Fused imidazole derivatives, their preparation method and pharmaceutical applications

Abstract

The present disclosure relates to fused imidazole derivatives, their preparation methods, and their pharmaceutical applications. Specifically, the present disclosure relates to fused imidazole derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, particularly their use as GLP-1 receptor agonists and in the preparation of medicaments for treating and / or preventing diabetes. Each group in the general formula is as defined in the specification. TIFF2023520003000073.tif4479

Description

[Technical Field]

[0001] The present disclosure relates to the pharmaceutical field, and to fused imidazole derivatives, their preparation methods, and pharmaceutical applications. In particular, the present disclosure relates to fused imidazole derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing the derivatives, and their use in the field of diabetes treatment as GLP-1 receptor agonists. [Background technology]

[0002] Diabetes mellitus (DDM) is a multifactorial metabolic disease characterized by chronic hyperglycemia accompanied by abnormalities in glucose, lipid, and protein metabolism due to defective insulin secretion or action. Diabetes is an ancient disease caused by an absolute or relative deficiency of insulin in the body, which leads to elevated blood glucose levels, resulting in the excretion of large amounts of glucose in the urine and resulting in symptoms such as polydipsia, polyuria, polyphagia, and weight loss.

[0003] Generally, there are two types of diabetes. Patients with type 1 diabetes, or insulin-dependent diabetes, produce very little or no insulin themselves. Insulin is the hormone that regulates the body's use of glucose. Patients with type 2 diabetes, or non-insulin-dependent diabetes, have plasma insulin levels equal to or higher than those of non-diabetic patients. However, these patients are resistant to insulin, which promotes glucose and lipid metabolism in key insulin-sensitive tissue cells, such as muscle, liver, and adipose tissue. Even high plasma insulin levels cannot overcome the patients' significant insulin resistance.

[0004] Insulin resistance is caused not only by a decrease in the number of insulin receptors but also by defects in insulin receptors, but the underlying mechanism remains unclear. Due to insulin response resistance, insulin is unable to activate glucose uptake, oxidation, and storage in muscle tissue, and is unable to effectively suppress lipolysis in adipose tissue and glucose production and secretion in the liver.

[0005] Glucagon-like peptide 1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract.

[0006] GLP-1 exerts its effects by binding to specific receptors that are widely distributed. Currently, GLP-1 receptors have been identified 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 generally do not differ significantly between patients with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes. However, after a meal, β cells exhibit a defective response to GLP-1, and under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. The extremely short duration of action of the human body's own GLP-1 (t1 / 2 < 1.5 minutes after intravenous injection) makes it unsuitable for clinical diabetes treatment.

[0007] Peptide GLP-1 receptor agonists (e.g., liraglutide, exenatide, etc.) have the effect of improving blood glucose levels in patients with type 2 diabetes by reducing fasting and postprandial glucose. However, because peptide GLP-1 has low oral bioavailability and is inconvenient to administer, there is great demand for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0008] Patent applications that disclose GLP-1 receptor small molecule agonists include WO2009111700, WO2010114824, WO2018109607, WO2019239319, and WO2018056453, among others. Summary of the Invention

[0009] The present disclosure aims to provide compounds of general formula (I), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, Q is Q0 or Q2, i.e., [ka] and G 1 , G 2 and G 3 are homologous or different and each independently 7 or a N atom, Z 1 , Z 2 , Z 3 and Z 4 are homologous or different and each independently 8 or a N atom, Y is an O atom, an S atom, or an NR 9 and CR 10 R 11 Selected from W 1 and W 2 are identical or different and each independently represent an O atom, a S atom, or NR 12 and CR 13 R 14 Selected from R a and R b are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R1 are selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 2 are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 3are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 4 is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 5 are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 6are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 10 , R 11 , R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, or 3, and p is 0, 1, 2, 3, 4 or 5.

[0010] The present disclosure aims to provide compounds of general formula (I), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, Q is Q1 or Q2, i.e., [ka] and G 1 , G 2 and G 3 are homologous or different and each independently 7 or a N atom, Z 1 , Z 2 , Z 3 and Z 4 are homologous or different and each independently 8 or a N atom, Y is an O atom, an S atom, or an NR 9 and CR 10 R 11 Selected from W 1 and W 2 are identical or different and each independently represent an O atom, a S atom, or NR 12 and CR 13 R 14 Selected from R 1are selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 2 are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 3are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 4 is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 5 are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 6are identical or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the cycloalkyl group, the heterocyclyl group, the aryl group and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 9 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; R 10 , R 11 , R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, or 3, and p is 0, 1, 2, 3, 4 or 5.

[0011] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I), or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 1 is a CH or N atom, and G 2 and G 3 are both CH, and preferably G 1 , G 2 and G 3 are both CH.

[0012] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I), or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II), or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, R 1 , R 2 , Q and n are as defined in general formula (I). In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II), or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Z 1 , Z 2 and Z 3 are homologous or different and each independently 8 and Z 4 is the N atom, and R 8 is a hydrogen atom or a halogen.

[0013] In some preferred embodiments of the present disclosure, in the compound represented by the above general formula (I) or general formula (II), or in the form of a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, Y is an O atom or a S atom.

[0014] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II), or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Z 1 , Z 2 and Z 3 is CH and Z 4 is an N atom and / or Y is an O atom.

[0015] In some preferred embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II), or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of W 1 and W 2 are both O atoms.

[0016] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is Q3, Q4, Q5, or Q6, i.e., [ka] Selected from R 3 ~R 6 , R 8 , m, p and t are as defined in general formula (I).

[0017] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is Q3, Q4, or Q5, i.e., [ka] Selected from R 3 ~R 6 , m, p and t are as defined in general formula (I).

[0018] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is [ka] is.

[0019] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a tautomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (I).

[0020] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (II), or general formula (III) above, or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIIaa), or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (I).

[0021] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is 1 is C 1-6 is an alkyl group, 1-6 The alkyl group may optionally be a halogen, a hydroxy group, a C 1-6 is substituted with one or more substituents selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, and preferably R 1 is C 1-6 is an alkyl group, 1-6 The alkyl group is optionally substituted with one 3- to 6-membered heterocyclyl group, more preferably R 1 teeth [ka] is.

[0022] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is 2 are the same or different and each independently represents a hydrogen atom or C 1-6 It is an alkyl group.

[0023] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or general formula (II) or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, among which, R 3 are the same or different and each independently represent a hydrogen atom, a halogen, or C 1-6 It is selected from an alkyl group and a cyano group.

[0024] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is 4 is a hydrogen atom or C 1-6 is an alkyl group, C 1-6 Alkyl groups are preferred.

[0025] In some embodiments of the present disclosure, the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or a tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is 5 are the same or different and each independently represent a hydrogen atom, a halogen atom and C 1-6 alkyl groups, and / or R 6 are the same or different and each independently represent a hydrogen atom, a halogen atom and C 1-6 It is selected from alkyl groups.

[0026] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, n is 0 or 1.

[0027] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, t is 0 or 1.

[0028] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (II), general formula (III), or general formula (IIIaa), or in the form of a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, p is 0, 1, or 2, and 2 is preferred.

[0029] In some embodiments of the present disclosure, the compound represented by the above general formula (I) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, among which, G 1 is a CH or N atom, and G 2 and G 3 are both CH and Q is [ka] and R 1 teeth [ka] and R 2 are the same or different and each independently represents a hydrogen atom or C 1-6 is an alkyl group, and R 4 is a hydrogen atom or C 1-6is an alkyl group, and R 5 are the same or different and each independently represent a hydrogen atom, a halogen atom, and C 1-6 alkyl groups, R 6 are the same or different and each independently represent a hydrogen atom, a halogen atom, and C 1-6 alkyl groups, n is 0 or 1, t is 0 or 1, and p is 0, 1, or 2.

[0030] In some embodiments of the present disclosure, the compound represented by the above general formula (II) or its tautomer, meso form, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is [ka] and R 1 teeth [ka] and R 2 are the same or different and each independently represents a hydrogen atom or C 1-6 is an alkyl group, and R 4 is a hydrogen atom or C 1-6 is an alkyl group, and R 5 are the same or different and each independently represent a hydrogen atom, a halogen atom, and C 1-6 alkyl groups, R 6 are the same or different and each independently represent a hydrogen atom, a halogen atom, and C 1-6 alkyl groups, n is 0 or 1, t is 0 or 1, and p is 0, 1, or 2.

[0031] Table A Exemplary compounds of the present disclosure include, but are not limited to: [Table 1-1] [Table 1-2] [Table 1-3]

[0032] Another aspect of the present disclosure relates to a compound of general formula (IA), or in the form of a tautomer, meso-isomer, racemate, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, R w is C 1-6 is an alkyl group, G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in general formula (I).

[0033] Another aspect of the present disclosure relates to a compound represented by general formula (IIA), or in the form of a tautomer, meso-isomer, racemate, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , Q and n are as defined in general formula (II).

[0034] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA), or in the form of a tautomer, meso-isomer, racemate, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, R w is C 1-6 is an alkyl group, R 1, R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (III).

[0035] Another aspect of the present disclosure relates to a compound of general formula (IIIaaA), or in the form of a tautomer, meso-isomer, racemate, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof: [ka] Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (IIIaa).

[0036] Exemplary intermediate compounds of the present disclosure include, but are not limited to: [Table 2-1] [Table 2-2] [Table 2-3]

[0037] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (I), or any of its tautomeric, meso-, racemic, enantiomeric, diastereomeric, or mixtures thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] hydrolysis of a compound of general formula (IA) to obtain a compound of general formula (I), Among them, R w is C1-6 is an alkyl group, G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in general formula (I).

[0038] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (II), or a tautomeric, meso-, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] hydrolysis of a compound of general formula (IIA) to obtain a compound of general formula (II), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , Q and n are as defined in general formula (II).

[0039] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (III), or a tautomeric, meso-, racemic, enantiomeric, diastereomeric, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] hydrolysis of a compound of general formula (IIIA) to obtain a compound of general formula (III), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (III).

[0040] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IIIaa), or a tautomeric, meso, racemic, enantiomeric, diastereomeric, or mixture thereof, form or a pharmaceutically acceptable salt thereof, the method comprising: [ka] hydrolysis of a compound of general formula (IIIaaA) to obtain a compound of general formula (IIIaa), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (IIIaa).

[0041] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A of the present disclosure, or a tautomeric, meso-, racemic, enantiomeric, diastereomeric or mixture thereof form thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents or excipients.

[0042] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A, or a tautomer, meso form, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of them, in the preparation of a medicament for agonizing the GLP-1 receptor.

[0043] The present disclosure further relates to the use of a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A, or a tautomer, meso form, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the treatment of type 1 diabetes, type 2 diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, and the like. The present invention relates to use in the preparation of a medicament for the treatment and / or prevention of liver disorders, cardiovascular disease, atherosclerosis, high blood pressure, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance, preferably use in the preparation of a medicament for the treatment and / or prevention of type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease.

[0044] The present disclosure further relates to a method of agonizing the GLP-1 receptor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa), or Table A, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0045] The present disclosure further relates to the treatment and / or prevention of type 1 diabetes, type 2 diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, or hepatic insulin resistance. The present invention relates to a method for treating and / or preventing type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, or cardiovascular disease, and is preferably a method for treating and / or preventing type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis, or cardiovascular disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa), or Table A, or a tautomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

[0046] The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, as a medicament, or a pharmaceutical composition containing any of them.

[0047] The present disclosure further relates to a compound of general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A as a GLP-1 receptor agonist, or a tautomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of them.

[0048] The present disclosure further relates to the treatment of type 1 diabetes, type 2 diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes of adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance, or hepatic insulin resistance, more preferably type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease, or a compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIaa) or Table A, or a tautomer, meso form, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

[0049] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and may be acute or chronic. The term "acute complications" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary infections, respiratory infections, and urinary tract infections), while the term "chronic complications" includes, for example, microangiopathy (e.g., kidney disease, retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, and autonomic neuropathy), and gangrene. Major diabetic complications include diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy.

[0050] "Coronary heart disease" includes myocardial infarction and angina pectoris.

[0051] "Dementia" includes, for example, Alzheimer's disease, (early onset dementia) EOD, vascular dementia and diabetic dementia.

[0052] The active compound can be prepared into a form suitable for administration by any suitable route, and the composition of the present disclosure can be prepared using one or more pharmaceutically acceptable vectors by conventional methods. Thus, the active compound of the present disclosure can be prepared into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation administration. The compound of the present disclosure can also be prepared into sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, tablets, or syrups.

[0053] The dosage of the compound or composition used in the therapeutic methods of the present disclosure generally varies depending on the severity of the disease, the patient's weight, and the relative efficacy of the compound. However, as a general guideline, it is preferred that the active compound be in a unit dose form or a form that the patient can self-administer as a single dose. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled liquid, powder, granules, pill, suppository, reconstituted powder, or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

[0054] In addition to the active compound, the pharmaceutical composition according to the present disclosure may contain one or more additives selected from fillers (diluents), binders, wetting agents, disintegrants, excipients, etc. The composition may contain 0.1 to 99% by weight of the active compound, depending on the method of administration.

[0055] Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets. These excipients may be inert diluents, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over an extended period of time.

[0056] Oral formulations may be provided in soft gelatin capsules containing the active ingredient mixed with an inert solid diluent, or with a water-soluble or oily solvent.

[0057] Aqueous suspensions contain the active substance and mixing excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners.

[0058] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil.Oil suspensions may contain thickeners.In order to provide a smooth formulation, the above-mentioned sweeteners and flavoring agents may be added.These compositions can be preserved by adding antioxidants.

[0059] The pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain emollients, preservatives, coloring agents, and antioxidants.

[0060] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion can be infused into the patient's bloodstream via local injection of a large volume. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant, cyclical concentration of the compounds of the present disclosure. To maintain such a constant concentration, a continuous intravenous infusion device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0061] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. Such suspensions can be prepared using the above-mentioned suitable dispersing or wetting agents and suspending agents according to known techniques. The sterile injectable preparations may be sterile injectable solutions or suspensions prepared in non-toxic parenterally acceptable diluents or solvents. Sterile fixed oils can also be conveniently used as solvents or suspending media. For this purpose, any suitable fixed oil can be used. Fatty acids can also be used to prepare injectables.

[0062] The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid in the rectum, and therefore melts in the rectum to release the drug.

[0063] The compounds of the present disclosure can be administered by adding water to prepare aqueous turbid dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.

[0064] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's physical condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the composition of the drug, etc. Furthermore, the optimal treatment method, such as the treatment mode, the daily dose of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment plans.

[0065] Terminology Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0066] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, and the like. Silyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2 n-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and said substituents are preferably one or more substituents independently and optionally selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0067] The term "alkylene group" refers to a saturated, straight- or branched-chain aliphatic hydrocarbon group, a residue derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, and is a straight- or branched-chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH)-, 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCHCH-), 1,4-butylene (-CHCHCHCHCH-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available linkage site, and the substituent is preferably independently and optionally one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0068] The term "alkenyl group" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, of which alkyl is defined above. The alkenyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0069] The term "alkynyl group" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. The alkynyl group may be substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0070] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0071] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, in which the monocyclic rings share one carbon atom (referred to as a spiro atom), and may contain one or more double bonds. It is preferably 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups, with monospirocycloalkyl groups and bisspirocycloalkyl groups being preferred. More preferred are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include: [ka] Includes.

[0072] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and one or more rings may contain one or more double bonds. It is preferably 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic or tricyclic, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include: [ka] Includes.

[0073] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly linked, and may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] Includes.

[0074] The cycloalkyl ring includes the above cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl group, heteroaryl group, or heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, and benzocycloheptanyl, with indanyl and tetrahydronaphthyl being preferred.

[0075] The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably one or more substituents independently and optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0076] The term "alkoxy group" refers to an -O-(alkyl group), where alkyl is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. An alkoxy group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0077] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, sulfur, S(O), or S(O), but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms being carbon. Preferably, the group contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, the group contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms, of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, the group contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, the group contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups.

[0078] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which two monocyclic rings share one atom (referred to as a spiro atom), where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O), or S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups. Preferred are monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferred are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0079] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings optionally containing one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, and the remaining ring atoms are carbon. Preferably, the group has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, fused heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0080] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic heterocyclyl group in which any two rings share two atoms that are not directly linked, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O)2, and the remaining ring atoms are carbon. It is preferably 6-14 membered, more preferably 7-10 membered (e.g., 7, 8, 9 or 10 membered). Depending on the number of rings, bridged heterocyclyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, and are preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0081] The heterocyclyl ring includes the above heterocyclyl groups (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl group, heteroaryl group or cycloalkyl ring, in which the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] Includes:

[0082] The heterocyclyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and said substituents are preferably one or more substituents independently and optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0083] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl groups. The aryl ring includes the above aryl ring fused to a heteroaryl group, heterocyclyl group, or cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof are: [ka] Includes.

[0084] The aryl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably one or more independently and optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0085] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5 or 6-membered, and examples thereof include furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. The heteroaryl ring includes the above heteroaryl group fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include: [ka] Includes.

[0086] Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and preferably the substituents are independently and optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0087] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same or two different parent ring atoms, i.e., "divalent cycloalkyl," "divalent heterocyclyl," "arylene," and "heteroarylene."

[0088] The term "amino-protecting group" refers to a group that protects an amino group with an easily removable group so that the amino group is not altered when other parts of the molecule react. Non-limiting examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups can be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy, or nitro. Preferred amino-protecting groups are (trimethylsilicon)ethoxymethyl and tert-butoxycarbonyl.

[0089] The term "hydroxy protecting group" refers to groups known in the art that are suitable for protecting hydroxy groups, and is described in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. ​​GM Wuts). For example, the hydroxy protecting group is preferably a (C silyl group) such as a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group. 1-10 alkyl or aryl) silane groups, 1-10 It may be an alkyl group or a substituted alkyl group, preferably an alkyl group substituted with an alkoxy group or an aryl group, more preferably C 1-6 Alkoxy-substituted C 1-6 C substituted with alkyl or phenyl groups 1-6 Alkyl groups, most preferably C 1-4 Alkoxy-substituted C 1-4Alkyl groups include, for example, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and 2-tetrahydropyranyl (THP) groups; and alkyl groups include, for example, formyl, acetyl, benzoyl, and p-nitrobenzoyl groups (C 1-10 alkyl or aryl) acyl group, (C 1-6 Alkyl or C 6-10 (aryl)sulfonyl group, (C 1-6 Alkoxy or C 6-10 The hydroxy protecting group may be a (aryloxy)carbonyl group. The hydroxy protecting group is preferably p-nitrobenzoyl.

[0090] The term "cycloalkyloxy" refers to a cycloalkyl-O- group, in which the cycloalkyl group is as defined above.

[0091] The term "heterocyclyloxy" refers to a heterocyclyl-O- group, wherein the heterocyclyl group is as defined above.

[0092] The term "alkylthio" refers to alkyl-S-, in which the alkyl group is as defined above.

[0093] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein alkyl group is defined above.

[0094] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0095] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl group is defined above.

[0096] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0097] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] The term "hydroxy group" refers to -OH.

[0099] The term "mercapto" refers to -SH.

[0100] The term "amino group" refers to -NH2.

[0101] The term "cyano" refers to -CN.

[0102] The term "nitro group" refers to -NO2.

[0103] The term "oxo" or "oxo group" refers to "=O".

[0104] The term "carbonyl group" refers to C=O.

[0105] The term "carboxy" refers to -C(O)OH.

[0106] The term "carboxylic acid ester" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0107] The present disclosure further includes various deuterated forms of the compound of Formula (I). Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compound of Formula (I) by referring to relevant literature. The deuterated form of the compound of Formula (I) may be prepared using commercially available deuterated starting materials or may be synthesized by conventional techniques using deuterated reagents, including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, lithium aluminum deuteride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to that of non-deuterated compounds, and when deuteration is at a specific site, they may have better metabolic stability and offer several therapeutic advantages.

[0108] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0109] The term "substituted" refers to one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in a group, being independently replaced with a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or hydroxy group having free hydrogen may be unstable if it is bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0110] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors and excipients. The pharmaceutical composition facilitates administration to a living body and contributes to the absorption of active ingredients to further exert biological activity.

[0111] "Pharmaceutically acceptable salt" refers to a salt of a compound according to the present disclosure, which is safe and effective when used in a mammalian body and has the desired biological activity. Salts may be prepared independently during the final isolation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Bases for forming pharmaceutically acceptable salts generally include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonium. Acids for forming pharmaceutically acceptable salts generally include inorganic and organic acids.

[0112] The term "therapeutically effective amount" of a drug or pharmacologically active agent refers to a sufficient dose of the drug or agent to produce the desired effect while being non-toxic. The effective amount is determined by the individual and depends on the age and general condition of the subject, as well as the specific active agent, and an appropriate effective amount for an individual can be determined by one skilled in the art through routine testing.

[0113] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, applicable to contact with the tissues of patients without undue toxicity, irritation, allergic response or other problem or complication, and are effective for the desired use, with a reasonable benefit / risk ratio.

[0114] As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly indicates otherwise.

[0115] The term "about," when applied to parameters such as pH, concentration, temperature, etc., indicates that the parameter may be varied within ±10%, and in some cases, more preferably ±5%. As will be understood by those skilled in the art, parameters, if not critical, are generally presented as numbers only for purposes of illustration, not limitation.

[0116] The compounds of the present disclosure may include their isotopic derivatives. The term "isotopic derivative" refers to a compound that differs structurally only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure, but with "deuterium" or "tritium" substituted for hydrogen, or 18 F-fluorine labeling ( 18 F isotope) to replace the fluorine, or 11 C-, 13 C-, or 14 C-rich carbon ( 11 C-, 13 C-, or 14 C-carbon label, 11 C-, 13 C-, or 14 Compounds in which a carbon atom is substituted with a C-isotope (C-isotope) are within the scope of the present disclosure. Such compounds may be used, for example, as analytical tools or probes in bioassays, or as imaging tracers for in vivo diagnosis of disease, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies. Methods for synthesizing compounds according to the present disclosure To achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions:

[0117] Technical proposal 1 A method for preparing a compound represented by general formula (I) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the steps of: [ka] The method comprises the step of hydrolyzing a compound of general formula (IA) in the presence of a basic reagent to obtain a compound of general formula (I), Among them, R w is C 1-6 is an alkyl group, G 1 , G 2 , G 3 , R 1 , R 2 , Q and n are as defined in general formula (I).

[0118] Technical proposal 2 A method for preparing a compound represented by general formula (II) according to the present disclosure, or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the steps of: [ka] The method comprises the step of hydrolyzing a compound of general formula (IIA) in the presence of a basic reagent to obtain a compound of general formula (II), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , Q and n are as defined in general formula (II).

[0119] Technical proposal 3 A method for preparing a compound represented by general formula (III) according to the present disclosure, or a tautomer, meso-isomer, racemic form, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises the steps of: [ka] The method comprises the step of hydrolyzing a compound of general formula (IIIA) in the presence of a basic reagent to obtain a compound of general formula (III), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (III).

[0120] Technical proposal 4 A method for preparing a compound represented by general formula (IIIaa) according to the present disclosure, or a tautomer, meso-isomer, racemic isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprises: [ka] The method comprises the step of hydrolyzing a compound of general formula (IIIaaA) in the presence of a basic reagent to obtain a compound of general formula (IIIaa), Among them, R w is C 1-6 is an alkyl group, R 1 , R 2 , R 4 ~R 6 , n, p and t are as defined in general formula (IIIaa).

[0121] In the above Technical Schemes 1 to 4, the basic reagent includes organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butoxide, and the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably lithium hydroxide or lithium hydroxide monohydrate.

[0122] The reaction is preferably carried out in a solvent, and solvents that can be used include, but are not limited to, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof. DETAILED DESCRIPTION OF THE INVENTION

[0123] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0124] EXAMPLES The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are -6 The NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0125] For MS measurements, a mass spectrometer FINNIGAN LCQAd(ESI) (manufacturer: Thermo, model number: Finnigan LCQ advantage MAX) was used.

[0126] High performance liquid chromatography (HPLC) analysis was performed using high performance liquid chromatographs Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0127] For chiral HPLC analysis, a high performance liquid chromatograph, Agilent 1260 DAD, was used.

[0128] For preparative high performance liquid chromatography, preparative chromatographs Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 were used.

[0129] For chiral separation, a preparative chromatograph Shimadzu LC-20AP was used.

[0130] Combiflash Rf200 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0131] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography. The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and those for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0132] For silica gel column chromatography, 200-300 mesh silica gel manufactured by Yantai Huanghai Silica Gel was generally used as the vector.

[0133] Kinase mean inhibition rate and IC 50 The values ​​were measured using a microplate reader NovoStar (BMG, Germany).

[0134] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0135] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0136] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon with a volume of approximately 1 L connected to the reaction flask.

[0137] A hydrogen atmosphere refers to a hydrogen balloon with a volume of approximately 1 L attached to the reaction flask.

[0138] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenator and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenator were used.

[0139] The hydrogenation reaction was typically carried out by evacuating and filling with hydrogen three times.

[0140] A CEM Discover-S 908860 microwave reactor was used for the microwave reactions.

[0141] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0142] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0143] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reactions. The developing solvents used in the reactions, the column chromatography eluent systems and thin layer chromatography developing solvent systems used to purify the compounds included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: n-hexane / dichloromethane system, and D: ethyl acetate / dichloromethane / n-hexane system. The volume ratio of the solvents may be adjusted depending on the polarity of the compounds, or by adding a small amount of a basic or acidic reagent such as triethylamine and acetic acid.

[0144] TsOH is p-toluenesulfonic acid.

[0145] Example 1 (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1 [ka] [ka]

[0146] Step 1 3-Fluoro-4-((1',2',3',6'-tetrahydro-[2,4'-dipyridyl]-6-yl)oxy)methyl)cyanobenzene 1b

[0147] 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-tert-butyl formate 1a (96 mg, 234.4595 μmol, prepared by the method described in Intermediate 4 on page 51 of the patent application WO2018109607) was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (133 mg, 699.2014 μmol) was added and stirred at 60 °C for 4 hours. The mixture was cooled, filtered, washed with ethyl acetate (10 mL), and the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give compound 1b (126 mg). The product was used directly in the next step without further purification. MS m / z (ESI): 310.1 [M+1].

[0148] Step 2 (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 1d

[0149] (S)-2-(chloromethyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl 1c (55 mg, 186.6096 μmol, prepared according to the method described in Intermediate 23 on page 69 of Patent Application WO2018109607) and compound 1b (121 mg, 185.0889 μmol) were dissolved in acetonitrile (10 mL), potassium carbonate (128 mg, 926.1571 μmol) was added, and the mixture was stirred at 50 °C for 5 hours. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system A to obtain the title compound 1d (105 mg, yield: 99%). MS m / z (ESI): 568.1 [M+1].

[0150] Step 3 (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 1

[0151] Compound 1d (105 mg, 184.9865 μmol) was dissolved in a mixed solvent of acetonitrile (5 mL) and water (1 mL), and lithium hydroxide (6 mg, 250.5397 μmol) was added and stirred overnight at 40°C. The mixture was concentrated, the pH was adjusted to 5-6 with citric acid solution, 2 mL of acetonitrile was added, and after dissolution, 1 (20 mg, yield: 19%) was obtained by preparative high-performance liquid chromatography. MS m / z (ESI): 554.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.88 (d, J = 9.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 - 7.59 (m, 4H), 7.09 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 4.4 Hz, 1H), 5.49 (s, 2H), 5.11 - 5.01 (m, 1H), 4.79 (dd, J = 15.2, 7.3 Hz, 1H), 4.64 (dd, J = 15.3, 2.8 Hz, 1H), 4.50 - 4.43 (m, 1H), 4.41 - 4.31 (m, 1H), 4.06 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 13.5 Hz, 1H), 3.30 - 3.12 (m, 3H), 2.73 (q, J = 5.3 Hz, 2H), 2.65 (dd, J = 11.1, 7.1 Hz, 1H), 2.48 (s, 1H), 2.39 (t, J = 9.5 Hz, 1H).

[0152] Example 2 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2 [ka] [ka]

[0153] Step 1 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridine 2b

[0154] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-5,6-dihydropyridyl-1(2H)-tert-butyl formate 2a (65 mg, 0.15 mmol, obtained by the method disclosed in intermediate C5 on page 55 of the specification of patent application WO2019239319) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (70 mg, 0.37 mmol) was added, and the mixture was stirred at 60°C for 4 hours. The mixture was cooled, filtered, washed with ethyl acetate (10 mL), and the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the title compound 2b (75 mg, di-p-toluenesulfonate), which was used directly in the next step without purification. MS m / z (ESI): 346.1 [M+1].

[0155] Step 2 Methyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate 2c

[0156] Compound 2b (75 mg, 0.14 mmol, di-p-toluenesulfonate salt) was dissolved in 10 mL of acetonitrile, and compound 1c (40 mg, 0.14 mmol) and potassium carbonate (94 mg, 0.68 mmol) were added. The mixture was heated to 50° C. and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 2c (35 mg, yield: 42.7%). MS m / z (ESI): 604.1 [M+1].

[0157] Step 3 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 2

[0158] Compound 2c (35 mg, 0.06 mmol) was dissolved in 5 mL of acetonitrile, and lithium hydroxide monohydrate (3 mg, 0.07 mmol) and 1 mL of water were added at room temperature. The mixture was then reacted at 40°C for 16 hours. The mixture was cooled to room temperature and concentrated to remove the acetonitrile. The residue was adjusted to pH 6-7 with citric acid solution, dissolved in acetonitrile, and purified by high-performance liquid chromatography to obtain the title compound 2 (20 mg, yield: 58.5%). MS m / z (ESI): 590.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.80 (brs, 1H), 8.26(s, 1H), 7.81(d, 1H), 7.66 (d, 1H), 7.57-7.54 (m, 2H), 7.33 (d, 1H), 6.87-6.81 (m, 3H), 6.39-6.36 (m, 1H), 5.08-5.04 (m, 1H), 4.82-4.76 (m, 1H), 4.68-4.63 (m, 1H), 4.48-4.43 (m, 1H), 4.39-4.33 (m, 1H), 4.08-4.03 (m, 1H), 3.92-3.88 (m, 1H), 3.29-3.12 (m, 4H), 2.79-2.63 (m, 3H), 2.55-2.36 (m, 4H).

[0159] Example 3 2-((6-(1-(4-chloro-2-fluorobenzyl)ethoxy)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 3 [ka] [ka]

[0160] Step 1 2-Chloro-6-(1-(4-chloro-2-fluorophenyl)ethoxy)pyridine 3c

[0161] Potassium tert-butoxide (672 mg, 5.98 mmol) was added to tetrahydrofuran (10 mL), and 1-(4-chloro-2-fluorophenyl)ethanol 3b (523 mg, 2.99 mmol) was added at room temperature. The mixture was stirred at the same temperature for 45 minutes. 2,6-Dichloropyridine 3a (444 mg, 3.00 mmol) was added and the mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 3c (700 mg, yield: 81.7%).

[0162] Step 2 tert-Butyl 6-(4-chloro-2-fluorophenyl)ethoxy-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-carboxylate 3e

[0163] Compound 3c (309 mg, 999.32 μmol), anhydrous sodium carbonate (317 mg, 2.99 mmol), tetrakistriphenylphosphine palladium (58 mg, 50.19 μmol), water (4 mL), and dioxane (16 mL) were stirred overnight at 90 °C under argon gas protection. TLC showed the reaction was complete. The resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 3e (188 mg, yield: 43.5%). MS m / z (ESI): 433.1 [M+1].

[0164] Step 3 6-(1-(4-chloro-2-fluorophenyl)ethoxy)-1',2',3',6'-tetrahydro-2,4'-dipyridine 3f

[0165] Compound 3e (188 mg, 434.26 μmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid (206 mg, 1.08 mmol) was added, and the mixture was stirred at 60° C. for 4 hours. The mixture was cooled, filtered, washed with ethyl acetate (10 mL), and the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the title compound 3f (294 mg, di-p-toluenesulfonic acid salt, yield: 99.9%). MS m / z (ESI): 333.1 [M+1].

[0166] Step 4 2-((6-((4-chloro-2-fluorophenyl)ethoxy)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 3g

[0167] Compound 3f (270 mg, 398.69 μmol, 2TsOH) was dissolved in acetonitrile (5 mL), potassium carbonate (135 mg, 976.80 μmol) was added, and the mixture was heated to 50° C. and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 3g (81 mg, yield: 69.6%). MS m / z (ESI): 591.1 [M+1].

[0168] Step 5 2-((6-(1-(4-chloro-2-fluorophenyl)ethoxy)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 3

[0169] Compound 3g (80 mg, 135.3475 μmol) was dissolved in acetonitrile (5 mL) and water (1 mL). Lithium hydroxide monohydrate (8 mg, 190.47 μmol) was added and stirred at 40°C overnight. The mixture was concentrated and the pH was adjusted to 5-6 with citric acid. 10 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography using eluent system A to give the title compound 3 (35 mg, yield: 44.8%). MS m / z (ESI): 577.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 1.5 Hz, 1H), 7.66 (dd, J = 8.1, 3.2 Hz, 1H), 7.45 (td, J = 8.2, 2.7 Hz, 1H), 7.41 (dt, J = 10.2, 1.6 Hz, 1H), 7.24 (dt, J = 8.4, 1.5 Hz, 1H), 7.03 (dd, J = 7.5, 2.4 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.60 (td, J = 3.7, 1.9 Hz, 1H), 6.35 - 6.26 (m, 1H), 5.05 (ddd, J = 7.4, 5.0, 2.7 Hz, 1H), 4.79 (dd, J = 15.2, 7.3 Hz, 1H), 4.64 (dt, J = 15.4, 3.1 Hz, 1H), 4.51 - 4.42 (m, 1H), 4.36 (ddd, J = 6.1, 3.2, 1.8 Hz, 1H), 4.06 (dd, J = 13.5, 3.4 Hz, 1H), 3.90 (dd, J = 13.5, 5.6 Hz, 1H), 3.27 - 3.12 (m, 2H), 2.79 - 2.55 (m, 4H), 2.46 (s, 1H), 2.42 - 2.29 (m, 2H), 1.57 (d, J = 6.6 Hz, 3H).

[0170] Example 4 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4 [ka] [ka]

[0171] Step 1 (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridyl 4-methylbenzenesulfonate 4b

[0172] (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-1,2,3,6-tetrahydropyridyl-1(2H)-tert-butyl formate (4a, 88 mg, 0.20 mmol, prepared by the method disclosed in Example Intermediate C5 on page 55 of the specification of patent application WO2019239319 and obtained by chiral resolution) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (94 mg, 0.49 mmol) was added, and the mixture was stirred at 60°C for 4 hours, cooled, concentrated under reduced pressure, and washed with n-hexane (20 mL) to obtain crude product 4b (102 mg, p-toluenesulfonic acid salt), which was used directly in the next reaction without further purification. MS m / z (ESI): 345.9 [M+1].

[0173] Step 2 Methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate 4c

[0174] The crude product compound 4b (102 mg, 0.20 mmol, p-toluenesulfonate salt) was dissolved in 10 mL of acetonitrile, and compound 1c (50 mg, 0.17 mmol) and potassium carbonate (117 mg, 0.85 mmol) were added. The mixture was heated to 50° C. and stirred for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 4c (88 mg, yield: 85.9%). MS m / z (ESI): 604.1 [M+1].

[0175] Step 3 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid 4

[0176] Compound 4c (88 mg, 0.15 mmol) was dissolved in 5 mL of acetonitrile, and lithium hydroxide monohydrate (7 mg, 0.17 mmol) and 1 mL of water were added at room temperature. The mixture was then reacted at 40°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the acetonitrile. The residue was adjusted to pH 6-7 with citric acid solution, dissolved in acetonitrile, and purified by high-performance liquid chromatography (Waters-2767, elution system: ammonium bicarbonate, water, acetonitrile) to give the title compound 4 (50 mg, yield: 58.2%). MS m / z (ESI): 590.2 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 12.80 (brs, 1H), 8.27(s, 1H), 7.81(d, 1H), 7.66 (d, 1H), 7.57-7.54 (m, 2H), 7.33 (d, 1H), 6.87-6.81 (m, 3H), 6.39-6.36 (m, 1H), 5.08-5.04 (m, 1H), 4.82-4.76 (m, 1H), 4.68-4.63 (m, 1H), 4.48-4.43 (m, 1H), 4.39-4.33 (m, 1H), 4.17-4.06 (m, 1H), 4.00-3.90 (m, 1H), 3.32-3.19 (m, 2H), 2.86-2.73 (m, 2H), 2.70-2.64 (m, 1H), 2.60-2.53 (m, 1H), 2.46-2.34 (m, 2H), 2.03(s, 3H).

[0177] Example 5 (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 5 [ka] [ka]

[0178] Step 1 4-(((6-Bromopyridyl-2-yl)thio)methyl)-3-fluorobenzonitrile 5b

[0179] 3-Fluoro-4-(mercaptomethyl)benzonitrile 5a (309 mg, 1.84 mmol, prepared by the method described in US Patent Application Publication No. US2012329788A1, page 26, Intermediate I-2) was dissolved in toluene (10 mL). 2,6-Dibromopyridine (450 mg, 1.89 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (100 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (90 mg, 0.10 mmol), and N,N-diisopropylethylamine (600 mg, 4.64 mmol) were added and the mixture was heated at 100 °C in a microwave oven for 1 hour. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system B to give the title compound 5b (225 mg, 37.6% yield). MS m / z (ESI): 325 [M+1].

[0180] Step 2 tert-Butyl 6-((4-cyano-2-fluorobenzyl)thio)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-formate 5c

[0181] Compound 5b (255 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL) and N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridyl-4-boronic acid pinacol ester (220 mg, 0.71 mmol, Shaoyuan Chemical (Shanghai) Co., Ltd.), anhydrous sodium carbonate (220 mg, 2.08 mmol), tetrakistriphenylphosphine palladium (40 mg, 0.03 mmol), and water (3 mL) were added. The mixture was heated to 90 °C under a nitrogen atmosphere and stirred for 16 h. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system A to give the title compound 5c (260 mg, 87.8% yield). MS m / z (ESI): 426.1 [M+1].

[0182] Step 3 3-Fluoro-4-(((1',2',3',6'-tetrahydro-[2,4'-dipyridyl]-6-yl)thio)methyl)benzonitrile p-toluenesulfonate 5d

[0183] Compound 5c (125 mg, 0.29 mmol) was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (170 mg, 0.89 mmol) was added, followed by stirring at 60° C. for 4 hours. After cooling and filtration, the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the crude title product 5d (146 mg), which was used directly in the next step without further purification. MS m / z (ESI): 326.1 [M+1].

[0184] Step 4 (S)-2-((6-((4-cyano-2-fluorobenzyl)thio)-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 5e

[0185] Compound 1c (80 mg, 0.27 mmol) and compound 5d (146 mg, 0.29 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (200 mg, 1.44 mmol) was added, and the mixture was stirred at 50° C. for 5 hours. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system B to give the title compound 5e (158 mg, yield: 99%). MS m / z (ESI): 584.2 [M+1].

[0186] Step 5 (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 5

[0187] Compound 5e (150 mg, 0.26 mmol) was dissolved in 6 mL of a mixed solvent of acetonitrile and water (V:V = 5:1), lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added, and the mixture was stirred at 40 °C for 16 hours. The mixture was concentrated, the pH was adjusted to 5-6 with citric acid solution, acetonitrile (2 mL) was added, and the mixture was dissolved. The mixture was then purified by silica gel column chromatography using eluent system A to give the title compound 5 (90 mg, 61.5%). MS m / z (ESI): 570.1 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.71 (brs, 1H), 8.26 (s, 1H), 7.86-7.80 (m, 2H), 7.71-7.59 (m, 4H), 7.25 (d, 1H), 7.17 (d, 1H), 6.72 (s, 1H), 5.08-5.04 (m, 1H), 4.82-4.75 (m, 1H), 4.67-4.63 (m, 1H), 4.54 (s, 2H), 4.49- 4.44 (m, 1H), 4.38-4.32 (m, 1H), 4.09-3.91 (m, 2H), 3.28-3.21 (m, 2H), 3.17 (s, 2H), 2.78-2.72 (m, 2H), 2.69-2.62 (m, 1H), 2.43-2.34 (m, 1H).

[0188] Example 6 (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-5-fluoro-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 6 [ka] [ka]

[0189] Step 1 4-(((6-chloro-3-fluoropyridyl-2-yl)thio)methyl)-3-fluorobenzonitrile 6a

[0190] 3-Fluoro-4-(mercaptomethyl)benzonitrile 5a (280 mg, 1.67 mmol) was dissolved in toluene (10 mL), and 2,6-dichloro-3-fluoropyridine (280 mg, 1.69 mmol, Nanjing Yaoxi Technology Co., Ltd.), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (100 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (80 mg, 0.09 mmol), and N,N-diisopropylethylamine (550 mg, 4.26 mmol) were added. The mixture was heated at 100 °C in a microwave oven for 1 hour. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system B to give the title compound 6a (128 mg, 25.8% yield). MS m / z (ESI): 297.0 [M+1].

[0191] Step 2 tert-Butyl 6-((4-cyano-2-fluorobenzyl)thio)-5-fluoro-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-formate 6b

[0192] Compound 6a (128 mg, 0.43 mmol) was dissolved in 1,4-dioxane (10 mL) and N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridyl-4-boronic acid pinacol ester (22.15 g, 0.49 mmol, Shaoyuan Chemical (Shanghai) Co., Ltd.), anhydrous sodium carbonate (100 mg, 0.94 mmol), tetrakistriphenylphosphine palladium (50 mg, 0.04 mmol), and water (2 mL) were added. The mixture was heated to 90 °C under a nitrogen atmosphere and stirred for 4 h. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system B to give the title compound 6b (126 mg, 65.9% yield). MS m / z (ESI): 388.1 [M-55].

[0193] Step 3 3-Fluoro-4-(((5-fluoro-1',2',3',6'-tetrahydro-[2,4'-dipyridyl]-6-yl)thio)methyl)benzonitrile di-p-toluenesulfonate 6c

[0194] Compound 6b (126 mg, 0.28 mmol) was dissolved in ethyl acetate (5 mL), and p-toluenesulfonic acid monohydrate (160 mg, 0.84 mmol) was added, followed by stirring at 60° C. for 4 h. After cooling and filtration, the organic phase was collected, dried, filtered, and concentrated under reduced pressure to give the crude title product 6c (195 mg), which was used directly in the next step without further purification.

[0195] Step 4 (S)-2-((6-((4-cyano-2-fluorobenzyl)thio)-5-fluoro-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester 6d

[0196] Compound 1c (60 mg, 0.20 mmol) and compound 6c (195 mg, 0.28 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (150 mg, 1.09 mmol) was added, and the mixture was stirred at 50° C. for 5 hours. After cooling to room temperature and concentration, the mixture was purified by silica gel column chromatography using eluent system B to give the title compound 6d (96 mg, yield: 78.4%). MS m / z (ESI): 602.1 [M+1].

[0197] Step 5 (S)-2-((6-(4-cyano-2-fluorobenzyl)thio-5-fluoro-3',6'-dihydro-[2,4'-dipyridyl]-1'(2'H)-yl)methyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid 6

[0198] Compound 6d (86 mg, 0.14 mmol) was dissolved in 6 mL of a mixed solvent of acetonitrile and water (V:V = 5:1), and lithium hydroxide monohydrate (8 mg, 0.19 mmol) was added and stirred at 40 °C for 16 h. The mixture was concentrated, the pH was adjusted to 5-6 with citric acid solution, and acetonitrile (2 mL) was added and dissolved. The mixture was then purified by silica gel column chromatography using eluent system A to give the title compound 6 (26 mg, 31.0%). MS m / z (ESI): 588.2 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 12.77 (brs, 1H), 8.26 (d, 1H), 7.85 (dd, 2H), 7.81 (dd, 1H), 7.67-7.60 (m, 4H), 7.35 (dd, 1H), 6.66 (s, 1H), 5.09-5.04 (m, 1H), 4.82- 4.77 (m, 1H), 4.67-4.63 (m, 1H), 4.60 (s, 2H), 4.49-4.44 (m, 1H), 4.38-4.34 (m, 1H), 4.08-3.91 (m, 2H), 3.28-3.17 (m, 2H), 2.78-2.71 (m, 2H), 2.69-2.62 (m, 1H), 2.54- 2.51 (m, 1H), 2.43-2.36 (m, 1H).

[0199] Example 7 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridyl-5-carboxylic acid 7 [ka] [ka]

[0200] Step 1 Methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridyl-5-carboxylate 7b

[0201] The crude product, compound 4b (83 mg, 0.16 mmol), was dissolved in acetonitrile (5 mL), and the compound (S)-2-chloromethyl-3-(oxetanyl-2-ylmethyl)-3H-imidazo[4,5-b]pyridyl-5-methyl carboxylate 7a (45 mg, 0.15 mmol, prepared according to the method described in Intermediate P27 on page 85 of Patent Application WO2019239371A1) and potassium carbonate (100 mg, 0.72 mmol) were added. The mixture was heated to 50 °C and stirred for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give the title compound 7b (64 mg, yield: 69.5%). MS m / z (ESI): 605.1 [M+1].

[0202] Step 2 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolan-4-yl)-3,6-dihydropyridyl-1(2H)-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridyl-5-carboxylic acid 7

[0203] Compound 7b (64 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), and lithium hydroxide monohydrate (5 mg, 0.12 mmol) and water (1 mL) were added at room temperature. The mixture was then reacted at 40° C. for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the acetonitrile. The residue was adjusted to pH 6-7 with citric acid solution, dissolved in acetonitrile, and purified by silica gel column chromatography using eluent system A to obtain the title compound 7 (15 mg, yield: 24.0%). MS m / z (ESI): 591.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.14(d, 1H), 8.00(d, 1H), 7.57-7.53 (m, 2H), 7.34-7.32 (m, 1H), 6.87-6.81 (m, 3H), 6.39-6.36 (m, 1H), 5.18-5.13 (m, 1H), 4.85-4.81 (m, 1H), 4.72-4.68 (m, 1H), 4.49-4.44 (m, 1H), 4.38-4.34 (m, 1H), 4.12 (d, 1H), 4.01 (m, 1H), 3.28-3.23 (m, 2H), 2.81-2.72 (m, 2H), 2.69-2.64 (m, 1H), 2.59-2.54 (m, 1H), 2.48-2.39 (m, 2H), 2.02(s, 3H).

[0204] Biological evaluation Test Example 1: Evaluation of GLP-1 receptor agonist activity 1. Purpose of the test The purpose of this experiment was to test the agonistic activity of compound molecules on the GLP-1 receptor and to evaluate the in vitro activity of the molecules by the magnitude of EC50. TM Luciferase test system (ONE-Glo TMUsing the ONE-Glo Luciferase Assay System (Promega, E6110), the GLP-1R downstream signaling pathway is activated under the action of compound molecules, causing an increase in cAMP levels. cAMP binds to CRE, which then initiates transcriptional expression of the CRE downstream luciferase gene. When luciferase reacts with its substrate, it emits fluorescence, and the ONE-Glo TM The fluorescent signal measured by the reagent reflected the activity of the compound to agonize the GLP-1 receptor.

[0205] 2. Experimental Method A CHO-K1 / CRE-luc / GLP-1 receptor stable transfected cell line was constructed (GLP-1 receptor plasmid self-construction, CRE-luc plasmid Promega E8471). CHO-K1 / CRE-luc / GLP-1 receptor cells were digested, centrifuged, and resuspended. The single-cell suspension was homogenized and cultured in cell culture medium (DME / F-12 + 10% FBS) to a viable cell density of 2.5 × 10 cells. 5 The solution was adjusted to cells / mL and added to a 96-well cell culture plate (Corning, #3903) at 90 μL / well. The culture plate was cultured in an incubator (37°C, 5% CO2) for 16 hours. Compounds were dissolved in DMSO to prepare a stock solution with an initial concentration of 20 mM. The initial concentration of small molecule compounds was 0.2 mM, and they were diluted 3-fold, followed by 10 dilutions, with the 11th dilution being DMSO. Another 96-well plate was taken, and 95 μL of cell culture medium (DME / F-12 + 10% FBS) was added per well, followed by 5 μL of the sample to be tested at different concentrations per well. The mixture was mixed evenly, and then 10 μL of the sample to be tested at different concentrations was added to the cell culture plate, with each sample being placed in two parallel wells. The culture plate was then incubated in an incubator (37°C, 5% CO2) for 6 hours. The 96-well cell culture plate was removed, and 100 μL of ONE-Glo was added to each well. TM The reagent was added and incubated at room temperature for 10 minutes. Chemiluminescence was measured in a microplate reader (EnVision 2105, PE).

[0206] 3. Data analysis Data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. EC 50 Values ​​were obtained and the results are shown in Table 1 below.

[0207] [Table 3] Conclusion: The compounds according to the present disclosure have good agonistic activity on the GLP-1 receptor.

[0208] Test Example 2: Effect of the compounds of the present disclosure on the hERG potassium ion channel 1. Purpose of the test The blocking effect of compounds of the present disclosure on hERG potassium current was tested in stable cell lines transfected with the hERG potassium channel using automated patch clamp.

[0209] 2. Testing Method 2.1 Experimental materials and equipment 2.1.1 Experimental materials: [Table 4] 2.1.2 Experimental equipment: [Table 5] 2.2 Fully automated patch clamp experiment procedure pCDNA3.1(+), which contained the hERG gene, was transfected into HEK293 cells, and monoclonal HEK293-hERG stable cell lines were selected by adding G418. The HEK293-hERG stable cell lines were subcultured at a density of 1:4 in MEM / EBSS medium (10% FBS, 400 μg / mL G418, 1% MEM non-essential amino acid solution (100x), 1% sodium pyruvate solution) for 48–72 hours of culture for automated patch clamp experiments. On the day of the experiment, cells were digested with 0.25% pancreatin (Life Technologies, 12563-029), collected by centrifugation, and resuspended in extracellular solution (140 mM NaCl, 4 mM KCl, 1 mM MgCl2, 2 mM CaCl2). 2、 Cells were resuspended in 5 mM glucose monohydrate, 10 mM HEPES, pH 7.4, 298 mOsmol (298 mOsmol). The cell suspension was placed in the cell bank of the Patchliner instrument, which then placed the cells onto a chip (NPC-16) using a negative pressure controller. Single cells were then aspirated into the chip wells using negative pressure. After forming a whole-cell pattern, the instrument acquired hERG currents using a preset hERG current-voltage program. The instrument then automatically perfused compounds from low to high concentrations. Currents at each compound concentration and blank control currents were analyzed using a HEAK EPC10 patch clamp amplifier (Nanion) and data analysis software provided by Pathliner software and Pathcontrol HT software. 2.3 Test Results The blocking effect of the compounds of the present disclosure on hERG potassium current was measured by the above test, and the measured IC 50 The values ​​are shown in Table 2.

[0210] [Table 6] Conclusion: The compounds disclosed herein have low inhibitory effects on hERG and can reduce the side effects caused by the hERG channel.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Among them, Q is Q0 or Q2, i.e., 【Chemistry 2】 and G １ , G ２ and G ３ are each independently CR ７ or a N atom, Z １ , Z ２ , Z ３ and Z ４ are each independently CR ８ or a N atom, Y is a S atom, W １ and W ２ are each independently an O atom, an S atom, or NR １２ and CR １３ R １４ Selected from R ａ and R ｂ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group; R １ are selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ２ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ３ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ４ is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ５ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ６ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R ７ and R ８ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 12 is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R13 and R １４ are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, or 3, and p is 0, 1, 2, 3, 4 or 5; A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

2. Q is Q1 or Q2, i.e., 【Transformation 3】 That is, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. G １ is a CH or N atom, and G ２ and G ３ and R are each CH, or a pharmaceutically acceptable salt thereof.

4. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. Q is Q4, i.e., 【Transformation 5】 That is, The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof: 【Transformation 6】 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. A compound represented by formula (IIIaa), or a pharmaceutically acceptable salt thereof: 【Transformation 7】 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R １ is C １－６ is an alkyl group, １－６ The alkyl group may optionally be a halogen, a hydroxy group, a C １－６ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is substituted with one or more substituents selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group.

9. R ２ are each independently a hydrogen atom or C １－６ The compound according to any one of claims 1 to 8, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

10. R ３ are each independently a hydrogen atom, a halogen, or C １－６ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein the group is selected from an alkyl group and a cyano group.

11. R ４ is a hydrogen atom or C １－６ The compound according to any one of claims 1 to 10, which is an alkyl group, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1-6 alkyl group.

13. R ５ are each independently a hydrogen atom, a halogen, or C １－６ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from alkyl groups.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 6 is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group.

15. the below described: 【Transformation 8】 、 【Chemistry 9】 、 【Chemistry 10】 、 【Chemistry 11】 , and 【Chemistry 12】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

16. A compound represented by formula (IA), or a pharmaceutically acceptable salt thereof, 【Chemistry 13】 Among them, R ｗ is C １－６ is an alkyl group, Q is Q0 or Q2, i.e., 【Chemistry 14】 and G 1 , G 2 and G 3 are each independently CR 7 or an N atom; Z 1 , Z 2 , Z 3 and Z 4 are each independently CR 8 or an N atom; Y is a S atom, W 1 and W 2 are each independently selected from an O atom, an S atom, NR 12 and CR 13 R 14 ; R a and R b are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 1 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 2 is independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 3 is each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 4 is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5 is each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 6 is independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents selected from a halogen atom, an alkyl group, alkenyl group, alkynyl group, alkoxy group, a haloalkyl group, a haloalkoxy group, cyano group, amino group, nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 7 and R 8 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 12 is independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an amino group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 13 and R 14 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, or 3, and p is 0, 1, 2, 3, 4 or 5; A compound of formula (IA), or a pharmaceutically acceptable salt thereof:

17. the below described: 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

18. 10. A method for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising: 【Chemistry 16】 hydrolysis of a compound of formula (IA) to obtain a compound of formula (I), Among them, R ｗ is C １－６ is an alkyl group, method.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents or excipients.

20. The pharmaceutical composition according to claim 19, for agonizing the GLP-1 receptor.

21. 20. The pharmaceutical composition of claim 19 for treating type 1 diabetes, type 2 diabetes, idiopathic type 1 diabetes, latent autoimmune diabetes in adults (LADA), maturity-onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, diabetic complications, obesity, hyperglycemia, impaired glucose tolerance, cardiovascular disease, atherosclerosis, hypertension, hyperlipidemia, coronary heart disease, cerebral infarction, stroke, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, insulin resistance or hepatic insulin resistance.

22. The pharmaceutical composition of claim 19 for treating type 1 diabetes, type 2 diabetes, obesity, diabetic complications, non-alcoholic steatohepatitis or cardiovascular disease.

23. The pharmaceutical composition of claim 21 for treating obesity.

24. The pharmaceutical composition of claim 21 for treating type 2 diabetes.

25. The pharmaceutical composition of claim 21 for treating diabetic complications.

26. The pharmaceutical composition described in claim 25, wherein the diabetic complication is diabetic retinopathy, diabetic kidney disease, or diabetic neuropathy.

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