Nitrogen-containing heteroaromatic ring derivative regulator as well as preparation method and application thereof

Abstract

The invention relates to a nitrogen-containing heteroaromatic ring derivative regulator as well as a preparation method and application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and an application of the compound as a regulator in the preparation of drugs for treating metabolic diseases and related diseases, each substituent in the general formula (I) being as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a nitrogen-containing heteroaromatic ring derivative regulator, a preparation method and application thereof. Background Art

[0002] Diabetes mellitus is a common endocrine metabolic disease. It is caused by metabolic disorders due to various reasons, leading to multi-system and multi-organ damage. The incidence rate is high. There are about 425 million diabetics in the world. The incidence rate of diabetes in China is about 10%, of which type 2 diabetes accounts for 90%. The incidence rate is still increasing, and the age of patients is getting younger and younger.

[0003] Currently, there are many types of drugs on the market for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, α-glucosidase inhibitors, etc., among which GLP-1 receptor agonists are the most popular.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, central nervous system and peripheral nervous system neurons. After activation, GLP-1 receptors have physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, suppressing appetite and delaying gastric emptying. Clinical evidence shows that compared with other hypoglycemic drugs, GLP-1 receptor agonists have better blood sugar lowering effects and are less likely to have side effects such as hypoglycemia. In addition, it has additional cardiovascular benefits, and can reduce food intake and delay gastric emptying, which is beneficial for weight control.

[0005] Currently, the GLP-1 receptor agonists on the market are all peptide drugs, most of which need to be administered subcutaneously, and patients' compliance is poor. In addition, the bioavailability of oral peptides is very low. Therefore, there is a great clinical demand for the development of oral small molecule GLP-1 receptor agonists.

[0006] Currently, no small molecule GLP-1 receptor agonists have been approved, and three small molecule GLP-1 receptor agonists have entered the clinical research stage, such as PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv, which are currently in the clinical phase I / II research stage. Among them, PF-06882961 has shown significant hypoglycemic and weight-reducing effects in early clinical trials, and its safety is similar to that of peptide GLP-1 receptor agonists. It is expected to bring more treatment options for patients with diabetes, obesity, and NASH in the future.

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

[0008] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0009]

[0010] in,

[0011] R 1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0012] R 2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0013] R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0014] R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR a1 Rb1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl;

[0015] Or, any two R 4 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0016] R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , Rb3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0017] M1 is O, S, N, C or CH;

[0018] M2 is O, S, N, C or CH;

[0019] M2 is O, S, N, C or CH;

[0020] x is 0, 1, 2, 3, 4, or 5;

[0021] y is 0, 1, 2, 3, or 4;

[0022] z is 0, 1, 2, 3, or 4;

[0023] m is 0, 1, 2 or 3;

[0024] Wherein, the compound of general formula (I) is not

[0025]

[0026] In certain further preferred embodiments of the present invention, the compound of general formula (I) is

[0027] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy;

[0028] Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0029] More preferred are hydrogen, deuterium, fluorine, chlorine, cyano or methoxy.

[0030] In certain further preferred embodiments of the present invention, the compound of general formula (I) is

[0031] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy;

[0032] Preferred are hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0033] More preferred are hydrogen, deuterium, fluorine, chlorine or methyl.

[0034] In certain further preferred embodiments of the present invention, the compound of general formula (I) is

[0035] R 3 are each independently selected from hydrogen, deuterium or fluorine;

[0036] Preferred are hydrogen and deuterium.

[0037] In certain further preferred embodiments of the present invention, the compound of general formula (I) is

[0038] R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NRa3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl;

[0039] Preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl;

[0040] More preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, -C(O)NR a1 R b1 、-C(O)NR a2S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms or 5-10 membered heteroaryl containing 1-4 heteroatoms, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl;

[0041] More preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-6 Cycloalkyl, 5-6 membered heterocyclyl containing 1-4 atoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, optionally further substituted or unsubstituted by halogen, amino, nitro, hydroxy, cyano, oxo, methyl, trifluoromethyl, oxo 3-8 Cycloalkyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S, oxo-substituted or unsubstituted C 6-10 Aryl and oxo substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S atoms, substituted with one or more substituents;

[0042] More preferably, R 4 Each independently selected from Optionally further substituted by one or more substituents of hydroxyl, cyano, oxo, methyl, trifluoromethyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S atoms;

[0043] Or, more preferably, R 4 Each independently selected from

[0044] In certain further preferred embodiments of the present invention, the compound of general formula (I) is

[0045] R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms;

[0046] Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-4 atoms selected from N, O or S, C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S;

[0047] More preferred are hydrogen, deuterium, hydroxy, methyl and methoxy.

[0048] In certain further preferred embodiments of the present invention, the compound of general formula (I) is further represented by general formula (I-1):

[0049]

[0050] In certain further preferred embodiments of the present invention, the compound of general formula (I) is further represented by general formula (II):

[0051]

[0052] in,

[0053] Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl;

[0054] R 1 , R 2 , R 3 , x, y, z, M1, M2, and M3 are as described in the general formula (I).

[0055] In certain further preferred embodiments of the present invention, the compound of general formula (II):

[0056] Ring A is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms or 5-10 membered heteroaryl containing 1-4 heteroatoms, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl;

[0057] Preferably, ring A is selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclyl containing 1-4 atoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, optionally further substituted or unsubstituted by halogen, amino, nitro, hydroxy, cyano, oxo, methyl, trifluoromethyl, oxo 3-8 Cycloalkyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S, oxo-substituted or unsubstituted C 6-10 Aryl and oxo substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S atoms, substituted with one or more substituents;

[0058] More preferably, ring A is selected from Optionally further substituted by one or more substituents selected from hydroxy, cyano, oxo, methyl, trifluoromethyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S atoms.

[0059] In certain further preferred embodiments of the present invention, the compound of general formula (II) is further represented by general formula (II-1):

[0060]

[0061] In certain further preferred embodiments of the present invention, the compound of general formula (I) is further represented by general formula (III):

[0062]

[0063] in,

[0064] R 4 Selected from -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 ;

[0065] R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3, R b4 , R b5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0066] R 1 , R 2 , R 3 , x, y, and z are as described in the general formula (I).

[0067] In certain further preferred embodiments of the present invention, the compound of general formula (III):

[0068] R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms;

[0069] Preferred are hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-4 atoms selected from N, O or S, C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S;

[0070] More preferred are hydrogen, deuterium, hydroxy, methyl and methoxy.

[0071] In certain further preferred embodiments of the present invention, the compound of general formula (III):

[0072] R 4 Selected from

[0073] In certain further preferred embodiments of the present invention, the compound of general formula (III) is further represented by general formula (III-1):

[0074]

[0075] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0076] In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as the free base, is 0.1% to 95%, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0077] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0078] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0079] In certain embodiments of the present invention, the pharmaceutical composition, calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0080] In certain embodiments of the invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0081] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0082] The present invention further relates to the use of any of the compounds of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of GLP-1 receptor agonist drugs.

[0083] The present invention further relates to the use of the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs for treating metabolic-related diseases, wherein the metabolic-related diseases are selected from diabetes, obesity or non-alcoholic fatty liver disease-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic fatty liver disease.

[0084] The present invention further relates to a method for using the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in preparing drugs for treating metabolic diseases and related diseases.

[0085] The present invention also relates to a method for treating, preventing and / or treating metabolic-related diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0086] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with GLP-1 receptor modulators.

[0087] The present invention also relates to a method for treating metabolic disease-related diseases in mammals, which comprises administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0088] Detailed description of the invention

[0089] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0090] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 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. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

[0091] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH2-, "ethylene" means -(CH2)2-, "propylene" means -(CH2)3-, "butylene" means -(CH2)4-, etc.

[0092] The term "alkenylene" means that one of the hydrogen atoms of the alkenyl group is further substituted, for example, "vinylene" means -CH2=CH2-, "propenylene" means -CH2-=CH2-CH2-, etc. The alkenylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further 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; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0093] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0094] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0095]

[0096] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0097]

[0098] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0099]

[0100] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0101]

[0102] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0103] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, but does not include -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; further preferably, it contains 3 to 8 ring atoms; further preferably, it contains 3 to 6 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen, oxygen or sulfur. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl, etc.; preferably, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, Piperazinyl and pyranyl; more preferably pyrrolidinyl, azetidinyl, oxetanyl, oxhexane, piperidinyl, Piperazinyl and pyranyl. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups; wherein the spirocyclic, condensed ring and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0104] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0105]

[0106]

[0107] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0108]

[0109] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0110]

[0111] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0112]

[0113] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0114] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0115]

[0116] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0117] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 10 yuan, more preferably 5 to 8 yuan, and most preferably 5 or 6 yuan, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0118]

[0119] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0120] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, preferably containing an alkyl of 1 to 8 carbon atoms, more preferably an alkyl of 1 to 6 carbon atoms, more preferably an alkyl of 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0121] "Alkenyl" refers to alkenyl, also known as olefin group, preferably alkenyl containing 2 to 8 carbon atoms, more preferably alkenyl containing 2 to 6 carbon atoms, most preferably alkenyl containing 2 to 3 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group can be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0122] "Alkynyl" refers to (CH≡C-), preferably an alkynyl containing 2 to 8 carbon atoms, more preferably an alkynyl containing 2 to 6 carbon atoms, and most preferably an alkynyl containing 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0123] The term "alkynylene" means that one of the hydrogen atoms of the alkynyl group is further substituted, for example, "ethynylene" means -C≡C-, "propynylene" means -C≡C-CH2-, etc. Alkynylenes (containing more than three carbon atoms) may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0124] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0125] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0126] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0127] “C 1-6 "Cyanoalkyl" refers to -C 1-6 Alkyl CN, such as -CH2CN, -CH2CH2CN, etc.

[0128] “C 1-6 "Carboxyl" refers to -C 1-5 AlkylCOOH.

[0129] "Hydroxy" refers to an -OH group.

[0130] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0131] "Amino" refers to -NH2.

[0132] "Cyano" refers to -CN.

[0133] "Nitro" refers to -NO2.

[0134] "Carboxy" refers to -C(O)OH.

[0135] "THF" refers to tetrahydrofuran.

[0136] "TFA" refers to trifluoroacetic acid.

[0137] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0138] "LiHMDS" refers to lithium bistrimethylsilylamide.

[0139] Indicates a single bond or a double bond.

[0140] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0141] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0142] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0143] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0144] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0145] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0146] Intermediate Im-1

[0147]

[0148] first step

[0149] 2-Bromo-5-fluoropyridine 1-oxide

[0150] In a 50mL reaction bottle, 2-bromo-5-fluoropyridine (2.00g, 11.4mmol) was dissolved in chloroform (30mL), and then urea hydrogen peroxide (2.14g, 22.7mmol) and trifluoroacetic anhydride (4.77g, 22.7mmol) were added. The reaction solution was stirred at room temperature for 12 hours. The reaction was stopped, and a Na2SO3 aqueous solution (20mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (15mL×2). The combined organic phases were washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product 2-bromo-5-fluoropyridine 1-oxide (1.9g), with a yield of 87.0%.

[0151] MS m / z(ESI):191.9[M+H]+.

[0152] Step 2

[0153] 2-Bromo-5-fluoro-4-nitropyridine 1-oxide

[0154] In a 50 mL reaction bottle, 2-bromo-5-fluoropyridine 1-oxide (1.9 g, 9.90 mmol) was dissolved in sulfuric acid (20 mL), and then nitric acid (2.14 g, 22.7 mmol) was added. The reaction solution was stirred at 100 ° C for 4 hours. The reaction was stopped, and water (100 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product 2-bromo-5-fluoro-4-nitropyridine 1-oxide (1.6 g), with a yield of 68.2%.

[0155] MS m / z(ESI):236.9[M+H]+.

[0156] Step 3

[0157] (S)-2-Bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide

[0158] 2-Bromo-5-fluoro-4-nitropyridine N-oxide (1.6 g, 6.75 mmol) and K2CO3 (1.86 g, 13.50 mmol) were dissolved in tetrahydrofuran (30 mL) in a 50 mL reaction bottle, and then (S)-oxabutane-2-ylmethylamine (588.2 mg, 6.75 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. The reaction was stopped, and water (20 mL) was added to quench the reaction, and ethyl acetate (15 mL×2) was used for extraction. The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product (S)-2-bromo-4-nitro-5-((oxabutane-2-ylmethyl)amino)pyridine 1-oxide (1.9 g), with a yield of 92.5%.

[0159] MS m / z(ESI):303.9[M+H]+.

[0160] Step 4

[0161] (S)-6-Bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine

[0162] At room temperature, ((S)-2-bromo-4-nitro-5-((oxetane-2-ylmethyl)amino)pyridine 1-oxide (1 g, 3.28 mmol) and Zn powder (2.1 g, 32.8 mmol) were dissolved in methanol (25 mL), and then acetic acid (985 mg, 16.4 mmol) was added dropwise, heated to 60 ° C and stirred for 2 hours. Cool to room temperature, filter, adjust the filtrate to pH = 7 with saturated sodium bicarbonate, extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, filter, and spin dry to obtain the title product (S)-6-bromo-N3-(oxetane-2-ylmethyl)pyridine-3,4-diamine (804 mg), yield: 95%.

[0163] MS m / z(ESI):258.0[M+H]+.

[0164] Step 5

[0165] (S)-4-Amino-5-((oxetan-2-ylmethyl)amino)picolinonitrile

[0166] At room temperature, (S)-6-bromo-N3-(oxetane-2-ylmethyl)pyridine-3,4-diamine (500 mg, 1.94 mmol), RuPhos-Pd-G3 (324.5 mg, 0.39 mmol), X-Phos (186 mg, 0.39 mmol) and Zn(CN)2 (458 mg, 3.9 mmol) were dissolved in NMP (15 mL), replaced with nitrogen three times, heated to 130°C and stirred for 0.5 hours. Cooled to room temperature, filtered, the filtrate was extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product (S)-4-amino-5-((oxetane-2-ylmethyl)amino)picolinonitrile (345 mg), with a yield of 87.1%.

[0167] MS m / z(ESI):205.1[M+H]+.

[0168] Step 6

[0169] (S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

[0170] At room temperature, (S)-4-amino-5-((oxetane-2-ylmethyl)amino)picolinonitrile (300 mg, 1.47 mmol) was dissolved in tetrahydrofuran (5 mL), and then a solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise, stirred at room temperature for 30 minutes, then heated to 60°C, reacted for 2 hours, cooled to room temperature, and LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then washed with saturated sodium bicarbonate solution (15 mL×3), washed with saturated sodium chloride solution (15 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the title product (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (350 mg), with a yield of 90.7%.

[0171] MS m / z(ESI):263.0[M+H]+.

[0172] Intermediate Im-2

[0173] tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0174]

[0175] first step

[0176] tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0177] Dissolve 1-(3-bromo-2-hydroxyphenyl)ethane-1-one (20 g, 0.09 mol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32 g, 0.10 mol), Pd(dppf)Cl2·CH2Cl2 (7.6 g, 9.40 mmol), and anhydrous potassium carbonate (39 g, 0.28 mol) in 250 mL of a mixed solvent of dioxane and water (4:1). Heat the reaction to 100°C and stir for 8 hours. The reaction was stopped, and the reaction solution was cooled to ambient temperature. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (26 g, colorless oil) in a yield of 88.1%.

[0178] MS m / z(ESI):318.1[M+H]+.

[0179] Step 2

[0180] tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0181] Tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (26 g, 0.08 mol) and Pd / C (2.6 g, 10% wt.) were dispersed in methanol (300 mL), hydrogen was introduced 3 times, and air was exhausted. The reaction solution was stirred for 12 hours. The reaction was stopped, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate (25 g, white solid), yield: 95.6%. MS m / z (ESI): 320.1 [M+H] +.

[0182] Example 1

[0183] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[0185] first step

[0186] 4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester

[0187] Dissolve tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate (9.25 g, 28.97 mmol) in tetrahydrofuran (100 mL). Cool the solution in a dry ice / ethanol bath, slowly add LiHMDS (66.6 mL, 66.63 mmol, 1M THF solution) to it, and stir and react for 30 minutes after addition. Dissolve 1-(4-chloro-2-fluorophenyl)ethane-1-one (5 g, 28.97 mmol) in THF (30 mL), slowly add this solution dropwise to the above reaction solution, and stir and react for 40 minutes while maintaining the temperature of the dry ice / ethanol bath. The reaction was stopped, the dry ice / ethanol bath was removed, saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL×2). The organic phases were combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (7.6 g), in a yield of 53.3%.

[0188] MS m / z(ESI):492.2[M+H]+.

[0189] Step 2

[0190] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one

[0191] Dissolve tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate (5g, 10.16mmol) and p-toluenesulfonic acid (5.25g, 30.48mmol) in toluene (50mL). Heat the reaction solution to 100°C and stir for 5 hours. Stop the reaction, cool the reaction solution to room temperature, add 2M sodium hydroxide solution to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (50mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with an eluent system of dichloromethane and methanol to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one (2.36g), yield: 62.1%.

[0192] MS m / z(ESI):374.1[M+H]+.

[0193] Step 3

[0194] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol

[0195] 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one (2g, 5.35mmol) was dissolved in methanol (30mL). Sodium borohydride (396mg, 10.70mmol) was slowly added to the solution in batches under an ice bath. After the addition, the ice bath was removed and the reaction solution was naturally heated to ambient temperature for 2 hours. The reaction was stopped and saturated ammonium chloride solution was added to the reaction solution to quench the reaction. The pH was adjusted to 10 with 1M sodium hydroxide solution, and extracted with dichloromethane (50mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol (1.88g), with a yield of 93.5%. The compound was used directly in the next step without purification.

[0196] MS m / z(ESI):376.1[M+H]+.

[0197] Step 4

[0198] 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine

[0199] Dissolve 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol (1.50 g, 3.99 mmol) and p-toluenesulfonic acid (2.06 g, 11.97 mmol) in toluene (20 mL). Heat the reaction solution to 100°C and stir for 30 minutes. Stop the reaction, cool the reaction solution to room temperature, add 2M sodium hydroxide solution to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine (1.02 g), with a yield of 71.4%. The compound was used directly in the next step without purification.

[0200] MS m / z(ESI):358.1[M+H]+.

[0201] Step 5

[0202] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

[0203] Disperse 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine (500 mg, 1.40 mmol), (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (367.05 mg, 1.40 mmol), and anhydrous potassium carbonate (386.98 mg, 2.80 mmol) in acetonitrile (10 mL). Heat the reaction solution to 50°C and stir vigorously for 3 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using ethyl acetate as an eluent. The purified sample was chirally resolved to give the title product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (600 mg) in a yield of 73.5%.

[0204] MS m / z(ESI):584.2[M+H]+.

[0205] Step 6

[0206] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidic acid methyl ester

[0207] At room temperature, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (500 mg, 856.03 μmol) was dissolved in methanol (15 mL), sodium methoxide (92.49 mg, 1.71 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Add 20 mL of water, extract with ethyl acetate (30 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to give the title product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidic acid methyl ester (450 mg), yield: 85.3%.

[0208] MS m / z(ESI):616.2[M+H]+.

[0209] Step 7

[0210] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-

[0211] (((S)-Oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide

[0212] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidic acid methyl ester (104.59 mg, 0.17 mmol) and 2-hydrazino-2-oxoacetamide (35 mg, 0.34 mmol) were dissolved in n-butanol (5 mL), DIEA (66 mg, 0.51 mmol) was added, the atmosphere was replaced with nitrogen three times and the reaction was carried out at 120°C under nitrogen protection for 16 hours. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (70 mg), yield: 61.6%.

[0213] MS m / z(ESI):669.2[M+H]+.

[0214] Step 8

[0215] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-

[0216] (((S)-Oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[0217] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (50 mg, 74.72 μmol) and DIEA (30 mg, 232.13 μmol) were dissolved in DCM, TFAA (24 mg, 114.27 μmol) was added and stirred at room temperature for 10 minutes. Add 50 mL of water, extract with ethyl acetate (10 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and spin dry. Purify the residue using prep-HPLC to give the title product 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile (25 mg), yield: 51.3%.

[0218] MS m / z(ESI):651.2[M+H]+.

[0219] The similar preparation method of reference example 1 gave examples 2-37

[0220]

[0221]

[0222]

[0223] Biological test evaluation

[0224] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0225] 1. Determination of the ability of the compounds of the present invention to stimulate the production of cAMP in human GLP1 receptor stably transfected cell lines

[0226] 1. Experimental purpose:

[0227] The purpose of this test case is to test the ability of compounds to activate human GLP-1 receptors on the cell surface. 50 Characterize the ability of compounds to activate human GLP-1 receptor.

[0228] 2. Experimental reagents and instruments:

[0229] 2.1 Experimental instruments:

[0230] Microplate reader (BioTek Synergy H1);

[0231] Pipette (Eppendorf & Rainin).

[0232] 2.2 Experimental reagents:

[0233] DMEM / F12 medium was purchased from Gibco, catalog number 11330032;

[0234] Casein was purchased from Sigma, catalog number C3400;

[0235] The 384-well plate was purchased from Sigma, catalog number CLS4514;

[0236] IBMX was purchased from Sigma, catalog number I7018;

[0237] Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio, catalog number 62AM4PEC.

[0238] 3. Experimental methods:

[0239] Take out the frozen human GLP1 receptor stable cell line CHO-K1 / GLP-1R / CRE-luc from the liquid nitrogen tank, put it in a 37℃ water bath to thaw quickly, resuspend it with DMEM / F12 medium, wash the cells after centrifugation, resuspend it with experimental buffer, that is, DMEM / F12 medium containing 0.1% casein, adjust the cell density with experimental buffer, and plate it in a 384-well plate at a density of 2500 cells / 5μL / well, then add 2.5μL of IBMX working solution prepared with buffer to each well, the final concentration of IBMX is 0.5mM, and 2.5μL of gradient dilution compound sample (starting at 1000nM, 3-fold dilution, 11 concentrations), centrifuge at 1000rpm for 1min, shake for 30 seconds to mix, and incubate at room temperature for 30 minutes. Use Cisbio cAMP-Gs Dynamic kit for detection, cAMP-d2 and Anti-cAMP-Eu 3+ -Cryptate were diluted 20 times with cAMP Lysis & Detection Buffer and mixed well. Add 5 μL of diluted cAMP-d2 solution to each well, and then add 5 μL of diluted Anti-cAMP-Eu3 + -Cryptate solution, shake for 30 seconds to mix, and incubate at room temperature in the dark for 1 hour. Use Biotek Synergy H1 microplate reader to read HTRF signals, with excitation wavelength of 320nm and emission wavelengths of 620nm and 665nm.

[0240] 4. Experimental data processing method:

[0241] The signal ratio (665nm / 620nm*10,000) was calculated and the EC was obtained by nonlinear fitting of the signal ratio and sample concentration using a four-parameter equation in GraphPad Prism 6. 50 value.

[0242] In some embodiments, the compounds of the embodiments of the present invention show good biological activity in the experiment of stimulating human GLP1 receptor stably transfected cell lines to produce cAMP. The EC50 of the compounds of the present invention in the experiment of stimulating hGLP1R stably transfected cell lines to produce cAMP is less than about 100nM, preferably less than about 50nM, further preferably less than about 10nM, more preferably less than about 5nM, more preferably less than about 1nM, and most preferably less than 0.1nM among the compounds listed in the present invention.

[0243] II. Effect of a single administration of the compound of the present invention on intraperitoneal glucose tolerance in GLP-1R humanized mice

[0244] 1. Purpose of the test:

[0245] The effect of a single administration of the compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance test (ipGTT) experiment of GLP-1R humanized C57BL / 6 mice was evaluated.

[0246] 2. Experimental materials:

[0247] C57BL / 6_hGLP-1R, male, 5-8 weeks; clean bench; electronic balance; active blood glucose meter; glucose.

[0248] 3 Experimental operation and data processing:

[0249] 3.1. One day before the experiment, the animals were randomly divided into groups according to their body weight, with 5 animals in each group. All animals were deprived of food overnight and fasted for more than 16 hours before drug administration;

[0250] 3.2. Use pure water to prepare 0.2g / mL glucose solution, filter it through a 0.22μm filter membrane and set aside;

[0251] 3.3. On the test day, the blood glucose level of each animal was measured by tail snip method before administration and recorded as the Baseline value;

[0252] Blood glucose test method: Place the mouse in a restrainer, disinfect the tail tip with an alcohol cotton ball, then cut off a small part of the tail tip with scissors, discard the first drop of blood, and drop the second drop of blood onto the prepared blood glucose test strip to test the blood glucose value;

[0253] 3.4. Administer the drug according to the animal's body weight and record the administration time for each animal. Measure the blood glucose level of each animal one hour after administration and record it as the blood glucose level at 0 min;

[0254] 3.5. Then, according to the body weight on that day, pure water or glucose solution was immediately injected intraperitoneally, with a volume of 10 mL / kg and a glucose dose of 2 g / kg;

[0255] 3.6. Measure the blood glucose level of each mouse 15, 30, 60, 90 and 120 min after the injection of pure water or glucose solution and record the time and data;

[0256] 3.7. After the test, all animals resumed eating.

[0257] 3.8 Data processing:

[0258] Draw the blood glucose (BG)-time curve and calculate the area under the blood glucose-time curve. The calculation formula is:

[0259] AUC(mmol / L.hr)=(BG0+BG15)×0.25 / 2+(BG15+BG30)×0.25 / 2+

[0260] (BG30+BG60)×0.5 / 2+(BG60+BG90)×0.5 / 2+(BG90+BG120)×0.5 / 2.

[0261] Note: BG0, BG15, BG30, BG60, BG90 and BG120 represent the blood glucose values ​​before sugar administration (0 min), 15, 30, 60, 90 and 120 min after sugar administration, respectively.

[0262] The blood glucose reduction rate at each time point and AUC was calculated based on the average blood glucose value and blood glucose AUC at each time point. The calculation formula was: blood glucose reduction rate = (blood glucose in the drug administration group / AUC - blood glucose in the model control group / AUC) / blood glucose in the model control group / AUC × 100%.

[0263] The compounds of the embodiments of the present invention can effectively reduce blood sugar in mice, with a blood sugar reduction rate of more than 20%, preferably a blood sugar reduction rate of more than 40%, and more preferably a blood lipid reduction rate of more than 60%.

[0264] III. Effects of long-term administration of the compounds of the present invention on body weight and food intake of GLP-1R humanized mice fed a high-fat diet

[0265] 1. Experimental purpose:

[0266] The purpose of this test is to evaluate the effects of chronic administration of compounds on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0267] 2. Experimental reagents and instruments

[0268] C57BL / 6_hGLP-1R, male, 5-8 weeks old, purchased from Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[0269] 60% high fat diet (HFD), purchased from Shanghai Bopai Biotechnology Co., Ltd. (D12492, Research Diet)

[0270] Clean bench (CJ-2F, Suzhou Fengshi Experimental Animal Equipment Co., Ltd.

[0271] Electronic balance (BSA2202S-CW, Sartorius)

[0272] 3. Experimental Methods

[0273] 3.1 On the day of starting high-fat diet feeding, C57BL / 6 mice were randomly divided into two groups according to body weight. The first group was Blank, with 7 mice, and was fed a normal control diet. The remaining animals were the modeling group and were fed a high-fat diet until the end of the experiment.

[0274] 3.2 At the 8th week of HFD feeding, the modeling group animals were randomly divided into groups according to body weight, with 7 animals in each group. The first group was the Vehicle group (Vehicle: 0.5% CMC-Na + 1% Tween 80), which was given a solvent; the remaining groups were the drug-administered groups; the drug administration scheme: oral administration of the corresponding compound, the administration cycle was 14 days, once a day, the dosage was 10 mg / kg, and the administration volume was 10 mL / kg. The Blank group continued to be fed with normal feed, and no drug administration was performed.

[0275] 3.3 The day of drug administration is defined as Day 0.

[0276] 3.4 Each time the drug is administered, the animals are weighed and the data are recorded. Oral administration is performed according to body weight, and the administration volume is 10 mL / kg.

[0277] 3.5 Starting from the 0th day of the experiment, the food intake of each group of mice was measured every three days. Specifically, the feed was replaced by weighing each time after administration and the added and remaining amounts were recorded.

[0278] 3.6 Day 14 On the endpoint day, all mice were euthanized in order according to the grouping order, and the livers were removed and weighed after dissection.

[0279] 4. Experimental data processing and statistical analysis

[0280] The body weight and body weight change rate of mice after administration were summarized and statistically analyzed. The body weight change rate was calculated as: (BWt-BW0) / BW0×100%. BWt represents the body weight of mice on the tth day of the experiment, and BW0 represents the body weight of mice on the 0th day of the experiment.

[0281] The food intake was calculated as follows: (added amount (g) - remaining amount (g)) / number of animals in each cage. The cumulative food intake was the sum of the daily food intake of each animal during the dosing period.

[0282] The experimental data were analyzed and plotted using GraphPad Prism software. The t-test method was used to compare two groups. The one-way ANOVA method was used to compare three or more groups. p<0.05 was defined as a statistically significant difference.

[0283] Long-term administration of the compounds of the present invention has a good weight-reducing effect on GLP-1R humanized C57BL / 6 mice fed with a high-fat diet, with a weight-reducing rate greater than 5%, and more preferably greater than 10%.

[0284] Pharmacokinetics in Balb / C mice

[0285] 1. Research objectives:

[0286] Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in the plasma of mice at a dose of 5 mg / kg after oral administration.

[0287] 2. Experimental plan

[0288] 2.1 Trial Drugs:

[0289] Solvent formula: 0.5% CMC-Na (1% Tween 80);

[0290] The compound of the present invention is self-made.

[0291] 2.2 Experimental Animals:

[0292] Balb / C Mouse 18 (6 / example), male, Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0293] 2.3 Administration:

[0294] Eighteen male Balb / C mice were fasted overnight and administered orally at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[0295] 2.4 Sample collection:

[0296] Before and after administration of the mice, 0.1 mL of blood was collected from the eye sockets at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in EDTA-K2 tubes, centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, and stored at -80°C.

[0297] 2.5 Sample processing:

[0298] 1) Add 160uL acetonitrile to 40uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5 to 20 minutes.

[0299] 2) Take 100uL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0300] 2.6 Liquid phase analysis

[0301] Liquid phase conditions: Shimadzu LC-20AD pump

[0302] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0303] Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0304] Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is acetonitrile

[0305] Flow rate: 0.8mL / min

[0306] Elution time: 0-4.0 minutes, eluent is as follows:

[0307]

[0308] The compounds of the present invention showed good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

[0309] 5. Pharmacokinetics in SD rats

[0310] 1. Research objectives:

[0311] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 50 mg / kg.

[0312] 2. Experimental plan

[0313] 2.1 Trial Drugs:

[0314] Solvent formula: 0.5% CMC-Na (1% Tween 80);

[0315] The embodiments of the present invention are self-made.

[0316] 2.2 Experimental Animals:

[0317] There were 3 male SD rats in each group.

[0318] 2.3 Administration:

[0319] Three male SD rats were fasted overnight and then PO-administered at a dose of 50 mg / kg in a dosing volume of 10 mL / kg.

[0320] 2.4 Sample collection:

[0321] Before and after administration, 0.2 mL of blood was collected from the jugular vein of rats at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. The blood was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate plasma, which was stored at -80°C and fed 4 hours after administration.

[0322] 2.5 Sample processing:

[0323] 1) 40uL of plasma sample was added to 160uL of acetonitrile for precipitation, and after mixing, centrifuged at 3500×g for 5 to 20 minutes.

[0324] 2) Take 100uL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0325] 2.6 Liquid phase analysis

[0326] Liquid phase conditions: Shimadzu LC-20AD pump

[0327] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0328] Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0329] Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

[0330] Flow rate: 1.0mL / min

[0331] Elution time: 0-4.0 minutes, eluent is as follows:

[0332]

[0333]

[0334] 3. Test results and analysis

[0335] The main pharmacokinetic parameters were calculated using WinNonlin 8.2.

[0336] The compounds of the present invention showed good metabolic properties, exposure AUC and maximum blood concentration C max All performed well.

Claims

1. A compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, R 1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl; Or, any two R 4 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; M1 is O, S, N, C or CH; M2 is O, S, N, C or CH; M2 is O, S, N, C or CH; x is 0, 1, 2, 3, 4, or 5; y is 0, 1, 2, 3, or 4; z is 0, 1, 2, 3, or 4; m is 0, 1, 2 or 3; Wherein, the compound of general formula (I) is not 2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy, more preferably hydrogen, deuterium, fluorine, chlorine, cyano or methoxy; R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy, more preferably hydrogen, deuterium, fluorine, chlorine or methyl; R 3 Each is independently selected from hydrogen, deuterium or fluorine, preferably hydrogen and deuterium; R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Haloalkyl, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl; Preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl; More preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms or 5-10 membered heteroaryl containing 1-4 heteroatoms, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl; More preferably, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 , C 3-6 Cycloalkyl, 5-6 membered heterocyclyl containing 1-4 atoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, optionally further substituted or unsubstituted by halogen, amino, nitro, hydroxy, cyano, oxo, methyl, trifluoromethyl, oxo 3-8 Cycloalkyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S, oxo-substituted or unsubstituted C 6-10 Aryl and oxo substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S atoms, substituted with one or more substituents; More preferably, R 4 Each independently selected from Optionally further substituted by one or more substituents of hydroxyl, cyano, oxo, methyl, trifluoromethyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S atoms; Or, more preferably, R 4 Each independently selected from R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms, preferably hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-4 atoms selected from N, O or S, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, more preferably hydrogen, deuterium, hydroxyl, methyl, methoxy.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II): in: Ring A is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and substituted or unsubstituted 5-10 membered heteroaryl; Preferably, ring A is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms or 5-10 membered heteroaryl containing 1-4 heteroatoms, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, oxo-substituted or unsubstituted C 3-8 Cycloalkyl, oxo-substituted or unsubstituted 3-8 membered heterocyclic group, oxo-substituted or unsubstituted C 6-10 substituted by one or more substituents of aryl and oxo-substituted or unsubstituted 5-10 membered heteroaryl; More preferably, ring A is selected from C 3-6 Cycloalkyl, 5-6 membered heterocyclyl containing 1-4 atoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, optionally further substituted or unsubstituted by halogen, amino, nitro, hydroxy, cyano, oxo, methyl, trifluoromethyl, oxo 3-8 Cycloalkyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S, oxo-substituted or unsubstituted C 6-10 Aryl and oxo substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S atoms, substituted with one or more substituents; Further preferably, ring A is selected from Optionally further substituted by one or more substituents of hydroxyl, cyano, oxo, methyl, trifluoromethyl, oxo-substituted or unsubstituted 5-6-membered heterocyclic group containing 1-4 atoms selected from N, O or S atoms; R 1 , R 2 , R 3 , x, y, z, M1, M2, M3 as described in claim 1.

4. The compound according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (II-1):

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (III): in, R 4 Selected from -C(O)NR a1 R b1 、-C(O)NR a2 S(O)2NR a3 R b3 、-P(O)R a4 R b4 、-S(O)2R b2 、-S(O)2NR a5 R b5 ; Preferably, R 4 Selected from R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; Preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms; More preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, nitro, hydroxyl, cyano, carboxyl, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group containing 1-4 atoms selected from N, O or S, C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S; More preferably, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R b4 , R b5 Each is independently selected from hydrogen, deuterium, hydroxyl, methyl, methoxy; R 1 , R 2 , R 3 , x, y, z as described in claim 1.

6. The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (III-1):

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: The compound structure is as follows:

8. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 7, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a GLP-1 receptor agonist drug.

10. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating metabolic-related diseases; preferably, the metabolic-related diseases are selected from diabetes, obesity or non-alcoholic fatty liver disease-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic fatty liver disease.

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