: Synthesis of 4-bromo-7-methylbenzofuran The compound 4-bromo-2-(2,2-diethoxyethoxy)-1-toluene (40 g, 132.2 mmol) and polyphosphoric acid (68 g, 829.4 mmol) were added to 1,2-dichloroethane (400 mL) and reacted overnight at 85 °C under nitrogen gas protection. The solvent was removed under reduced pressure, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE = 100%) to obtain 17 g of a colorless liquid product with a yield of 60.8%.

[0476] 1 HNMR (400MHz,CDCl3) δ 7.68 (d,J=4Hz,1H),7.30 - 7.26 (m,1H),6.97 (d,J=8.0Hz,1H),6.80 (d,J=4Hz,1H),2.48 (s,3H).

[0477] Step 3: Synthesis of 7-methylbenzofuran-4-cyano The compound 4-bromo-7-methylbenzofuran (16 g, 75.8 mmol) was added to N,N-dimethylformamide (160 mL), and cuprous cyanide (33.95 g, 378.5 mmol) was added. The mixture was reacted overnight at 120 °C under nitrogen gas protection. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE = 100%) to obtain 8.3 g of a colorless liquid product in 69.7% yield.

[0478] 1 HNMR (400MHz, CDCl3) δ 7.78 (d,J=4Hz,1H),7.49 (d,J=8Hz,1H),7.16 (d,J=8Hz,1H),6.98 (s,1H),2.59 (s,3H).

[0479] Step 4: Synthesis of 2-chloro-7-methylbenzofuran-4-cyano The compound 7-methylbenzofuran-4-cyano (1 g, 6.4 mmol) was added to tetrahydrofuran (15 mL). The mixture was cooled to -78 °C under nitrogen gas protection. At this temperature, lithium diisopropylamide (2.6 mL) was added and stirred for 1 hour. Hexachloroethane (1.6 g, 6.8 mmol) was added, the cryopump was removed, and the mixture was stirred overnight. The mixture was diluted with water (45 mL) at 0 °C and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 5%) to obtain 800 mg of a colorless liquid product, with a yield of 65.6%.

[0480] 1 HNMR (400MHz, CDCl3) δ 7.48 (d,J=8Hz,1H),7.15(d,J=8Hz,1H),6.81 (s,1H),2.56 (s,3H).

[0481] Step 5: Synthesis of 7-(bromomethyl)-2-chlorobenzofuran-4-cyano The compound 2-chloro-7-methylbenzofuran-4-cyano (800 mg, 4.2 mmol), azodiisobutyronitrile (137 mg, 0.8 mmol), and N-bromosuccinimide (1.1 g, 6.2 mmol) were added to 1,2-dichloroethane (36 mL) and reacted overnight at 85 °C under nitrogen gas protection. The mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1%) to give 700 mg of a colorless liquid product in 61.9% yield.

[0482] 1 HNMR (400MHz, CDCl3) δ 7.56 (d,J =8.0Hz,1H),7.39 (d,J=8.0Hz,1H),6.86 (s,1H),4.71 (s,2H).

[0483] Step 6: Synthesis of methyl 2-((4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxa-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound methyl 2-((4-(6-hydroxypyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-ox-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.23 mmol) (see Example 25, Step 9 for synthesis), 7-(bromomethyl)-2-chlorobenzofuran-4-cyano (74 mg, 0.27 mmol) and potassium carbonate (95.6 The resulting mixture (20 mL, 0.68 mmol) was added to N,N-dimethylformamide (5 mL) and reacted at 60° C. for 1.5 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 50%) to give 79 mg of a colorless oily product in a 48.7% yield.

[0484] LC-MS: [M+H] + =623.3.

[0485] Step 7: Synthesis of 2-((4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxa-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxa-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (79 mg, 0.13 mmol) and lithium hydroxide (15.2 mg, 0.63 mmol) were added to 1,4-dioxane (1.6 mL) and water (0.4 mL) and reacted at 40 °C for 3 hours. The pH was adjusted to 6-7 with acetic acid (0.2 mL). The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: acetonitrile:water (v / v) = 40%) to give 34 mg of a white solid product in 44% yield.

[0486] LC-MS: [M+H] + =609.2, 1 HNMR (400MHz,DMSO-d6) δ 12.69 (s,1H),8.20 (d,J=1.6Hz,1H),7.85 - 7.76 (m,2H),7.68 (t,J=7.8Hz,1H),7.62 (d,J=8.4Hz,1H),7.56 (d,J=7.9Hz,1H),7.39 (s,1H),7.07 (d,J=7.5Hz,1H),6.77 (d,J=8.1Hz,1H),6.63 (s,1H),5.70 (s,2H),5.03 - 5.01 (m,1H),4.67 - 4.28 (m,4H),3.04 - 2.89 (m,2H),2.73 - 2.64 (m,1H),2.45 - 2.28 (m,5H),2.08 - 1.92 (m,2H),1.51 - 1.40 (m,1H).

[0487] Example 27 Synthesis of 2-(((1s,4R)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 27A) and 2-(((1r,4S)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 27B) [ka]

[0488] Step 1: Synthesis of 4-chloro-2-fluoro-7-methylbenzofuran The compound 4-chloro-7-methylbenzofuran (20 g, 120 mmol) was added to anhydrous tetrahydrofuran (500 mL) and cooled to -78 °C under nitrogen gas protection. n-Butyllithium (2.5 mol / L tetrahydrofuran / cyclohexane solution) (58 mL, 145 mmol) and N-fluorobisbenzenesulfonamide (41.6 g, 132 mmol) were slowly added and reacted at this temperature for 4 h. An aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE(v) = 100%) to obtain 9.45 g of a colorless liquid product in a 42.6% yield.

[0489] 1 HNMR (500MHz,CDCl3) δ 7.13 (d,J=8.1Hz,1H),6.97 (d,J=8.0Hz,1H),5.94 (d,J=6.6Hz,1H),2.42 (s,3H).

[0490] Step 2: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran The compound 4-chloro-2-fluoro-7-methylbenzofuran (11.4 g, 61.76 mmol) and azodiisobutyronitrile (2.03 g, 12.35 mmol) were added to 1,2-dichloroethane (120 mL), and N-bromosuccinimide (16.49 g, 92.64 mmol) was slowly added. The mixture was then reacted overnight at 85 ° C under nitrogen gas protection. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to obtain 9.8 g of a white solid product in a 60.2% yield.

[0491] 1 HNMR (500MHz,CDCl3) δ 7.24 - 7.20 (m,2H),6.01 (d,J=6.6Hz,1H),4.65 (s,2H).

[0492] Step 3: Synthesis of ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate The compound 4-oxocyclohexaneethyl acetate (20 g, 108.55 mmol) and 2,6-di-tert-butylpyridine (24.92 g, 130.3 mmol) were added to dichloromethane (160 mL), cooled in an ice bath, and trifluoromethanesulfonic anhydride (35.22 g, 124.84 mmol) was added dropwise. The mixture was allowed to react at room temperature for 2.5 h. The organic phase was washed with water (40 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 5%) to obtain 24.56 g of a colorless liquid product, with a yield of 71.5%.

[0493] 1HNMR (500MHz,CDCl3) δ 5.72 (s,1H),4.15 (q,J=7.1Hz,2H),2.49 - 2.39 (m,1H),2.38 - 2.31 (m,2H),2.30 (d,J=7.1Hz,2H),2.18 - 2.09 (m,1H),1.97 - 1.89 (m,2H),1.57 - 1.48 (m,1H),1.26 (t,J=7.1Hz,3H).

[0494] Step 4: Synthesis of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)ethyl acetate (26 g, 82.1 mmol), bis(pinacolato)diboron (25 g, 98.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene]dichloride palladium dichloromethane complex (3.35 g, 4.1 mmol), and potassium acetate (16.1 g, 164.2 mmol) were added to 1,4-dioxane (300 mL) and reacted at 100 °C for 2 h under nitrogen gas protection. The mixture was cooled to room temperature, quenched by adding water (300 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 5%) to obtain 19.5 g of a pale yellow liquid product in an 81% yield.

[0495] 1 HNMR (500MHz,CDCl3) δ 6.50 (s,1H),4.15 - 4.10 (m,2H),2.30 - 2.19 (m,4H),2.15 - 2.03 (m,2H),1.84 - 1.73 (m,2H),1.40 - 1.28 (m,1H),1.25 (s,12H),1.28 - 1.23 (m,3H).

[0496] Step 5: Synthesis of ethyl 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate The compound 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (29 g, 98.5 mmol), 2-benzyloxy-6-bromopyridine (26 g, 98.5 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (4.02 mg, 4.93 mmol), and potassium carbonate (273 g, 197.2 mmol). The residue was added to 1,4-dioxane (240 mL) and water (60 mL), reacted at 100°C under nitrogen gas protection for 2 h, cooled to room temperature, filtered by suction, added water (300 mL) to the filtrate, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 7%) to give 23.43 g of a pale yellow liquid product, the yield was 67.6%.

[0497] 1 HNMR (500MHz,CDCl3) δ 7.51 (t,J=7.8Hz,1H),7.49 - 7.44 (m,2H),7.36 (t,J=7.4Hz,2H),7.29 (t,J=7.4Hz,1H),6.93 (d,J=7.4Hz,1H),6.78 (tt,J=3.8,1.7Hz,1H),6.63 (d,J=8.2Hz,1H),5.41 (s,2H),4.16 (q,J=7.1Hz,2H),2.66 - 2.59 (m,1H),2.52 - 2.40 (m,2H),2.34 (d,J=7.2Hz,2H),2.23 - 2.13 (m,1H),2.04 - 1.93 (m,2H),1.52 - 1.42 (m,1H),1.27 (t,J=7.2Hz,3H).

[0498] Step 6: Synthesis of ethyl 2-((1s,4s)-4-(6-hydroxypyridin-2-yl)cyclohexyl)acetate (27A-1) and ethyl 2-((1r,4r)-4-(6-hydroxypyridin-2-yl)cyclohexyl)acetate (27B-1) 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (23.43 g, 66.67 mmol) was dissolved in ethanol (180 mL), 10% palladium carbon (water content 60%, 2.3 g) was added, and the mixture was purged with hydrogen gas three times. The mixture was reacted overnight with hydrogen gas at room temperature and atmospheric pressure, and the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and triturated with methyl tert-butyl ether (50 mL). A white solid product (13.18 g) was obtained, with a yield of 75.1%. Chiral separation (instrument: SFC-80, separation column: CHIRALCEL OD (30*250mm 5μm) Daircel, column temperature: 35℃, mobile phase: A=CO2, 20%B=IPA, flow rate: 45mL / min) gave 11.5min pre-peak 27A-1 and 14.3min post-peak 27B-1, with a 1:1 ratio of 27A-1 to 27B-1.

[0499] 27A-1: 1 HNMR (400MHz,CDCl3) δ 12.45 (brs,1H),7.39 (dd,J=9.0,6.9Hz,1H),6.47 (d,J=9.0Hz,1H),6.11 (d,J=6.9Hz,1H),4.14 (q,J=7.1Hz,2H),2.56 (d,J=7.8Hz,2H),2.05 - 1.80 (m,5H),1.56 - 1.43 (m,2H),1.26 (t,J=7.1Hz,3H),1.25 - 1.08 (m,2H). LC-MS (ESI): [M+H] + =264.2.

[0500] 27B-1: 1HNMR (400MHz,CDCl3) δ 12.05 (brs,1H),7.37 (dd,J=9.1,6.9Hz,1H),6.40 (d,J=9.0Hz,1H),6.04 (d,J=6.9Hz,1H),4.13 (q,J=7.2Hz,2H),2.52 - 2.41 (m,1H),2.23 (d,J=6.7Hz,2H),2.05 - 1.80 (m,5H),1.56 - 1.43 (m,2H),1.26 (t,J=7.1Hz,3H),1.25 - 1.08 (m,2H). LC-MS (ESI): [M+H] + =264.2.

[0501] Step 7: Synthesis of ethyl 2-((1s,4s)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetate (27A-2) and ethyl 2-((1r,4r)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetate (27B-2) Synthesis of 27A-2 Compound 27A-1 (1.0 g, 38.0 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (1.05 g, 3.99 mmol), and cesium carbonate (2.48 g, 7.5.9 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at room temperature for 2 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 10%) to give 1.52 g of a colorless liquid product in an 89.8% yield.

[0502] LC-MS (ESI): [M+H] + =446.2.

[0503] Synthesis of 27B-2 Compound 27B-1 (10 g, 37.97 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (10.5 g, 39.85 mmol), and cesium carbonate (24.75 g, 75.95 mmol) were added to N,N-dimethylformamide (100 mL) and reacted at room temperature for 2 h. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 8-30%) to give 15.2 g of a colorless liquid product in 89.8% yield.

[0504] 1 HNMR (500MHz,CDCl3) δ 7.48 (t,J=7.8Hz,1H),7.32 (d,J=8.2Hz,1H),7.22 (d,J=8.2Hz,1H),6.71 (d,J=7.3Hz,1H),6.59 (d,J=8.2Hz,1H),6.00 (d,J=6.6Hz,1H),5.59 (s,2H),4.15 (q,J=7.2Hz,2H),2.55 - 2.50 (m,1H),2.24 (d,J=6.7Hz,2H),1.95 - 1.83 (m,5H),1.61 - 1.52 (m,2H),1.28 (t,J=7.2Hz,3H),1.20 - 1.09 (m,2H). LC-MS (ESI): [M+H] + =446.3.

[0505] Step 8: Synthesis of 2-((1s,4s)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetic acid (27A-3) and 2-(4-(6-(((1r,4r)-4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetic acid (27B-3) Synthesis of 27A-3 27A-2 (1.32 g, 2.96 mmol) was dissolved in 1,4-dioxane (10 mL) and water (5 mL), and lithium hydroxide monohydrate (1.2 g, 29.6 mmol) was added. The mixture was reacted at 60°C for 1.5 h, cooled in an ice bath, and diluted hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.3 g of a pale yellow solid product, with a yield of 91.1%.

[0506] 1 H NMR (500MHz,DMSO-d6) δ 11.96 (s,1H),7.62 (t,J=7.8Hz,1H),7.39 (q,J=8.2Hz,2H),6.88 (d,J=7.3Hz,1H),6.68 (d,J=8.2Hz,1H),6.49 (d,J=6.3Hz,1H),5.58 (s,2H),2.70 - 2.63 (m,1H),2.21 (d,J=7.5Hz,2H),2.10 - 1.95 (m,1H),1.83 - 1.71 (m,2H),1.63 - 1.49 (m,4H),1.48 - 1.39 (m,2H). LC-MS (ESI): [M+H] = 418.2.

[0507] Synthesis of 27B-3 Compound 27B-2 (15 g, 33.64 mmol) was dissolved in 1,4-dioxane (100 mL) and water (50 mL), and lithium hydroxide monohydrate (7.06 g, 168.2 mmol) was added. The mixture was reacted at 60°C for 2 h, cooled in an ice bath, and diluted hydrochloric acid was added to adjust the pH to 4. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 13.2 g of a pale yellow solid product, with a yield of 93.9%.

[0508] 1H NMR (500MHz,DMSO-d6) δ 11.99 (s,1H),7.60 (t,J=7.8Hz,1H),7.40 (q,J=8.2Hz,2H),6.82 (d,J=7.3Hz,1H),6.66 (d,J=8.2Hz,1H),6.49 (d,J=6.4Hz,1H),5.56 (s,2H),2.50 - 2.45 (m,1H),2.13 (d,J=6.9Hz,2H),1.85 - 1.75 (m,4H),1.73 - 1.64 (m,1H),1.51 - 1.39 (m,2H),1.15 - 1.03 (m,2H). LC-MS (ESI): [M+H] = 418.2.

[0509] Step 9: Synthesis of methyl 4-(2-((1s,4R)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (27A-4) and methyl 4-(2-((1r,4S)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (27B-4) Synthesis of 27A-4 Compound 27A-3 (1.13 g, 2.43 mmol), (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methylbenzoate (580 mg, 2.43 mmol), and HOAT (500 mg, 3.65 mmol) were added to N,N-dimethylformamide (10 mL), EDCI (940 mg, 4.84 mmol) and N,N-diisopropylethylamine (790 mg, 6.08 mmol), and the mixture was allowed to react overnight at 40 °C. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 0 to 5%) to give a white solid product (1.04 g, 67.1%).

[0510] 1HNMR (500MHz,CDCl3) δ 7.77 (d,J=7.8Hz,1H),7.66 (s,1H),7.55 (d,J=8.5Hz,1H),7.52 (d,J=8.1Hz,2H),7.31 (d,J=8.1Hz,1H),7.22 (d,J=8.3Hz,1H),6.79 (d,J=7.4Hz,1H),6.61 (d,J=8.3Hz,1H),5.99 (d,J=6.5Hz,1H),5.60 (s,2H),5.04 - 4.96 (m,1H),4.70 - 4.66 (m,1H),4.58 - 4.51 (m,1H),3.89 (s,3H),3.42 - 3.21 (m,2H),2.80 - 2.65 (m,2H),2.55 - 2.46 (m,1H),2.43 - 2.35 (m,2H),2.31 - 2.24 (m,1H),2.02 - 1.87 (m,3H),1.81 - 1.65 (m,5H). LC-MS (ESI): [M+H] + =636.3.

[0511] Synthesis of 27B-4 Compound 27B-3 (13.2 g, 31.59 mmol), (S)-4-amino-3-((oxetan-2-ylmethyl)amino)methylbenzoate (7.46 g, 31.59 mmol), and HOAT (5.59 g, 41.07 mmol) were added to N,N-dimethylformamide (130 mL), cooled in an ice bath, EDCI (9.08 g, 47.38 mmol) and N,N-diisopropylethylamine (9.17 g, 63.18 mmol) were added, and the reaction was continued at 40 °C overnight. The reaction mixture was slowly poured into ice water (1.1 L), suction filtered, and the filter cake was washed with water (30 mL × 2). The filter cake was triturated with EtOAc:PE (v / v) = 1:1 to give 13.6 g of a white solid product, with a yield of 71.2%.

[0512] 1HNMR (500MHz,CDCl3) δ 7.81 (d,J=8.3Hz,1H),7.70 (s,1H),7.58 (d,J=8.3Hz,1H),7.53 (s,1H),7.48 (t,J=7.7Hz,1H),7.32 (d,J=8.2Hz,1H),7.22 (d,J=8.2Hz,1H),6.71 (d,J=7.4Hz,1H),6.58 (s,1H),6.00 (d,J=6.6Hz,1H),5.59 (s,2H),5.09 - 5.02 (m,1H),4.78 - 4.71 (m,1H),4.64 - 4.57 (m,1H),3.89 (s,3H),3.45 - 3.29 (m,2H),2.78 - 2.71 (m,1H),2.59 - 2.50 (m,2H),2.37 - 2.30 (m,2H),2.01 - 1.91 (m,5H),1.66 - 1.56 (m,2H),1.25 - 1.15 (m,2H). LC-MS (ESI): [M+H] + =636.4.

[0513] Step 10: Synthesis of methyl 2-(((1s,4R)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (27A-5) and methyl 2-(((1r,4S)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (27B-5) Synthesis of 27A-5 Compound 27A-4 (940 mg, 1.48 mmol) was added to glacial acetic acid (10 mL) and reacted at 80°C for 4 h. The solvent was removed under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (10 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 15 to 75%) to give 670 mg of a pale yellow solid product in a 73.6% yield.

[0514] 1 HNMR (500MHz,CDCl3) δ 8.07 (s,1H),7.95 (d,J=10.0Hz,1H),7.73 (d,J=8.5Hz,1H),7.52 (t,J=7.7Hz,1H),7.33 (d,J=8.3Hz,1H),7.24 (d,J=8.4Hz,1H),6.81 (d,J=7.4Hz,1H),6.61 (d,J=8.2Hz,1H),6.00 (d,J=6.6Hz,1H),5.61 (s,2H),5.19 - 5.11 (m,1H),4.59 - 4.55 (m,1H),4.46 - 4.28 (m,3H),3.94 (s,3H),3.00 (d,J=7.3Hz,2H),2.83 - 2.75 (m,1H),2.74 - 2.64 (m,1H),2.48 - 2.34 (m,2H),2.10 - 1.99 (m,2H),1.83 - 1.53 (m,6H). LC-MS (ESI): [M+H] + =618.4.

[0515] Synthesis of 27B-5 Compound 27B-4 (13.5 g, 21.22 mmol) was added to glacial acetic acid (150 mL) and reacted at 80 °C for 2 h. The solvent was removed under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. The mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 40 ~ 60%) to give 12 g of a light brown solid product in 91.5% yield.

[0516] 1 HNMR (500MHz,CDCl3) δ 8.09 (s,1H),7.96 (dd,J=8.5,1.6Hz,1H),7.74 (d,J=8.4Hz,1H),7.47 (t,J=7.7Hz,1H),7.31 (d,J=8.3Hz,1H),7.22 (d,J=8.2Hz,1H),6.71 (d,J=7.3Hz,1H),6.58 (d,J=8.2Hz,1H),5.99 (d,J=6.6Hz,1H),5.58 (s,2H),5.21 - 5.17 (m,1H),4.64 - 4.60 (m,1H),4.48 - 4.35 (m,3H),3.94 (s,3H),2.94 (d,J=7.3Hz,2H),2.77 - 2.70 (m,1H),2.61 - 2.52 (m,1H),2.47 - 2.40 (m,1H),2.18 - 2.07 (m,1H),2.00 - 1.91 (m,4H),1.67 - 1.53 (m,4H). LC-MS (ESI): [M+H] + =618.5.

[0517] Step 11: Synthesis of 2-(((1s,4R)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (27A) and 2-(((1r,4S)-4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexyl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (27B) Synthesis of 27A Compound 27A-5 (530 mg, 0.86 mmol) and lithium hydroxide monohydrate (181 mg, 4.29 mmol) were added to 1,4-dioxane (10 mL) and water (5 mL) and reacted at 40°C for 2 h. Water (30 mL) was added, and the pH was adjusted to 6 with 2 M diluted hydrochloric acid in an ice bath. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH: DCM (v / v) = 3%) to give 470 mg of a white solid product, with a yield of 90.7%.

[0518] 1 HNMR (500MHz,DMSO-d6) δ 12.64 (s,1H),8.18 (s,1H),7.79 (d,J=8.4Hz,1H),7.68 - 7.59 (m,2H),7.42 (q,J=8.2Hz,2H),6.93 (d,J=7.3Hz,1H),6.69 (d,J=8.1Hz,1H),6.48 (d,J=6.3Hz,1H),5.59 (s,2H),5.04 - 4.96 (m,1H),4.64 - 4.55 (m,1H),4.52 - 4.38 (m,2H),4.30 - 4.22 (m,1H),2.97 (d,J=7.3Hz,2H),2.75 - 2.59 (m,2H),2.42 - 2.28 (m,2H),2.01 - 1.87 (m,2H),1.72 - 1.51 (m,6H). LC-MS (ESI): [M+H] + =604.5.

[0519] Synthesis of 27B Compound 27B-5 (11.5 g, 18.61 mmol) and lithium hydroxide monohydrate (2.34 g, 55.82 mmol) were added to 1,4-dioxane (80 mL) and water (40 mL) and reacted at 40 °C for 2 h. Water (200 mL) was added, and the pH was adjusted to 6 with trifluoroacetic acid in an ice bath. The mixture was filtered under suction, washed once with water (50 mL), dissolved in dichloromethane, and the organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) to give 8.2 g of a white solid product in 71% yield. Compound 27B was grown as a single crystal, and single crystal diffraction showed that compound 27B was trans.

[0520] 1 HNMR (500MHz,DMSO-d6) δ 12.66 (s,1H),8.21 (s,1H),7.79 (dd,J=8.3,1.5Hz,1H),7.61 (dd,J=15.6,8.0Hz,2H),7.43 - 7.37 (m,2H),6.84 (d,J=7.3Hz,1H),6.66 (d,J=8.2Hz,1H),6.49 (d,J=6.4Hz,1H),5.56 (s,2H),5.07 - 5.00 (m,1H),4.67 - 4.60 (m,1H),4.55 - 4.45 (m,2H),4.35 - 4.29 (m,1H),2.95 - 2.84 (m,2H),2.74 - 2.67 (m,1H),2.58 - 2.51 (m,1H),2.42 - 2.35 (m,1H),2.08 - 1.97 (m,1H),1.92 - 1.77 (m,4H),1.54 - 1.44 (m,2H),1.27 - 1.18 (m,2H). LC-MS (ESI): [M+H] + =604.3.

[0521] Example 28 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 28) [ka]

[0522] Step 1: Synthesis of tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate The compound (1-(aminomethyl)cyclopropyl)methanol (2.5 g, 24.72 mmol) and di-tert-butyl dicarbonate (2.5 g, 24.72 mmol) were dissolved in DCM (50 mL), and diisopropylethylamine (8.2 mL, 49.43 mmol) was added. The mixture was stirred at room temperature for 3 h. Stirring was stopped, water (40 mL) was added, and the mixture was extracted three times with dichloromethane (15 mL × 3). The organic phases were combined, washed twice with dilute hydrochloric acid (1 M), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated. The product was purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 3:2) to give 4.24 g of a pale yellow viscous material in 85.2% yield.

[0523] 1 H NMR (500MHz,CDCl3) δ 4.98 (s,1H),3.37 (d,J=6.5Hz,2H),3.25 (s,1H),3.10 (d,J=6.4Hz,2H),1.44 (d,J=5.8Hz,9H),0.45 - 0.40 (m,4H).

[0524] Step 2: Synthesis of (1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl methanesulfonate The compound ((1-(hydroxymethyl)cyclopropyl)methyl) tert-butyl carbamate (1.81 g, 8.99 mmol) was dissolved in DCM (40 mL) and triethylamine (2.5 mL, 17.99 mmol) was added. Methanesulfonyl chloride (0.8 mL, 10.79 mmol) was slowly added at 0 °C, and the reaction was continued with stirring for 2 h. Stirring was stopped, and the reaction was quenched by adding water (50 mL). The mixture was extracted three times with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give 2.0 g of a pale yellow viscous material, with a yield of 79.6%.

[0525] Step 3: Synthesis of tert-butyl ((1-(cyanomethyl)cyclopropyl)methyl)carbamate The compound (1-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)methyl methanesulfonate (2.0 g, 7.16 mmol) and cyanotrimethylsilane (1.9 mL, 14.32 mmol) were dissolved in acetonitrile (30 mL). Tetrabutylammonium fluoride (4.2 mL, 14.32 mmol) was added, and the mixture was heated to 80 °C and reacted for 2 h. Heating was stopped and the mixture was cooled to room temperature. The solvent was concentrated, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 10:1) to obtain 850 mg of a pale yellow solid in 56.5% yield.

[0526] 1 H NMR (500MHz,CDCl3) δ 4.75 (s,1H),3.13 (d,J=6.4Hz,2H),2.48 (s,2H),1.44 (s,9H),0.61 (d,J=3.7Hz,4H).

[0527] Step 4: Synthesis of 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride The compound ((1-(cyanomethyl)cyclopropyl)methyl) tert-butyl carbamate (700 mg, 3.33 mmol) was dissolved in DCM (10 mL) and then a solution of hydrochloric acid in 1,4-dioxane (1 mL) was added. The mixture was stirred at room temperature for 4 h. The stirring was stopped, and the solvent was concentrated to give 400 mg of a white solid, with a yield of 81.9%.

[0528] LC-MS (ESI): [M-HCl+ H] + =111.2.

[0529] Step 5: Synthesis of methyl 3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate The compound methyl 3-fluoro-4-nitrobenzoate (500 mg, 2.51 mmol) and 2-(1-(aminomethyl)cyclopropyl)acetonitrile hydrochloride (368 mg, 2.51 mmol) were dissolved in a mixture of tetrahydrofuran (12 mL) and methanol (8 mL). Triethylamine (2.1 mL, 15.06 mmol) was added and the mixture was heated to 60 °C for 6 h. Stirring was stopped, the solvent was concentrated, and the mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 5:1) to give 240 mg of a yellow solid, a yield of 33.0%.

[0530] LC-MS (ESI): [M+ H] + =290.0.

[0531] Step 6: Synthesis of methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate The compound methyl 3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (230 mg, 0.80 mmol) was dissolved in a mixture of ethyl acetate (8 mL) and ethanol (8 mL). Palladium on carbon (23 mg, 10% Pd, containing 40-60% water) was added, and the mixture was protected with hydrogen gas and reacted at room temperature overnight. The reaction mixture was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:1) to give 130 mg of a white solid in 63.1% yield.

[0532] 1 H NMR (500MHz,CDCl3) δ 7.49 (dd,J=8.1,1.9Hz,1H),7.30 (d,J=1.8Hz,1H),6.69 (d,J=8.1Hz,1H),4.05 - 3.88 (m,2H),3.85 (s,3H),3.13 (s,3H),2.56 (s,2H),0.71 (dt,J=6.2,2.0Hz,4H) LC-MS (ESI): [M+H] + =260.2.

[0533] Step 7: Synthesis of methyl 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate The compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid (150 mg, 0.36 mmol) and methyl 4-amino-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (112 mg, 0.43 mmol) were added to N,N-dimethylformamide (4 mL), and HATU (247 mg, 0.65 mmol) and DIPEA (140 mg, 1.08 mmol) were added, followed by reaction at 40° C. overnight. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:2) to give 215 mg of a light brown solid product, with a yield of 90.7%.

[0534] 1 HNMR (500MHz,CDCl3) δ 7.71 - 7.66 (m,1H),7.57 - 7.51 (m,2H),7.41 (d,J=1.9Hz,1H),7.32 (d,J=8.2Hz,1H),7.22 (d,J=8.2Hz,1H),6.95 (d,J=7.4Hz,1H),6.76 (s,1H),6.64 (d,J=8.1Hz,1H),5.99 (d,J=6.6Hz,1H),5.62 (s,2H),3.89 (s,3H),3.16 (s,2H),2.80 (s,2H),2.67 - 2.59 (m,1H),2.52 - 2.42 (m,4H),2.34 - 2.26 (m,1H), 2.10 - 2.00 (m,2H), 1.59 - 1.49 (m,1H), 0.74 - 0.71 (m,4H). (No peak for NH LC-MS (ESI): [M+H] + =657.4.

[0535] Step 8: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-(((1-(cyanomethyl)cyclopropyl)methyl)amino)benzoate (210 mg, 0.32 mmol) was added to glacial acetic acid (5 mL) and reacted at 70 °C for 9 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and concentrated under reduced pressure (10 mL × 2). The product was purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 45%) to give 135 mg of a light brown solid product in 66.1% yield.

[0536] 1 HNMR (500MHz,CDCl3) δ 8.15 (s,1H),7.98 (d,J=8.5Hz,1H),7.75 (d,J=8.5Hz,1H),7.52 (t,J=7.9Hz,1H),7.31 (d,J=8.2Hz,1H),7.22 (d,J=8.2Hz,1H),6.94 (d,J=7.5Hz,1H),6.74 (d,J=4.8Hz,1H),6.64 (d,J=8.2Hz,1H),5.99 (d,J=6.5Hz,1H),5.61 (s,2H),4.36 (s,2H),3.96 (s,3H),3.04 - 2.94 (m,2H),2.69 - 2.60 (m,1H),2.56 - 2.40 (m,3H),2.32 (s,2H),2.15 - 1.96 (m,3H),0.79 (d,J=3.6Hz,2H),0.77 (d,J=3.6Hz,2H). LC-MS (ESI): [M+H] + =639.4.

[0537] Step 9: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (135 mg, 0.21 mmol) and lithium hydroxide monohydrate (62 mg, 1.48 mmol) were added to 1,4-dioxane (3 mL) and water (3 mL), and the reaction was carried out at 40 ° C. for 1 h. The mixture was cooled in an ice bath, adjusted to pH = 4 with 2 M diluted hydrochloric acid, added with water (40 mL), and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH: DCM (v / v) = 10%) to obtain 96 mg of a white solid product, with a yield of 69.6%.

[0538] 1 HNMR (500MHz,DMSO-d6) δ 12.76 (s,1H),8.22 (s,1H),7.81 (d,J=8.3Hz,1H),7.66 (t,J=8.4Hz,2H),7.47 - 7.34 (m,2H),7.07 (d,J=7.4Hz,1H),6.80 - 6.68 (m,2H),6.49 (d,J=6.4Hz,1H),5.59 (s,2H),4.45 (s,2H),3.03 - 2.91 (m,2H),2.60 (s,2H),2.55 - 2.42 (m,2H),2.41 - 2.29 (m,2H),2.16 - 1.91 (m,2H),1.57 - 1.44 (m,1H),0.66 (d,J=15.5Hz,4H). LC-MS (ESI): [M+H-HCl] + =625.4.

[0539] Example 29 Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid hydrochloride (Compound 29) [ka]

[0540] Step 1: Synthesis of 1-ethyl-1-hydro-imidazole-5-formamide The compound 1-ethyl-1-hydro-imidazole-5-carboxylic acid (485 mg, 3.46 mmol) was dissolved in thionyl chloride (6 mL) and DMF (0.05 mL) was added. The mixture was heated to 80 °C and reacted for 5 h, then cooled to room temperature. The solvent was concentrated, and tetrahydrofuran (10 mL) was added. Aqueous ammonia (3 mL, 19.47 mmol) was slowly added, and the mixture was stirred at room temperature overnight. The stirring was stopped, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to obtain 266 mg of a white solid in 55.2% yield.

[0541] LC-MS (ESI): [M+H] + =140.2.

[0542] Step 2: Synthesis of (1-ethyl-1-hydro-imidazol-5-yl)methylamine hydrochloride The compound 1-ethyl-1-hydro-imidazole-5-formamide (1.0 g, 7.19 mmol) was dissolved in THF (35 mL) and borane dimethyl sulfide (7.2 mL, 14.37 mmol) was added. The mixture was heated to 70 °C and stirred for 8 h. Methanol (10 mL) was slowly added and the mixture was stirred at room temperature for 10 min. Then, a solution of hydrochloric acid in 1,4-dioxane (1 mL) was added and the mixture was stirred for 2 h. A white solid precipitated. The solvent was concentrated to give 842 mg of a white solid, with a yield of 85.1%.

[0543] LC-MS (ESI): [M-HCl+ H] + =126.3.

[0544] Step 3: Synthesis of methyl 3-(((1-ethyl-1-hydro-imidazol-5-yl)methyl)amino)-4-nitrobenzoate The compound methyl 3-fluoro-4-nitrobenzoate (600 mg, 3.01 mmol) and (1-ethyl-1-hydro-imidazol-5-yl)methylamine hydrochloride (487 mg, 3.01 mmol) were dissolved in a mixture of THF (15 mL) and methanol (10 mL). Triethylamine (2.5 mL, 18.08 mmol) was added, and the mixture was heated to 60 °C and reacted overnight. Stirring was stopped, the solvent was concentrated, and the mixture was diluted with water (30 mL) and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was purified by silica gel column chromatography (DCM:MeOH (v / v) = 15:1) to obtain 482 mg of a yellow solid, with a yield of 52.6%.

[0545] 1 H NMR (500MHz,CDCl3) δ 8.22 (d,J=8.8Hz,1H),7.92 (t,J=5.1Hz,1H),7.67 (d,J=1.9Hz,1H),7.54 (s,1H),7.31 (dd,J=8.9,1.7Hz,1H),7.09 (s,1H),4.52 (d,J=4.9Hz,2H),3.99 (q,J=7.3Hz,2H),3.94 (s,3H),1.46 (t,J=7.4Hz,3H). LC-MS (ESI): [M+ H] + =305.3.

[0546] Step 4: Synthesis of methyl 4-amino-3-(((1-ethyl-1-hydro-imidazol-5-yl)methyl)amino)benzoate The compound methyl 3-(((1-ethyl-1-hydro-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (400 mg, 1.31 mmol) was dissolved in methanol (15 mL) and placed under palladium carbon (210 mg, 10% Pd, containing 40-60% water), protected with hydrogen gas, and stirred overnight at room temperature. The stirring was stopped, the mixture was filtered through diatomaceous earth, the solvent was concentrated, and the mixture was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 303 mg of a white solid, a yield of 84.0%.

[0547] 1 H NMR (500MHz,CDCl3) δ 7.49 (d,J=8.3Hz,1H),7.46 (s,1H),7.42 (s,1H),6.89 (s,1H),6.68 (d,J=8.1Hz,1H),4.24 (s,2H),3.99 (q,J=7.3Hz,2H),3.86 (s,3H),1.43 (t,J=7.4Hz,3H). LC-MS (ESI): [M+ H] + =275.2.

[0548] Step 5: Synthesis of methyl 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate The compound 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid (200 mg, 0.48 mmol) and methyl 4-amino-3-(((1-ethyl-1-hydro-imidazol-5-yl)methyl)amino)benzoate (158 mg, 0.58 mmol) were added to N,N-dimethylformamide (4 mL), and HATU (329 mg, 0.87 mmol) and DIPEA (155 mg, 1.20 mmol) were added, followed by reaction at 40° C. overnight. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 5%) to give 209 mg of a light brown solid product, with a yield of 64.7%.

[0549] 1 HNMR (500MHz,CDCl3) δ 7.81 (s,1H),7.79 (br.s,1H),7.54 - 7.46 (m,3H),7.43 (s,1H),7.30 (d,J=8.1Hz,1H),7.21 (d,J=8.2Hz,1H),7.03 (s,1H),6.91 (d,J=7.5Hz,1H),6.71 (s,1H),6.63 (d,J=8.2Hz,1H),5.98 (d,J=6.6Hz,1H),5.59 (s,2H),4.30 (s,2H),4.07 - 4.00 (m,2H),3.88 (s,3H),2.59 - 2.51 (m,1H),2.47 - 2.36 (m,5H),2.03 - 1.92 (m,3H),1.45 (t,J=7.3Hz,3H). LC-MS (ESI): [M+H] + =672.4.

[0550] Step 6: Synthesis of methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 4-(2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)methyl benzoate (200 mg, 0.30 mmol) was added to glacial acetic acid (5 mL) and reacted at 70 °C for 20 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate and concentrated under reduced pressure (20 mL × 2). The product was purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 10%) to give 106 mg of a pale yellow solid product in 54.5% yield.

[0551] 1 HNMR (500MHz,CDCl3) δ 8.07 - 7.94 (m,2H),7.77 (d,J=8.2Hz,1H),7.56 - 7.47 (m,2H),7.31 (d,J=7.9Hz,1H),7.29 - 7.20 (m,1H),6.93 (d,J=7.4Hz,1H),6.76 (d,J=6.9Hz,1H),6.72 (s,1H),6.64 (d,J=8.0Hz,1H),5.99 (d,J=6.6Hz,1H),5.61 (s,2H),5.36 (s,2H),3.93 (s,3H),3.82 (q,J=7.2Hz,2H),2.94 - 2.84 (m,2H),2.64 - 2.54 (m,1H),2.50 - 2.37 (m,2H),2.38 - 2.27 (m,1H),2.06 - 1.94 (m,2H),1.59 - 1.50 (m,1H),1.25 (d,J=5.5Hz,3H). LC-MS (ESI): [M+H] + =654.4.

[0552] Step 7: Synthesis of 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid hydrochloride The compound 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.15 mmol) and lithium hydroxide monohydrate (52 mg, 1.24 mmol) were added to 1,4-dioxane (3 mL) and water (3 mL), and the reaction was carried out at 40 °C for 1.5 h. The mixture was cooled in an ice bath, adjusted to pH = 6 with 2 M diluted hydrochloric acid, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH: DCM (v / v) = 18%) to obtain 73 mg of a white solid product, with a yield of 74.6%.

[0553] 1 HNMR (500MHz,DMSO-d6) δ 8.13 (s,1H),7.82 (d,J=8.4Hz,1H),7.72 - 7.61 (m,3H),7.45 - 7.36 (m,2H),7.04 (d,J=7.4Hz,1H),6.75 - 6.67 (m,2H),6.49 (d,J=6.3Hz,1H),6.45 (s,1H),5.64 (s,2H),5.59 (s,2H),3.96 (q,J=7.7Hz,2H),2.99 - 2.86 (m,2H),2.56 - 2.49 (m,1H),1.42 - 2.24 (m,2H),2.20 - 2.10 (m,1H),2.04 - 1.87 (m, 2H), 1.49 - 1.37 (m, 1H), 1.13 (t, J = 7.8 Hz, 3H). (No COOH peak) LC-MS (ESI): [M+H-HCl] + =640.4.

[0554] Example 30 Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexenyl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 30) [ka]

[0555] Step 1: Synthesis of 6-chloro-5-nitro-2-carboxylic acid pyridine The compound 2-chloro-6-methyl-3-nitropyridine (8.0 g, 46.36 mmol) was added to concentrated sulfuric acid (40 mL), and potassium dichromate (20.46 g, 69.54 mmol) was slowly added at room temperature. The reaction was stirred overnight at room temperature. Ice water (500 mL) was slowly added under ice bath conditions, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.26 g of a pale yellow solid (88.0% yield).

[0556] LC-MS (ESI): [M+H] + =203.0.

[0557] Step 2: Synthesis of 6-chloro-5-nitro-2-methylpyridine carboxylate The compound 6-chloro-5-nitro-2-carboxylic acid pyridine (200 mg, 0.99 mmol) was dissolved in methanol (15 mL), concentrated sulfuric acid (0.5 mL, 0.99 mmol) was added, and the mixture was heated to 68 °C and reacted overnight. The solvent was concentrated, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent PE: EtOAc (v / v) = 2:1) to give 185 mg of a white solid, with a yield of 86.5%.

[0558] LC-MS (ESI): [M+ H] + =217.1, 1 H NMR (500MHz,CDCl3) δ 8.31 (dd,J=8.3,0.8Hz,1H),8.22 (dd,J=8.2,0.8Hz,1H),4.04 (d,J=0.9Hz,3H).

[0559] Step 3: Synthesis of methyl (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate The compound 6-chloro-5-nitro-2-methylpyridine carboxylate (1.3 g, 6.0 mmol) and (S)-oxetane-2-methylamine (0.58 g, 6.6 mmol) were dissolved in tetrahydrofuran (20 mL), and potassium carbonate (1.24 g, 9.00 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 2:1) to give 1.09 g of a yellow solid, a yield of 68.0%.

[0560] LC-MS (ESI): [M+ H] + =268.2, 1 H NMR (500MHz,DMSO-d6) δ 8.58 (dd,J=8.4,1.0Hz,1H),8.51 (t,J=5.8Hz,1H),7.31 (dd,J=8.4,1.0Hz,1H),5.01 - 4.93 (m,1H),4.56 -4.52 (m,1H),4.48 - 4.45 (m,1H),3.96 - 3.87 (m,4H),3.82 (dt,J=13.8,5.2Hz,1H),2.68 - 2.58 (m,1H),2.53 - 2.49 (m,1H).

[0561] Step 4: Synthesis of methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate The compound (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (1.09 g, 4.08 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL), and palladium on carbon (10% Pd, containing 40-60% water, 185 mg, 1.74 mmol) was added. The mixture was protected with hydrogen gas. The reaction was stirred at room temperature for 8 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The product was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 885 mg of an oily yellow viscous product in 91.5% yield.

[0562] LC-MS (ESI): [M+ H] + =238.1, 1H NMR (500MHz,DMSO-d6) δ 7.23 (d,J=7.8Hz,1H),6.68 (d,J=7.8Hz,1H),5.95 (t,J=5.6Hz,1H),5.61 (s,2H),4.92 - 4.87 (m,1H),4.54 - 4.50 (m,1H),4.45 (dt,J=9.0,5.9Hz,1H),3.72 (s,4H),3.62 (dt,J=13.8,5.2Hz,1H),2.65 - 2.57 (m,1H),2.44 - 2.39 (m,1H).

[0563] Step 5: Synthesis of 2-(benzyloxy)-6-bromopyridine The compound 2-bromo-6-hydroxypyridine (2.0 g, 11.49 mmol) and benzyl bromide (2.16 g, 12.64 mmol) were dissolved in DMF (15 mL), and potassium carbonate (3.18 g, 22.99 mmol) was added. The mixture was heated to 60 °C and reacted for 2 h. The mixture was then cooled to room temperature. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (25 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 5% EtOAc:PE (v / v)) to give 2.1 g of a colorless liquid product, with a yield of 69.2%.

[0564] Step 6: Synthesis of ethyl 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetate 2-(Benzyloxy)-6-bromopyridine (500 mg, 1.97 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (608 mg, 2.07 mmol), potassium carbonate (408 mg, 2.95 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichloride palladium(II) dichloromethane complex (80 mg, 0.10 mmol) were added to 1,4-dioxane (8 mL) and water (2 mL). The mixture was heated to 90 °C under nitrogen gas protection and reacted for 4.5 h. The mixture was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 673 mg of a colorless liquid product, with a yield of 97.3%.

[0565] 1 H NMR (500MHz,CDCl3) δ 7.51 (t,J=7.8Hz,1H),7.48 - 7.44 (m,2H),7.36 (t,J=7.4Hz,2H),7.29 (t,J=7.4Hz,1H),6.93 (d,J=7.4Hz,1H),6.78 (tt,J=3.8,1.7Hz,1H),6.63 (d,J=8.2Hz,1H),5.41 (s,2H),4.16 (q,J=7.1Hz,2H),2.66 - 2.59 (m,1H),2.51 - 2.40 (m,2H),2.34 (d,J=7.2Hz,2H),2.22 - 2.15 (m,1H),2.02 - 1.94 (m,2H),1.52 - 1.44 (m,1H),1.27 (t,J=7.2Hz,3H).

[0566] Step 7: Synthesis of 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid The compound 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (490 mg, 1.39 mmol) and lithium hydroxide monohydrate (293 mg, 6.98 mmol) were added to 1,4-dioxane (5 mL) and water (4 mL) and reacted at 50 °C for 2 h. The pH was adjusted to 4 with dilute hydrochloric acid in an ice bath and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 386 mg of a pale yellow solid, a yield of 85.6%.

[0567] LC-MS (ESI): [M+H] + =324.2, 1 H NMR (500MHz,CDCl3) δ 7.51 (t,J=7.8Hz,1H),7.46 (d,J=7.6Hz,2H),7.36 (t,J=7.5Hz,2H),7.33 - 7.26 (m,1H),6.93 (d,J=7.4Hz,1H),6.77 (d,J=4.2Hz,1H),6.64 (d,J=8.2Hz,1H),5.41 (s,2H),2.68 - 2.60 (m,1H),2.54 - 2.44 (m,2H),2.40 (d,J=7.2Hz,2H),2.26 - 2.14 (m,1H),2.05 - 1.96 (m,2H),1.55 - 1.46 (m,1H).

[0568] Step 8: Synthesis of methyl 5-(2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetic acid (375 mg, 1.16 mmol) and (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (250 mg, 1.05 mmol) were added to N,N-dimethylformamide (5 mL), HATU (601 mg, 1.58 mmol) and DIPEA (341 mg, 2.64 mmol) were added, and the mixture was reacted at 50 ° C overnight. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 70%) to obtain 301 mg of a light brown oily product, with a yield of 52.6%.

[0569] LC-MS (ESI): [M+H] + =543.4, 1 H NMR (500MHz,CDCl3) δ 8.06 - 7.98 (m,2H),7.53 - 7.44 (m,4H),7.37 - 7.25 (m,3H),6.92 (d,J=7.4Hz,1H),6.75 (s,1H),6.64 (d,J=8.0Hz,1H),5.40 (s,2H),5.30 - 5.21 (m,1H),5.08 - 5.00 (m,1H),4.70 - 4.61 (m,1H),4.59 - 4.50 (m,1H),3.91 (s,3H),3.82 - 3.73 (m,1H),2.69 - 2.56 (m,2H),2.54 - 2.35 (m,4H),2.32 - 2.21 (m,1H),2.08 - 1.84 (m,3H),1.54 - 1.44 (m,1H).

[0570] Step 9: Synthesis of 2-((4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound 5-(2-(4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)methyl benzoate (500 mg, 0.92 mmol) was dissolved in tetrahydrofuran (15 mL), potassium tert-butoxide (259 mg, 2.31 mmol) was added, and the reaction was carried out at 85°C for 2 hours. The solvent was removed under reduced pressure, water (50 mL) was added, and the pH was adjusted to 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 463 mg of a light brown solid product, with a yield of 98.4%.

[0571] LC-MS (ESI): [M+H] + =511.4.

[0572] Step 10: Synthesis of methyl 2-((4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound 2-((4-(6-(benzyloxy)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (0.7 g, 1.37 mmol), methanol (439 mg, 13.7 mmol), and 1-hydroxy-7-azobenzotriazole (280 mg, 2.06 mmol) were dissolved in a mixture of dichloromethane (10 mL) and DMF (5 mL), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (657 mg, 3.43 mmol) was added. The mixture was cooled in an ice bath, and DIPEA (532 mg, 4.12 mmol) was added. The mixture was reacted at room temperature overnight, the solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 60%) to obtain 208 mg of a white solid, with a yield of 28.9%.

[0573] LC-MS (ESI): [M+H] + =525.5.

[0574] Step 11: Synthesis of (S)-2-((4-(6-hydroxypyridin-2-yl)cyclohexenyl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylate (190 mg, 0.36 mmol) was dissolved in methanol (5 mL), and palladium carbon (118 mg, 10% Pd, containing 40-60% water) was added. The mixture was reacted overnight at room temperature under hydrogen gas protection at 1 atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated to give 127 mg of a pale yellow viscous product, with a yield of 80.3%.

[0575] LC-MS (ESI): [M+ H] + =437.4.

[0576] Step 12: Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexenyl)methyl)-3-(-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate The compound (S)-2-((4-(6-hydroxypyridin-2-yl)cyclohexenyl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg, 0.23 mmol) was dissolved in DMF (5 mL), and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (61 mg, 0.23 mmol) and potassium carbonate (143 mg, 1.03 mmol) were added. The mixture was reacted at 60°C for 3 h, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 40%) to give 35 mg of a yellow oil, with a yield of 24.6%.

[0577] LC-MS (ESI): [M+H] +=619.5, 1 HNMR (500MHz,CDCl3) δ 8.08 (d,J=8.2Hz,1H),8.03 (d,J=8.3Hz,1H),7.52 (t,J=7.9Hz,1H),7.37 - 7.29 (m,1H),7.24 (d,J=8.3Hz,1H),6.81 (d,J=7.3Hz,1H),6.61 (d,J=8.2Hz,1H),5.99 (d,J=6.6Hz,1H),5.61 (s,2H),5.21 - 5.17 (m,1H),4.64 - 4.53 (m,3H),4.35 - 4.30 (m,1H),3.99 (s,3H),3.16 - 3.05 (m,2H),2.83 - 2.68 (m,2H),2.52 - 2.42 (m,2H),2.07 - 1.99 (m,2H),1.83 - 1.62 (m,6H).

[0578] Step 13: Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexenyl)methyl)-3-(-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid The compound (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)cyclohexenyl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (35 mg, 0.06 mmol) and lithium hydroxide monohydrate (13 mg, 0.31 mmol) were added to 1,4-dioxane (3 mL) and water (1.5 mL), and the reaction was carried out at 40 °C for 1 h. The pH was adjusted to 6 with 2 M diluted hydrochloric acid in an ice bath, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH: DCM (v / v) = 5%) to obtain 25 mg of a pale yellow solid product, with a yield of 71.4%.

[0579] LC-MS (ESI): [M+H] + =605.4, 1 HNMR (500MHz,CDCl3) δ 8.24 - 8.13 (m,2H),7.52 (t,J=8.0Hz,1H),7.36 - 7.32 (m,1H),7.25 (d,J=8.3Hz,1H),6.82 (d,J=7.4Hz,1H),6.62 (d,J=8.3Hz,1H),6.00 (d,J=6.6Hz,1H),5.62 (s,2H),5.24 - 5.15 (m,1H),4.65 - 4.46 (m,3H),4.39 - 4.29 (m,1H),3.81 - 3.63 (m,2H),3.16 - 3.04 (m,2H),2.83 - 2.70 (m,2H),2.52 - 2.39 (m,2H),2.09 - 1.95 (m,2H),1.86 - 1.67 (m,4H).

[0580] Example 31 Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 31) [ka]

[0581] Step 1: Synthesis of methyl (4-chloro-2-fluorobenzofuran-7-yl)acetate The compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (0.60 g, 2.28 mmol) was added to DMF (12 mL) and potassium acetate (1.10 g, 11.21 mmol) was added. The reaction was allowed to proceed at 50 °C for 1.5 h. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 5% EtOAc:PE (v / v)) to give 340 mg of a pale yellow liquid. The yield was 61.5%.

[0582] Step 2: Synthesis of (4-chloro-2-fluorobenzofuran-7-yl)methanol The compound (4-chloro-2-fluorobenzofuran-7-yl)methyl acetate (340 mg, 1.40 mmol) was added to a mixture of 1,4-dioxane (9 mL) and water (3 mL), followed by the addition of lithium hydroxide monohydrate (177 mg, 4.22 mmol). The reaction was allowed to proceed at room temperature for 2 h. The mixture was diluted with water (6 mL) and extracted three times with ethyl acetate (3 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by silica gel column chromatography (eluent: 20% EtOAc:PE (v / v)) to give 222 mg of a white solid (79.0% yield).

[0583] 1 H NMR (500MHz,CDCl3) δ 7.24 (s,2H),6.00 (d,J=6.6Hz,1H),4.92 (d,J=6.1Hz,2H).

[0584] Step 3: Synthesis of 2-chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine The compound (4-chloro-2-fluorobenzofuran-7-yl)methanol (222 mg, 1.11 mmol) and 2,4-dichloro-5-fluoropyrimidine (194 mg, 1.16 mmol) were dissolved in acetonitrile (10 mL), and cesium carbonate (545 mg, 1.67 mmol) was added under ice bath conditions. The mixture was warmed to room temperature and reacted for 14 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The product was purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to give 318 mg of a white solid in 86.8% yield.

[0585] LC-MS (ESI): [M+H] + =331.1, 1H NMR (500MHz,DMSO-d6) δ 8.64 (d,J=2.6Hz,1H),7.50 (d,J=8.2Hz,1H),7.46 (d,J=8.3Hz,1H),6.55 (d,J=6.4Hz,1H),5.73 (s,2H).

[0586] Step 4: Synthesis of ethyl 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetate 2-Chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (200 mg, 0.60 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (213 mg, 0.72 mmol), potassium carbonate (167 mg, 1.21 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichloride palladium(II) dichloromethane complex (49 mg, 0.06 mmol) were added to 1,4-dioxane (4 mL) and water (1 mL). The mixture was heated to 90 °C under nitrogen gas protection and reacted for 5 h. The reaction was quenched by adding water (100 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 183 mg of a colorless liquid product, with a yield of 65.5%.

[0587] LC-MS (ESI): [M+H] += 463.3, 1H NMR (500MHz,CDCl3) δ 8.27 (d,J=2.6Hz,1H),7.32 (d,J=8.2Hz,1H),7.26 (d,J=8.2Hz,1H),7.11 (s,1H),6.02 (d,J=6.6Hz,1H),5.73 (s,2H),4.16 (q,J=7.1Hz,2H),2.76 - 2.67 (m,1H),2.50 - 2.42 (m,2H),2.35 - 2.31 (m,2H),2.22 - 2.12 (m,1H),2.06 - 1.90 (m,2H),1.47 - 1.39 (m,1H),1.27 (t,J=8.8Hz,3H).

[0588] Step 5: Synthesis of 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetic acid The compound 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)ethyl acetate (170 mg, 0.37 mmol) and lithium hydroxide monohydrate (78 mg, 1.86 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40 °C for 1 h. Dilute hydrochloric acid was added in an ice bath to adjust the pH to 4, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 156 mg of a pale yellow solid, with a yield of 97.7%.

[0589] LC-MS (ESI): [M+H] + =435.2, 1H NMR (500MHz,CDCl3) δ 8.28 (d,J=2.6Hz,1H),7.32 (d,J=8.2Hz,1H),7.26 (d,J=8.2Hz,1H),7.13 - 7.10 (m,1H),6.02 (d,J=6.6Hz,1H),5.73 (s,2H),2.76 - 2.68 (m,1H),2.54 - 2.43 (m,2H),2.40 (d,J=7.1Hz,2H),2.23 - 2.15 (m,1H),2.06 - 1.96 (m,2H),1.52 - 1.42 (m,1H).

[0590] Step 6: Synthesis of methyl 4-(2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate The compound 2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetic acid (155 mg, 0.36 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (93 mg, 0.39 mmol) were added to dichloromethane (4 mL) and N,N-dimethylformamide (2 mL), and HATU (203 mg, 0.53 mmol) and DIPEA (115 mg, 0.89 mmol) were added, followed by reaction at 50° C. overnight. The solvent was removed under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:DCM (v / v) = 65%) to give 206 mg of a pale yellow solid product, with a yield of 88.5%.

[0591] LC-MS (ESI): [M+H] + =653.4, 1H NMR (500MHz,CDCl3) δ 8.27 (d,J=2.5Hz,1H),7.82 (s,2H),7.58 (d,J=8.3Hz,1H),7.53 (s,1H),7.33 (d,J=8.1Hz,1H),7.26 (d,J=2.3Hz,1H),7.13 (s,1H),6.02 (d,J=6.6Hz,1H),5.73 (s,2H),5.07 - 5.02 (m,1H),4.76 - 4.69 (m,1H),4.65 - 4.55 (m,1H),3.90 (s,3H),3.45 - 3.28 (m,3H),2.77 - 2.68 (m,2H),2.57 - 2.40 (m,4H),2.35 - 2.26 (m,1H),2.12 - 1.98 (m,2H) ,1.54 - 1.46 (m,1H).

[0592] Step 7: Synthesis of methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate The compound 4-(2-(4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)methyl benzoate (96 mg, 0.15 mmol), p-toluenesulfonic acid monohydrate (28 mg, 0.15 mmol) were added to tetrahydrofuran (4 mL) and reacted at 75 °C for 4 h. The solvent was removed under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 70%) to obtain 46 mg of a light brown solid product, with a yield of 49.3%.

[0593] LC-MS (ESI): [M+H] + =635.4.

[0594] Step 8: Synthesis of 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid The compound 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (40 mg, 0.06 mmol) and lithium hydroxide monohydrate (27 mg, 0.64 mmol) were added to 1,4-dioxane (3 mL) and water (1.5 mL), and the mixture was reacted at 40° C. for 1 hour. The mixture was cooled in an ice bath, adjusted to pH 6 with 2 M aqueous acetic acid, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent MeOH:DCM (v / v) = 5%) to give 9 mg of a white solid product, with a yield of 21.6% and an HPLC purity of 93.81%.

[0595] LC-MS (ESI): [M+H] + =621.3, 1 HNMR (500MHz,CDCl3) δ 8.27 (d,J=2.6Hz,1H),8.16 (s,1H),8.04 (d,J=8.4Hz,1H),7.79 (d,J=8.5Hz,1H),7.32 (d,J=8.3Hz,1H),7.26 (d,J=2.3Hz,1H),7.13 (s,1H),6.01 (d,J=6.6Hz,1H),5.71 (s,2H),5.22 - 5.15 (m,1H),4.64 - 4.60 (m,1H),4.50 - 4.32 (m,3H),3.05 (d,J=6.8Hz,2H),2.79 - 2.70 (m,2H),2.56 - 2.41 (m,4H),2.18 - 2.11 (m,1H),2.08 - 1.99 (m,2H).

[0596] Example 32 Synthesis of 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy-d2)pyridin-2-yl)cyclohex-3-en-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 32) [ka]

[0597] Step 1: Synthesis of methyl (4-chlorobenzofuran-7-yl)acetate The compound 7-(bromomethyl)-4-chlorobenzofuran (2.50 g, 10.18 mmol) was added to DMF (20 mL) and potassium acetate (7.00 g, 71.28 mmol) was added. The reaction was allowed to proceed at room temperature for 3 h. Water (80 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2.0 g of a brown oil, with a yield of 87.4%.

[0598] Step 2: Synthesis of (4-chlorobenzofuran-7-yl)methanol The compound (4-chlorobenzofuran-7-yl)methyl acetate (2.0 g, 8.90 mmol) was added to a mixture of 1,4-dioxane (30 mL) and water (8 mL), followed by the addition of lithium hydroxide monohydrate (1.12 g, 26.71 mmol). The mixture was heated to 42 °C and reacted for 2 h. The mixture was cooled to room temperature, diluted with water (60 mL), and extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by silica gel column chromatography (eluent: PE: EtOAc (v / v) = 3:1) to obtain 1.6 g of a white solid in 98.4% yield.

[0599] LC-MS (ESI): [M-HO+H] + =165.0, 1H NMR (500MHz,DMSO-d6) δ 8.10 (d,J=2.2Hz,1H),7.33 (q,J=8.0Hz,2H),6.99 (d,J=2.2Hz,1H),5.36 (d,J=5.3Hz,1H),4.79 (d,J=2.8Hz,2H).

[0600] Step 3: Synthesis of 4-chlorobenzofuran-7-carboxylic acid The compound (4-chlorobenzofuran-7-yl)methanol (390 mg, 2.14 mmol) was dissolved in 1,4-dioxane (12 mL), potassium bromide (26 mg, 0.22 mmol), sodium bicarbonate (269 mg, 3.20 mmol), and water (4 mL) were added, cooled in an ice bath, and 2,2,6,6-tetramethylpiperidine oxide (17 mg, 0.11 mmol) was added with stirring. 10% aqueous sodium hypochlorite solution (6.4 mL) was added, and the mixture was reacted at room temperature for 30 min. Water (60 mL) was added, and the pH was adjusted to 5 with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:DCM (v / v) = 60%) to obtain 146 mg of a white solid product in 34.8% yield.

[0601] 1 HNMR (500MHz,DMSO-d6) δ 8.24 (s,1H),7.86 (d,J=8.2Hz,1H),7.47 (d,J=8.2Hz,1H),7.12 (s,1H).

[0602] Step 4: Synthesis of (4-chlorobenzofuran-7-yl)methan-d2-ol The compound 4-chlorobenzofuran-7-carboxylic acid (275 mg, 1.40 mmol) was dissolved in dichloromethane (20 mL), CDI (272 mg, 1.68 mmol) was added, and the mixture was reacted at room temperature for 30 min. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined and washed with saturated aqueous ammonium chloride solution (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Deuterated methanol-d4 (8 mL) was added, and the mixture was cooled in an ice bath. The mixture was cooled, and sodium borohydride (70 mg, 1.67 mmol) was added with stirring. The mixture was allowed to react at room temperature for 30 min. Deuterated water (0.5 mL) was added to quench the reaction. The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 20%) to obtain 103 mg of a white solid product in a 39.9% yield.

[0603] 1 HNMR (500MHz,DMSO-d6) δ 8.11 (d,J=2.2Hz,1H),7.37 - 7.30 (m,2H),7.00 (d,J=2.2Hz,1H),5.30 (s,1H).

[0604] Step 5: Synthesis of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy-d2)pyridine The compound (4-chlorobenzofuran-7-yl)methan-d2-ol (138 mg, 0.75 mmol) and 2-bromo-6-fluoropyridine (157 mg, 0.89 mmol) were dissolved in DMF (5 mL), and cesium carbonate (484 mg, 1.49 mmol) was added. The reaction was allowed to proceed overnight at room temperature. Water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 5% EtOAc:PE (v / v)) to give 212 mg of a white solid (83.3% yield).

[0605] 1H NMR (500MHz,CDCl3) δ 7.68 (d,J=2.2Hz,1H),7.42 (t,J=7.8Hz,1H),7.37 (d,J=7.9Hz,1H),7.24 (d,J=7.9Hz,1H),7.08 (d,J=7.5Hz,1H),6.89 (d,J=2.3Hz,1H),6.73 (d,J=8.2Hz,1H).

[0606] Step 6: Synthesis of ethyl 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy-d2)pyridin-2-yl)cyclohex-3-en-1-yl)acetate 2-Bromo-6-((4-chlorobenzofuran-7-yl)methoxy-d2)pyridine (210 mg, 0.62 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (201 mg, 0.68 mmol), potassium carbonate (172 mg, 1.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocene dichlor...

Claims

1. A compound as shown in formula (X) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug of a compound of formula (X), 【Chemistry 1】 Ring A １ is a 5- to 6-membered heteroaryl group, a phenyl group, a 5- to 6-membered heterocyclyl group, and C ５－６ cycloalkyl groups, Ring C is a 5- to 6-membered heteroaryl group; Z is O, S, N (R ｚ ) and C(R ｚ ) ２ is selected from Each R ｃ , R ２ and R ３ are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R ４ , R ５ , R ６ , R ７ , R ９ each independently represents H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Each R ａ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ phenyl group, 5- to 6-membered heteroaryl group, and 【Chemistry 2】 wherein said -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ the phenyl or 5- to 6-membered heteroaryl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Each R ｚ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group, -C(=O)NHC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group, -C(=O)NHC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Each R ｂ are independently H, F, Cl, Br, I, oxo, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; R ８ is H, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) wherein C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) optionally represents 1, 2 or 3 R ８ａ is replaced by Each R ８ａ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ cycloalkyl group and 3- to 6-membered heterocyclyl group, １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has 1, 2 or 3 R ８ｂ is replaced by Each R ８ｂ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ selected from a cycloalkyl group and a 3- to 6-membered heterocyclyl group; R １０ is C ３－６ cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, ３－６ The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxyl, amino, cyano, nitro, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group or C １－６ may be substituted with an alkylamino group, R Ｓ , R Ｍ , R Ｎ are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or, R Ｓ , R Ｍ is concatenated to C ３－６ forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group; 【Chemistry 3】 represents a single bond or a double bond, m is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; A compound wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. As shown in formula (I-a) or (I-b) or (I-c), 【Chemistry 4】 Here, ring A １ is a 5- to 6-membered heteroaryl group, a phenyl group, a 5- to 6-membered heterocyclyl group, and C ５－６ cycloalkyl groups, X ５ , X ６ , X ７ , X ９ Each independently represents C(R ｃ ) and N; X ４ , X ８ is O, S, C (R ｃ ) ２ and N(R ｃ ) are selected from Each Y is independently C(R Ｙ ) and N; Z is independently O, S, or N (R ｚ ) and C(R ｚ ) ２ is selected from Each R ｃ , R １ , R ２ and R ３ are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R ４ , R ６ , R ７ each independently represents H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Each R ａ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ phenyl group, 5- to 6-membered heteroaryl group, and 【Chemistry 5】 wherein said -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ the phenyl or 5- to 6-membered heteroaryl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; R Ｙ And each R ｚ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Each R ｂ are independently H, F, Cl, Br, I, oxo, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; R ８ is H, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) wherein C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) optionally represents 1, 2 or 3 R ８ａ is replaced by Each R ８ａ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ cycloalkyl group and 3- to 6-membered heterocyclyl group, １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has 1, 2 or 3 R ８ｂ is replaced by Each R ８ｂ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ selected from a cycloalkyl group and a 3- to 6-membered heterocyclyl group; R １０ is C ３－６ cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, ３－６ The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxyl, amino, cyano, nitro, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group or C １－６ may be substituted with an alkylamino group, R Ｓ , R Ｍ , R Ｎ are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or, R Ｓ , R Ｍ is concatenated to C ３－６ forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group; 【Chemistry 6】 represents a single bond or a double bond, m is 0, 1, 2, 3 or 4; 2. The compound of claim 1, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof.

3. As shown in formula (II-a) or (II-b) or (II-c) or (II-d) or (II-e) or (II-f) or (II-g) or (II-h) or (II-i), 【Chemistry 7】 【Chemistry 8】 Here, X １ , X ２ , X ３ Each independently represents C(R ａ ) and N; X ５ , X ６ , X ７ , X ９ , Y １ , Y ４ Each independently represents C(R ｃ ) and N; X ４ , X ８ , Y ２ , Y ３ is O, S, C (R ｃ ) ２ and N(R ｃ ) are selected from Y is C(R Ｙ ) and N; Z is O, S, N (R ｚ ) and C(R ｚ ) ２ is selected from Each R ａ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ phenyl group, 5- to 6-membered heteroaryl group, and 【Chemistry 9】 wherein said -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－６ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－６ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ the phenyl or 5- to 6-membered heteroaryl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Each R ｃ , R １ , R ２ and R ３ are independently H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, and C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R ４ , R ６ , R ７ each independently represents H, D, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, or C １－６ alkyl group, １－６ the alkyl group is optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R Ｙ And each R ｚ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Each R ｂ are independently H, F, Cl, Br, I, oxo, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, carboxyl group, -C(=O)OC １－６ Alkyl group or -C １－６ AlkyleneC(=O)OC １－６ alkyl group, wherein said -C(=O)OC １－６ Alkyl group and -C １－６ AlkyleneC(=O)OC １－６ the alkyl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; R ８ is H, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) wherein C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclyl group, -C １－６ Alkylene-R １０ and C １－６ Alkylene C(R Ｓ R Ｍ R Ｎ ) optionally represents 1, 2 or 3 R ８ａ is replaced by Each R ８ａ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ cycloalkyl group and 3- to 6-membered heterocyclyl group, １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ The cycloalkyl group or the 3- to 6-membered heterocyclyl group optionally has 1, 2 or 3 R ８ｂ is replaced by Each R ８ｂ are independently D, F, Cl, Br, I, CN, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Alkylamino group, C ３－６ selected from a cycloalkyl group and a 3- to 6-membered heterocyclyl group; R １０ is C ３－６ cycloalkyl groups, 3- to 8-membered heterocyclyl groups, and 5- to 10-membered heteroaryl groups, ３－６ The cycloalkyl group, the 3- to 8-membered heterocyclyl group, and the 5- to 10-membered heteroaryl group may independently and optionally contain 1, 2, 3, 4, or 5 of D, F, Cl, Br, I, oxo, hydroxyl, amino, cyano, nitro, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group or C １－６ may be substituted with an alkylamino group, R Ｓ , R Ｍ , R Ｎ are each independently selected from D, F, Cl, Br, I, a hydroxy group, an oxo group, an amino group, a nitro group, or a cyano group; Or, R Ｓ , R Ｍ is concatenated to C ３－６ forming a cycloalkyl group or a 3- to 6-membered heterocyclyl group; 【Chemistry 10】 2. The compound of claim 1, wherein: represents a single bond or a double bond; or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof.

4. R ８ is H, C １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C ３－６ Cycloalkyl groups, 3- to 6-membered heterocyclyl groups and -C １－３ Alkylene-R １０ and C is selected from １－３ Alkyl group, C ２－３ Alkenyl group, C ２－３ Alkynyl group, C ３－６ A cycloalkyl group, a 3- to 6-membered heterocyclyl group, or -C １－３ Alkylene-R １０ optionally 1, 2 or 3 R ８ａ is replaced by Optionally, R ８ａ are D, F, Cl, Br, I, CN, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Alkylamino group, C ４－６ cycloalkyl group and 5- to 6-membered heterocyclyl group, １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Alkylamino group, C ４－６ The cycloalkyl group or the 5- to 6-membered heterocyclyl group optionally has 1, 2 or 3 R ８ｂ is replaced by Optionally, R ８ｂ are D, F, Cl, Br, I, CN, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Alkylamino group, C ５－６ selected from a cycloalkyl group and a 5- to 6-membered heterocyclyl group; Optionally, R １０ is C ５－６ selected from a cycloalkyl group, a 5- to 6-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group; Optionally, R １０ is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an azetidinyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, 【Chemistry 11】 is selected from Optionally, R ８ H, 【Chemistry 12】 is selected from Optionally, R １ , R ２ , R ３ are each independently selected from H, D, F, Cl, Br, and I; Optionally, R ４ , R ６ , R ７ are each independently selected from H, D, F, Cl, Br, and I; Optionally, each R ａ are independently -C(=O)OH, -C(=O)NHC(=O)C １－３ Alkyl group, -C(=O)NHS(=O) ２ C １－３ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－３ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ phenyl group, 5- to 6-membered heteroaryl group, and 【Chemistry 13】 wherein said -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－３ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－３ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ the phenyl or 5- to 6-membered heteroaryl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Optionally, each R ａ is independently 【Chemistry 14】 The compound according to any one of claims 1 to 3, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof, selected from the group consisting of:

5. Each R ａ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, -C(=O)OH, -C(=O)NHC(=O)C １－３ Alkyl group, -C(=O)NHS(=O) ２ C １－３ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－３ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ phenyl group, 5- to 6-membered heteroaryl group, and 【Chemistry 15】 wherein said -C(=O)NHC(=O)C １－６ Alkyl group, -C(=O)NHS(=O) ２ C １－３ Alkyl group, -C(=O)NHS(=O) ２ N.H. ２ , -C(=O)NHS(=O) ２ N.H.C. １－３ Alkyl group, -C(=O)NHS(=O) ２ C ３－６ Cycloalkyl groups, -C(=O)NHS(=O) ２ the phenyl or 5- to 6-membered heteroaryl group is optionally and independently substituted with 1, 2, 3, 4 or 5 D, F, Cl, Br, I, hydroxy, oxo, amino, nitro or cyano groups; Optionally, each R ａ are independently H, F, Cl, Br, I, a hydroxy group, a cyano group, an amino group, 【Chemistry 16】 The compound according to any one of claims 1 to 3, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt or prodrug thereof, selected from the group consisting of:

6. 【Chemical 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 ​ 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof, of the compound of claim 1, wherein the compound is selected from one of the structures:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt, or prodrug thereof.

8. The pharmaceutical composition of claim 7, further comprising a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or any combination thereof.

9. Use of a compound according to any one of claims 1 to 6, a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, a pharma- ceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition according to claim 7 or 8, in the manufacture of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist mediated disease in a patient.

10. Use of the compound according to any one of claims 1 to 6, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 7 or 8, in the manufacture of a medicament for preventing and / or treating a disease and / or condition associated with the GLP-1 receptor downstream signaling pathway.

11. The use according to claim 10, characterized in that the disease and / or condition associated with the GLP-1 receptor downstream signaling pathway is selected from diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia and diabetic infection, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular disorders, epilepsy, atherosclerosis, Parkinson's disease and Alzheimer's disease.

12. Use of the compound according to any one of claims 1 to 6, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 7 or 8, in the manufacture of a drug for promoting insulin secretion or lowering blood glucose.

13. Use of the compound according to any one of claims 1 to 6, its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharma- ceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 7 or 8, in the manufacture of a medicament for preventing and / or treating diabetes.

14. The use according to claim 13, characterized in that the diabetes is type 1 diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early onset type II diabetes, maturity onset diabetes of the young, atypical diabetes of adolescence, malnutrition-related diabetes, latent adult autoimmune diabetes.

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