Heterocyclic compound having GLP-1 receptor agonist effect and use of heterocyclic compound

Abstract

The present invention relates to the field of medicines, and provides a heterocyclic compound having a GLP-1 receptor agonist effect and a use of the heterocyclic compound. The heterocyclic compound is a compound having a structure represented by formula (I), or an isomer, isotopically labeled compound, prodrug thereof, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof: (I). The agonist can be used for treating metabolic syndromes and has a significant therapeutic effect in reducing blood glucose or losing weight.

Description

A heterocyclic compound with GLP-1 receptor agonist effect and its application Technical Field

[0001] This invention relates to the field of chemical pharmaceuticals, specifically to the development of an oral small molecule agonist of GLP-1R that can enhance insulin secretion and lower blood glucose levels in a glucose-dependent manner. Background Technology

[0002] In recent years, with the improvement of people's living standards and changes in dietary habits, obesity has gradually become a global health problem, and its prevalence continues to increase worldwide. Obesity is a key risk factor for metabolic complications such as non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), cardiovascular disease, hypercholesterolemia, and hypertension.

[0003] Type 2 diabetes accounts for 90-95% of all diabetes cases, and its prevalence is increasing worldwide. According to the International Diabetes Federation (IDF), 382.5 million people were affected by T2DM in 2015, and this number is projected to exceed 578 million within 20 years.

[0004] Glucagon-like peptide-1 (GLP-1) is an incretin, a 30-amino acid polypeptide secreted by L cells in the small intestine. GLP-1 participates in the regulation of glucose homeostasis through signal transduction via its interaction with the GLP-1 receptor (GLP-1R). The insulinotropic effect of GLP-1 is glucose-dependent; once plasma glucose levels drop to normal, it will not further stimulate insulin secretion, thus reducing the risk of hypoglycemia. Furthermore, GLP-1 primarily regulates glucose homeostasis by promoting insulin gene transcription, stimulating pancreatic β-cell proliferation and regeneration, inhibiting β-cell apoptosis, and blocking glucagon release. It can also delay gastric emptying and promote satiety, thereby aiding in weight loss. In the intestine, GLP-1 can stimulate the division and proliferation of crypt cells, promoting intestinal growth. Intestinal intraepithelial lymphocytes, under the influence of GLP-1, can reduce inflammatory responses and protect intestinal tissue. In the brain, GLP-1 can reduce appetite and decrease addictive behaviors related to certain foods. GLP-1R is also expressed in the cardiovascular system, which can increase heart rate and cardiac output, and has a cardioprotective function.

[0005] Therefore, GLP-1 receptor agonists can be used to treat obesity and metabolic syndrome with significant clinical manifestations, and have been widely used in the treatment of type 2 diabetes. They also possess properties such as weight loss, protection of pancreatic β-cells, promotion of pancreatic β-cell proliferation, and minimal side effects. Furthermore, GLP-1 receptor agonists exhibit various biological effects, including reducing neuroinflammation, promoting nerve growth, improving cardiac function, suppressing appetite, delaying gastric emptying, regulating lipid metabolism, and reducing fat deposition. Moreover, GLP-1 receptor agonists have neuroprotective, anti-infective, cardiovascular protective, and metabolic regulatory effects, demonstrating promising application prospects. The relationship between GLP-1 receptor agonists and tumor occurrence, development, and prognosis in patients with type 2 diabetes mellitus is also receiving increasing attention.

[0006] GLP-1 receptor agonists (GLP-1RAs) can bind to GLP-1Rs and exert the same effects as GLP-1. All currently approved GLP-1 receptor agonists are synthetic analogs of the endogenous agonist GLP-1 or its paralogous homolog exendin-4, primarily optimized for pharmacokinetic properties through various modification methods to improve protein hydrolytic stability and / or avoid renal clearance. These FDA-approved peptide drugs are mainly used to treat type 2 diabetes mellitus (T2DM) or obesity; however, these peptide GLP-1 receptor agonist drugs usually require subcutaneous injection, leading to poor patient compliance. Currently, no small molecule GLP-1 receptor agonist drugs are approved for the treatment of T2DM or obesity; therefore, this invention aims to develop orally administered small molecule GLP-1 receptor agonists to meet this need.

[0007] Novo Nordisk's oral semaglutide Rybelsus is the first and only marketed oral GLP-1 receptor agonist, but its administration requirements are strict and cumbersome. Non-peptide oral small molecule GLP-1 receptor agonists have advantages such as oral administration, high stability, easy storage, and low cost, and represent the future trend in research and development.

[0008] Patent CN109790161B discloses a pyrazolopyridine derivative with GLP-1 receptor agonist activity, specifically compound 67. This compound is Orforglipron (LY3502970), an oral small-molecule GLP-1R agonist drug being developed by Eli Lilly. Phase II clinical trials reported that at 26 weeks, subjects experienced a weight loss of 8.6%-12.6%, and type 2 diabetic subjects experienced an average HbA1c reduction of 2.1%; at 36 weeks, subjects experienced a weight loss of 9.4%-14.7%. Due to the low oral bioavailability of this drug, a relatively high dosage is required.

[0009] There are currently no commercially available small molecule GLP-1R agonist drugs, and there is an urgent need to develop new GLP-1R agonist drugs. Summary of the Invention

[0010] In response to the above-mentioned technological status, this invention provides an oral small-molecule GLP-1 receptor agonist that can enhance insulin secretion and lower blood glucose levels in a glucose-dependent manner. This avoids the risk of hypoglycemia that is common with traditional T2DM treatments, maintaining intelligent and precise blood glucose control. Simultaneously, this molecule possesses functions such as weight loss, lipid reduction, cardiovascular protection, and treatment of non-alcoholic fatty liver disease. Compared to large-molecule peptide drugs, its potential advantages include: tolerability and safety similar to peptide GLP-1 receptor agonists, and convenient oral dosage form; good bioavailability; unlike oral large-molecule GLP-1 receptor agonists (such as oral smegglutide), it is not limited by food or dosage; and it can be developed for monotherapy or combination therapy.

[0011] In addition to the use of this oral small molecule agonist GLP-1R in the fields of diabetes and obesity, as research on this type of drug continues to deepen in the fields of chronic liver disease, kidney disease, and cardiovascular and cerebrovascular diseases, there is strong reason to expect that this type of product can be used to treat a range of indications such as non-alcoholic fatty liver disease (NASH), diabetic nephropathy (DKD), atherosclerotic cardiovascular disease (ASCVD), and Alzheimer's disease (AD).

[0012] This invention provides a GLP-1R agonist, which is a compound with the structure shown in formula (I), or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts:

[0013] Wherein, X1, X2, X4, X5, X6, X7, and X9 are each independently selected from C or N;

[0014] X3 is selected from C, N, O, or S;

[0015] Y1, Y3, Y4, and Y5 are each independently selected from C or N;

[0016] Y2 is selected from CR e O, S, NR e Or N;

[0017] Ring Z1 is selected from a benzene ring or a 6-membered heteroaromatic ring;

[0018] Ring Z2 is selected from 5-membered heteroaryl rings;

[0019] Ring Z3 is selected from 5-membered heterocyclic aromatic rings;

[0020] R e Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6Halogenated alkyl or C 1-6 Deuterated alkyl groups;

[0021] R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Substitution of aryl or 5-10 heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are optionally coated with one or more elements selected from deuterium, halogen, hydroxyl, cyano, amino, C. 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0022] R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three atoms selected from deuterium, halogen, OH, NH2, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0023] R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, the C 1-6 Alkyl, C1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2 is optionally surrounded by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0024] R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, amino, C. 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0025] R 10 Selected from C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 aryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. 10a replace;

[0026] R 10a Each is independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6Halogenated alkyl), -N(C) 1-6 (halogenated alkyl) 2, hydroxyl C 1-6 Alkyl-, cyano-C 1-6 Alkyl-, amino C 1-6 Alkyl group, or two R atoms attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups.

[0027] R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 aryl, 13-18-membered heteroaryl, wherein the 13-18-membered heterocyclic group, C 13-18 The aryl group and the 13-18 heteroaryl group are optionally substituted by one or more substituents, each independently selected from group A:

[0028] Group A:

[0029] a) Deuterium;

[0030] b) Oxo (=O);

[0031] c) Halogens;

[0032] d)OH;

[0033] e) Cyano group;

[0034] f) Among them, R 0 Selected from H, C 1-6 alkyl;

[0035] g)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 Alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups;

[0036] h)-C(=O)R C1 , where R C1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0037] i)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6The alkoxy group and the 3-12 membered heterocyclic group are substituents, wherein the 3-12 membered heterocyclic group is optionally replaced by one or more independently selected from C. 1-6 Alkyl substituents;

[0038] j)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0039] k) 3-12 membered heterocyclic groups, wherein the 3-12 membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0040] l) 5-10 heteroaryl groups, wherein the 5-10 heteroaryl groups are optionally selected independently by one or more deuterium, halogen, hydroxyl group, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N5 R N6 Substituents of R, wherein R N5 and R N6 Independently selected from H and C 1-6 Alkyl; or

[0041] m)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, NH2, CN, C. 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0042] Among them, when for hour, Not for Or when for hour, Not for

[0043] In this invention, as one embodiment, the... Selected from

[0044] Ring Z1 is selected from a benzene ring or a 6-membered heteroaromatic ring;

[0045] Ring Z2 is selected from 5-membered heteroaryl rings;

[0046] Preferably, ring Z1 is selected from a benzene ring or a 6-membered nitrogen-containing heteroaromatic ring;

[0047] Preferably, ring Z2 is selected from a 5-membered nitrogen-containing heteroaromatic ring, a 5-membered sulfur-containing heteroaromatic ring, or a 5-membered oxygen-containing heteroaromatic ring.

[0048] In this invention, as one embodiment, the... Selected from: (Preferred) );

[0049] Preferably, Selected from

[0050] In this invention, as one embodiment, the... Selected from

[0051] in, Represents a single bond or a double bond;

[0052] Among them, Y4 and Y5 are selected from C;

[0053] Preferably, Y2 is selected from CH or N;

[0054] Preferably, the Selected from

[0055] More preferably, the Selected from

[0056] In this invention, as one embodiment, the compound has the structure shown in formula (I-1):

[0057] In this invention, as one embodiment, the R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substituents of cycloalkyl groups;

[0058] Preferably, R1 Selected from phenyl or 5-6 heteroaryl groups; wherein the phenyl or 5-6 heteroaryl group is optionally selected by 1, 2, 3, 4 or 5 independently from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups;

[0059] Preferably, R 1 Selected from phenyl or pyridyl; wherein the phenyl or pyridyl group is optionally selected by 1, 2, 3, 4 or 5 independently from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups;

[0060] More preferably, R 1 Selected from phenyl; the phenyl group is optionally selected independently by 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substituents of cycloalkyl groups;

[0061] More preferably, the R 1 Selected from:

[0062] In this invention, as one embodiment, the R 10 Selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, optionally bound by 1, 2, 3, 4 or 5 R groups. 10a replace;

[0063] Preferably, R 10 Selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl; the C 3-8 Cycloalkyl, 4-7-membered heterocyclic, and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace;

[0064] Preferably, R 10 Selected from 6-membered heterocyclic groups, C 5-7 cycloalkyl, 5-6 membered heteroaryl; the 6 membered heterocyclic group, C 5-7Cycloalkyl groups and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace;

[0065] More preferably, R 10 Selected from tetrahydropyranyl, morpholinyl, cyclohexyl, and pyridyl; wherein the tetrahydropyranyl, morpholinyl, cyclohexyl, and pyridyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace;

[0066] Among them, R 10a Independently selected from deuterium, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic groups;

[0067] Preferably, R 10a Selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy groups or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0068] Preferably, R 10a Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy groups or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0069] Preferably, the R 10 Selected from The The land can be optionally divided by 1, 2, 3, 4 or 5 Rs. 10a replace;

[0070] More preferably, the R 10 Selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

[0071] In this invention, as one embodiment, the R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, or 3 elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups;

[0072] Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C1, C2, or C3. 1-6 Alkyl substituents;

[0073] Preferably, the Selected from (For example Preferred ), (Preferred) ); where the key marked with "#" is connected to

[0074] Preferably, the Selected from (Preferred) ), (Preferred) ); where the key marked with "#" is connected to

[0075] In this invention, as one embodiment, the R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl;

[0076] Preferably, R 3 R 4 Each element is independently selected from hydrogen, deuterium, and halogen; preferably, R 3 R 4 All are hydrogen;

[0077] R 5 Selected from C 1-6 Alkyl; preferably, R 5 Selected from C 1-4 alkyl.

[0078] In this invention, as one embodiment, the R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, and C. 1-6 alkyl;

[0079] Preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, and C. 1-4 alkyl;

[0080] Preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, and halogen.

[0081] In this invention, as one embodiment, group A is selected from:

[0082] 1) Deuterium;

[0083] 2) Oxygenation;

[0084] 3) Halogens;

[0085] 4)OH;

[0086] 5) Cyano group;

[0087] 6)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 alkyl;

[0088] 7)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be selected independently by one or more elements chosen from deuterium, halogen, hydroxyl, C. 1-6 Substitution of alkoxy groups and 3-7 membered heterocyclic groups;

[0089] 8)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0090] 9) 3-7 membered heterocyclic groups, wherein the 3-7 membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0091] 10) 5-10 heteroaryl groups, wherein the 5-10 heteroaryl groups are optionally selected independently by one or more deuterium, halogen, hydroxyl group, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N5 R N6 Substituents of R, wherein R N5 and R N6 Independently selected from H and C 1-6 Alkyl; or

[0092] 11)C 3-6 cycloalkyl, wherein C 3-6 The cycloalkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, NH2, CN, C. 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0093] Preferably, group A is selected from:

[0094] 1) Deuterium;

[0095] 2) Oxygenation;

[0096] 3) Halogens;

[0097] 4)OH;

[0098] 5) Cyano group;

[0099] 6)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 alkyl;

[0100] 7)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-7 membered heterocyclic groups;

[0101] 8)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0102] Preferably, group A is selected from: deuterium, oxo, halogen, hydroxyl, cyano, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene-, C 1-6 Alkoxy C 1-6 Alkylene-, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl-, hydroxyl C 1-6 Alkyloxy-;

[0103] Preferably, group A is selected from: deuterium, oxo, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0104] Preferably, group A is selected from: deuterium, oxometalate, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0105] Preferably, group A is selected from: deuterium, oxometalate, halogen, C 1-6 alkyl;

[0106] Preferably, group A is selected from: oxo, halogen, C 1-6 alkyl.

[0107] In this invention, as one embodiment, the R 2 Selected from 13-18 membered heterocyclic groups and 13-18 membered heteroaryl groups;

[0108] Preferably, R 2 Selected from group (1), group (2), group (3), or group (4):

[0109] Group (1):

[0110] in,

[0111] Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl;

[0112] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl;

[0113] Group (2):

[0114] in,

[0115] It can be a single bond or a double bond;

[0116] Ring B is selected from phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocyclic group;

[0117] The ring C is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered monocyclic heterocyclic group, C 5-6 Monocyclic cycloalkyl;

[0118] Group (3):

[0119] in,

[0120] Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl;

[0121] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl;

[0122] Ring D is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl;

[0123] Group (4)

[0124] in,

[0125] Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl;

[0126] Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl;

[0127] Ring D is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl;

[0128] In groups (1) to (4),

[0129] Wherein, ring A is phenyl;

[0130] R A Each is independently selected from deuterium, halogens, OH, CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0131] n is selected from 0, 1, and 2;

[0132] m is selected from 0, 1, 2, or 3;

[0133] y is selected from 0, 1, 2, or 3;

[0134] t is selected from 0, 1, or 2;

[0135] R B R C R D Substituents are each independently selected from group A;

[0136] Preferably, R A Each is independently selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0137] More preferably, R A Each is independently selected from deuterium, halogens, and C. 1-6 alkyl;

[0138] More preferably, R A Selected from halogens;

[0139] Preferably, n is selected from 0 or 1;

[0140] Preferably, m is selected from 0, 1, or 2;

[0141] Preferably, y is selected from 0 or 1;

[0142] Preferably, t is selected from 0;

[0143] Preferably, R B Selected from deuterium, halogen, oxo, C 1-6 Alkyl; more preferably, R B Selected from oxo, C 1-6 alkyl;

[0144] Preferably, R C Selected from deuterium, halogen, oxo, C 1-6 Alkyl; more preferably, R C Selected from oxo;

[0145] Preferably, R D Selected from deuterium, halogen, oxo, C 1-6 alkyl.

[0146] In this invention, as one of the implementation schemes,

[0147] The group (1) Selected from:

[0148] in,

[0149] M2, M3, M4, M5, M6, M7, and M8 are each independently selected from C, N, O, S, or P;

[0150] Between M2 and M3, between M3 and M4, between M5 and M6, between M6 and M7, and between M7 and M8, each is independently a single bond or a double bond, wherein the two adjacent chemical bonds are not simultaneously double bonds;

[0151] R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl;

[0152] R 21 R 22 R 31 R 32 R 41 R 42 R 51 R 52 R 61 R 62 R 71 R 72 R 81 R 82 Each is independently selected from: non-existent, hydrogen, deuterium, halogen, -C 1-6 Alkyl (preferably methyl), =O; and satisfying one of the following conditions:

[0153] 1)R 21 ,R 22 The atoms connected to it form a ring C;

[0154] 2)R 31 ,R 32 The atoms connected to it form a ring C;

[0155] 3)R 41 ,R 42 The atoms connected to it form a ring C;

[0156] 4)R 51 ,R 52 The atoms connected to it form a ring C;

[0157] 5)R 61 ,R 62 The atoms connected to it form a ring C;

[0158] 6)R71 ,R 72 The atoms connected to it form a ring C;

[0159] 7)R 81 ,R 82 The atoms connected to it form a ring C;

[0160] Wherein, the ring C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl; the 4-7 membered monocyclic heterocyclic group, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl groups are optionally surrounded by y R C The R that was replaced C Selected from any substituent in group A;

[0161] Preferably, M2, M3, M4, M5, M6, M7, and M8 are each independently selected from C, N, or O;

[0162] Preferably, the 4-7 member monocyclic heterocyclic group, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl groups are y R C The R that was replaced C Selected from the following substituents: deuterium, halogen, -C 1-6 Alkyl or =O;

[0163] More preferably, the ring C is selected from 4-6 member monocyclic heterocyclic groups, C 5-6 Monocyclic cycloalkyl groups, 7-9 membered bridged heterocyclic groups; the 4-6 membered monocyclic heterocyclic groups, C 5-6 Monocyclic cycloalkyl groups and 7-9 membered bridged heterocyclic groups are optionally surrounded by y R groups. C The R that was replaced C Selected from the following substituents: deuterium, halogen, -C 1-6 Alkyl or =O;

[0164] Preferably, the Selected from:

[0165] Preferably, the group (1) Selected from

[0166] In this invention, as one of the implementation schemes,

[0167] The group (2) Selected from:

[0168] in,

[0169] R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl;

[0170] M9, M 14 Each is independently selected from C, CH, N, O, or S;

[0171] M 10 M 13 Each is independently selected from C, CH, or N;

[0172] M 11 M 12 Each is independently selected from CH2 and CHR C C(R) C )2, O, S, NH or NR C ;

[0173] M 10 With M 13 Between, M 13 With M 14 Each bond can be a single or double bond independently, but not both at the same time;

[0174] R 91 R 141 Each is independently selected from: non-existent, hydrogen, deuterium, C 1-6 Alkyl (preferably methyl), halogen;

[0175] R C Selected from deuterium, halogens, C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be selected independently by one or more elements chosen from deuterium, halogen, hydroxyl, C. 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups;

[0176] Preferably, M9, M 14 Each is independently selected from C or N;

[0177] Preferably, M 10 M 13 Each is independently selected from C or N;

[0178] Preferably, group (2) Selected from

[0179] In this invention, as one of the implementation schemes,

[0180] The group (3) Selected from:

[0181] in,

[0182] R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl;

[0183] M 18 M 20 Each is independently selected from C, CH, N, or O;

[0184] M 17 M 21 Each is independently selected from CH2 and CHR D C(R) D )2, O, S, NH or NR D ;

[0185] R 17 R 18 Each is independently hydrogen, deuterium, halogen, C 1-6 Alkyl (preferably CH3) or =O;

[0186] R 181 R 201 Each independently represents: non-existent, hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl (preferably CH3) or =O;

[0187] R D Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be selected independently by one or more elements chosen from deuterium, halogen, hydroxyl, C. 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups;

[0188] Preferably, the group (3) Selected from

[0189] In this invention, as one of the implementation schemes,

[0190] The group (4) Selected from:

[0191] in,

[0192] R 13 R 14 R 15Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl;

[0193] M 16 It can be C, CH, N, or O;

[0194] M 15 Selected from CH2, CHR D C(R) D )2, O, S, NH or NR D ;

[0195] R 16 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl (preferably CH3) or =O;

[0196] R 161 Selected from non-existent, hydrogen, deuterium, halogen, C 1-6 Alkyl (preferably CH3) or =O;

[0197] R D Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups;

[0198] Preferably, the group (4) Selected from

[0199] In this invention, as one embodiment, the compound has the structure shown in formula (IA)-(II-G):

[0200] More preferably, it has the structure shown in formula (II-A-1):

[0201] Among them, K1, K2, K3, K4, and K5 are each independently selected from CH2 and CHR. C C(R) C )2, O, S, NH or NR C .

[0202] In this invention, as one embodiment, the compound described herein is as shown in formula (X):

[0203] in, Represents a single or double bond, two adjacent bonds. Not both are double bonds;

[0204] R 6aR 6b R 8 R 10 R 1 X4 and X5 are as defined in any embodiment of the present invention;

[0205] Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C1, C2, or C3. 1-6 Alkyl substituents; preferably, the... Selected from (For example Preferred ), The key marked with "#" is connected to

[0206] Preferably, X5 is N and X4 is C; or, X5 is C and X4 is N.

[0207] Preferably, R 8 Selected from hydrogen or halogens (e.g., F);

[0208] Preferably, R 1 Selected from phenyl; the phenyl group is optionally selected independently by one, two, or three halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substituents of saturated cycloalkyl groups; preferably, the R 1 Selected from:

[0209] Preferably, R 10 Selected from (Preferred) ),

[0210] In this invention, as one embodiment, the compound described herein is as shown in formula (X-1) or (X-2):

[0211] Among them, R 6a R 6b R 8 R 10 R 1 As defined in any embodiment of the present invention.

[0212] In this invention, as one embodiment, the compound described herein is as shown in formula (X-3) or (X-4):

[0213] Among them, R 10a R10b Each is independently selected from hydrogen or C1-4 alkyl (e.g., methyl); preferably, R 10a R 10b All are hydrogen, or R 10a R 10b All are C1-4 alkyl groups (e.g., methyl);

[0214] R 6a R 6b R 8 R 1 As defined in any of the embodiments described herein.

[0215] In this invention, as one embodiment, the C1-6 alkyl group, as an example, includes, but is not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, 3-methylpentyl, 2-ethylbutyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl.

[0216] In this invention, as one embodiment, the C3-6 cycloalkyl group, as an example, includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0217] In this invention, as one embodiment, the C1-6 alkoxy group, as an example, includes, but is not limited to, methoxy, ethoxy, propoxy, isooxypropyl, isobutoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexyl, 3-methylpentoxy, 2-ethylbutoxy, 2,2-dimethylbutoxy, or 2,3-dimethylbutoxy.

[0218] In this invention, as one embodiment, the C1-6 haloalkyl group, as an example, includes, but is not limited to, halomethyl, haloethyl, halopropyl, haloisopropyl, haloisobutyl, halon-butyl, halosec-butyl, halotert-butyl, halopentyl, haloisopentyl, halohexyl, haloisohexyl, halo3-methylpentyl, halo2-ethylbutyl, halo2,2-dimethylbutyl, or halo2,3-dimethylbutyl.

[0219] In this invention, as one embodiment, the C3-6 halocycloalkyl group, as an example, includes, but is not limited to, halocyclopropyl, halocyclobutyl, halocyclopentyl, or halocyclohexyl.

[0220] In this invention, as one embodiment, the C1-6 haloalkoxy group, as an example, includes, but is not limited to, halomethoxy, haloethoxy, halopropoxy, haloisopropyl, haloisobutoxy, halon-butoxy, halosec-butoxy, halotert-butoxy, halopentoxy, haloisopentoxy, halohexoxy, haloisohexyl, halo3-methylpentoxy, halo2-ethylbutoxy, halo2,2-dimethylbutoxy, or halo2,3-dimethylbutoxy.

[0221] In this invention, as one embodiment, the saturated or unsaturated C3-8 cycloalkyl group, as an example, includes, but is not limited to, cyclopropane, cyclopropylene, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, etc.

[0222] In this invention, as one embodiment, the saturated or unsaturated C3-8 heterocyclic group, as an example, includes, but is not limited to, cyclopropane, cyclopropene, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, etc., wherein one, two, or more carbon atoms in the ring are each independently replaced by O, N, or S.

[0223] In this invention, as one embodiment, the saturated or unsaturated C3-8 halocycloalkyl group, as an example, includes, but is not limited to, halocyclopropane, halocyclopropene, halocyclobutane, halocyclobutene, halocyclopentane, halocyclopentene, halocyclohexane, halocyclohexene, halocycloheptane, halocycloheptene, halocyclooctane, halocyclooctene, etc.

[0224] In this invention, as one embodiment, the saturated or unsaturated C3-8 halocyclic heterocyclic group, as an example, includes, but is not limited to, halocyclopropane, halocyclopropene, halocyclobutane, halocyclobutene, halocyclopentane, halocyclopentene, halocyclohexane, halocyclohexene, halocycloheptane, halocycloheptene, halocyclooctane, halocyclooctene, etc., wherein one, two, or more carbon atoms in the ring are each independently replaced by O, N, or S.

[0225] In one embodiment of the present invention, the halogen refers to F, Cl, Br or I.

[0226] In this invention, as one embodiment, the compound is selected from:

[0227] The present invention provides a compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers, diluents, or excipients.

[0228] The present invention provides a pharmaceutical composition comprising the above-described compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and another therapeutically active agent.

[0229] The present invention provides a pharmaceutical combination in which another therapeutic active agent includes an antidiabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent for treating non-alcoholic steatosis (NASH), or a combination of two or more of them.

[0230] Preferably, the antidiabetic agent is selected from the group consisting of: biguanides (e.g., metformin), sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinide, sodium-glucose linker 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose linker 1 (SGLT1) inhibitors, or combinations of two or more of these.

[0231] Preferably, the anti-obesity agent is selected from the group consisting of: neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human proislet peptide (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, and farnesoid X receptors. FXR receptor agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, sodium-glucose cotransporter 1 (SGLT-1) inhibitors, activin type 2 receptor (ActRII) inhibitors, apalinide receptor (APLNR) agonists, or combinations of two or more of these.

[0232] Preferably, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or a combination of two or more thereof.

[0233] Preferably, the agent for treating NASH is selected from the group consisting of: FXR agonist PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, apoptosis protease inhibitor, MAPK5 inhibitor, galactoglobulin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, niacin analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, hexokinase (KHK) inhibitor, ileal bile acid transporter (IBAT) inhibitor, apoptosis signal-regulated kinase 1 (ASK1) inhibitor, peroxisome proliferator-activated receptor (PPAR) agonist, diacylglycerol acyltransferase 2 (DGAT2) inhibitor, or a combination of two or more of these.

[0234] The present invention also provides the use of the compound of the present invention, its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and pharmaceutical compositions containing the compound of the present invention, its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, in the preparation of medicaments for the prevention and / or treatment of GLP-1 receptor-mediated diseases or disorders or for the modulation of GLP-1 receptors.

[0235] The present invention provides a method for regulating insulin levels in a patient requiring such regulation, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0236] The present invention provides a method for regulating insulin levels in patients who require such regulation, wherein the regulation causes an increase in insulin levels.

[0237] The present invention provides a method for regulating glucose levels in a patient requiring such regulation, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0238] The present invention provides a method for regulating glucose levels in patients who require such regulation, wherein the regulation causes a decrease in glucose levels.

[0239] This invention provides a method for preventing and / or treating GLP-1-related diseases, symptoms, or conditions, the method comprising: administering to the individual a therapeutically effective amount of the aforementioned compound, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical composition; or administering to the individual a therapeutically effective amount of the aforementioned pharmaceutical combination.

[0240] In this invention, as one embodiment, the GLP-1-related diseases, conditions, or symptoms include, but are not limited to: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile atypical diabetes (YOAD), young adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain caused by the use of other medications, idiopathic intracranial hypertension, and Wolfram syndrome. Syndrome, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, impaired glucose tolerance, diabetic complications, hypercholesterolemia, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction. Acute dyslipidemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depression, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, nonalcoholic fatty liver disease (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, or polycystic ovary syndrome.

[0241] In this invention, as one embodiment, the use of the compound of the invention, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administration to the individual of a therapeutically effective amount of the above-described pharmaceutical composition; or administration to the individual of a therapeutically effective amount of the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or disorders or for modulating GLP-1 receptors.

[0242] Terminology Explanation

[0243] The term "isomer" refers to compounds with the same chemical composition but different structures and properties, including but not limited to enantiomers, diastereomers, racemates, stereoisomers, tautomers, and geometric isomers.

[0244] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or further into two main categories: enantiomers and diastereomers.

[0245] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in a molecule between two positions.

[0246] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0247] The “racemate” refers to an equimolar mixture of two enantiomers that lack optical activity.

[0248] The term "cis-trans isomers" refers to stereoisomers formed because the two carbon atoms connected by a double bond cannot rotate freely around the σ bond. They are divided into cis isomers and trans isomers: cis isomers are those where the two identical atoms or groups are on the same side of the double bond; trans isomers are those where the two identical atoms or groups are on opposite sides of the double bond.

[0249] The term "isotope-labeled compound" refers to a compound in which one or more atoms in its molecule are replaced by its isotope or other easily identifiable nuclide.

[0250] The term "deuterated product" refers to a molecule obtained by replacing one or more hydrogen atoms (1H) in a molecule with deuterium atoms (D).

[0251] The term "N-oxide" refers to a binary compound composed of oxygen and nitrogen.

[0252] The term "metabolite" refers to compounds or substances produced during the metabolism of an organism.

[0253] The term "crystal form" refers to the phenomenon that molecules with the same chemical structure can form more than one molecular arrangement and crystal lattice structure during crystallization due to different crystallization conditions (such as solvent, temperature, cooling rate, etc.).

[0254] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. Taking C1-6 alkyl as an example, it is a straight-chain or branched group containing 1-6 carbon atoms, including but not limited to methyl, ethyl, propyl, pentyl, hexyl, tert-butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, and other aliphatic alkyl groups.

[0255] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group, which can be considered as a hydrocarbon group formed by removing one hydrogen atom from an olefin molecule. Taking C1-6 alkenyl as an example, it is a straight-chain or branched group containing 1-6 carbon atoms, including but not limited to vinyl, propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butene, 2-methyl-2-butene, hexenyl, and other alkenyl groups.

[0256] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic carbon chain structure molecule, for example, containing 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, including but not limited to cyclopropane, cyclobutane, cyclopentane, and cyclohexane. The cycloalkyl includes fused rings, spiro rings, bridged rings, and combinations thereof.

[0257] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, for example, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, or 6) ring atoms are each independently selected from nitrogen, oxygen, sulfur, or phosphorus heteroatoms, and the remaining ring atoms are carbon. The heterocyclic group includes fused rings, spirocyclic rings, bridged rings (e.g., 6-9 membered bridged heterocyclic groups), and combinations thereof; the heterocyclic group includes monocyclic heterocyclic groups, and groups with at least one heterocyclic ring in polycyclic (e.g., bicyclic, tricyclic) groups, such as benzo[a]heterocyclic groups.

[0258] The term "fused ring" refers to a saturated, partially unsaturated, or unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares a common ring edge with at least one of the other rings. The fused ring includes fused aromatic hydrocarbons, benzene fused heterocycles, heteroaryl fused heterocycles, benzene fused alkyl rings, heteroaryl fused alkyl rings, cycloalkyl fused heterocycles, cycloalkyl fused alkyl rings, and heterocyclic fused heterocycles.

[0259] The term "spirocyclic" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares a carbon atom with at least one of the other rings.

[0260] The term "bridged ring" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares three or more ring atoms with at least one of the other rings.

[0261] The term "aromatic heteroaryl" (also known as "heteroaryl") refers to a monocyclic or fused polycyclic group (i.e., a ring sharing adjacent ring edges) having a conjugated π-electron system and containing a heteroatom on the ring, wherein the heteroatom is selected from oxygen, sulfur, and nitrogen. Examples include 5-18 membered heteroaryl groups, preferably 5-12 membered or 13-18 membered heteroaryl groups, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, carbazoleyl, indolyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. "Heteroaromatic ring" (also known as "aromatic heterocyclic ring") refers to the ring system within the heteroaryl group.

[0262] The term "alkoxy" refers to -O-alkyl, where alkyl is defined as described above, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0263] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6-10 members, such as phenyl and naphthyl. "Aromatic ring" refers to the ring system within the aryl group.

[0264] The term "halogenated" refers to a group that can be replaced by any one or more F, Cl, Br, or I atoms.

[0265] The term "prodrug" refers to a compound obtained by those skilled in the art through chemical structural modification, which is inactive or has low activity in vitro, but releases the active pharmaceutical ingredient of the present invention through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect. This includes, but is not limited to, all prodrugs of the present invention that, when administered to humans or animals, can (directly or indirectly) provide the compound of the present invention or its active metabolites or residues.

[0266] The term "pharmaceutically acceptable salt" refers to anionic and cationic salts of compounds of the present invention, including but not limited to those of the present invention. More specifically, it refers to salts prepared by reacting compounds with specific substituents discovered in the present invention with relatively non-toxic acids or bases. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, sulfuric acid, phosphonic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and similar acids. Alkali salts include, but are not limited to, metal salts, alkaline earth metal salts, ammonium salts, or salts formed with organic bases, such as trialkylamines, pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and similar bases.

[0267] The term "pharmaceutically acceptable ester" refers to an ester suitable for use as a medicine formed by the compound of the active ingredient of the present invention with an acid or alcohol. This ester is formed by one or more hydroxyl groups of the active ingredient of the present invention with an acid. Acids suitable for forming esters include, but are not limited to: phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, etc. Alcohols suitable for forming esters include, but are not limited to: C1-C6 alkyl-OH, such as methanol, ethanol, n-propanol, isopropanol, etc.

[0268] The “pharmaceuticalally acceptable solvate” includes, but is not limited to, solvents such as water, ethanol, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, acetonitrile, tetrahydrofuran, acetone, or propylene glycol.

[0269] As used in this invention, carbon atoms marked with an asterisk (*) in a compound structural formula represent chiral centers and indicate that the compound is a specific stereoisomer. In stereochemical reaction formulas, two identically drawn compounds containing chiral centers marked with an asterisk (*) essentially represent two different stereoisomers of that structure. For example... Although compounds 1-8a and 1-8b are structurally identical, they are actually different stereoisomers of the structure shown in compound 1-7. Detailed Implementation

[0270] The following examples and test cases are used to further illustrate the present invention, but do not limit the scope of the present invention in any way.

[0271] Example: Synthesis of Compounds

[0272] The control compound LY3502970 was prepared according to patent CN109790161B; the structure of the control compound LY3502970 is as follows:

[0273] Example A: Preparation of Compound A

[0274] Step 1: Synthesis of compound A-8

[0275] Under ice bath conditions, sodium hydride (163 mg, 4.08 mmol) was added to a tetrahydrofuran (10 mL) solution of compound A-10 (575 mg, 2.04 mmol), and the mixture was stirred for 30 minutes. Then, a tetrahydrofuran (4 mL) solution of iodomethane (580 mg, 16.67 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound A-8. MS m / z (ESI): 296.1 [M+H] + .

[0276] Step 2: Preparation of compound A-2

[0277] Cyclopropylboronic acid (14.77 g, 171.96 mmol), triphenylphosphine (3.47 g, 13.23 mmol), potassium phosphate (98.15 g, 463 mmol), and palladium acetate (1.49 g, 6.61 mmol) were added to a solution of compound A-1 (25 g, 132 mmol) in toluene (300 mL) and water (30 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL × 3). The organic layers were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound A-2. MS m / z (ESI): 152.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ6.75(dd,J=10.4,8.8Hz,1H),6.35-6.25(m,1H),6.11(dd,J=6 .8,2.8Hz,1H),4.79(s,2H),1.95-1.84(m,1H),0.98-0.81(m,2H),0.64-0.50(m,2H).

[0278] Step 3: Synthesis of compound A-3

[0279] Sodium nitrite (10.0 g, 145 mmol) was added to a solution of compound A-2 (20 g, 132.45 mmol) in hydrochloric acid (80 mL) and water (80 mL) under ice bath conditions. After stirring the reaction mixture in an ice bath for 1 hour, a solution of stannous chloride dihydrate (5.14 g, 23.60 mmol) in hydrochloric acid (80 mL) and water (80 mL) was added. The reaction mixture was stirred in an ice bath for 2 hours. The reaction mixture was quenched with water (200 mL), adjusted to pH 8.0 with 50% NaOH aqueous solution, filtered, and the filtrate was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The crude compound A-3 was obtained by concentration under reduced pressure and used directly in the next step. MS m / z (ESI): 167.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ6.84(dd,J=10.0,8.8Hz,1H),6.56-6.50(m,1H),6.43(s,1H),6.35( dd,J=6.8,2.8Hz,1H),3.87(s,2H),2.00-1.90(m,1H),0.94-0.87(m,2H),0.66-0.61(m,2H).

[0280] Step 4: Synthesis of compound A-5:

[0281] Compound A-4 (22.9 g, 96.39 mmol) and pyridine hydrochloride (2.22 g, 19.28 mmol) were added to an ethanol (200 mL) solution of compound A-3 (16 g, 96.39 mmol). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic layers were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound A-5. MS m / z (ESI): 387.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.19-7.14(m,1H),7.04-6.95(m,2H),5.04(d,J=70.2Hz,1H),4.41-4.10(m,1H),3.50(s, 1H), 2.59 (s, 2H), 2.09-1.99 (m, 1H), 1.42 (s, 9H), 1.27 (d, J = 6.4Hz, 3H), 0.98-0.91 (m, 2H), 0.73-0.66 (m, 2H).

[0282] Step 5: Synthesis of compound A-6

[0283] Under ice bath conditions, N,N-diisopropylethylamine (30.0 g, 233 mmol) and phenyl p-nitrochloroformate (39.0 g, 194 mmol) were added to a tetrahydrofuran solution (300 mL) of aminoacetaldehyde dimethyl acetal (28.6 g, 272.02 mmol). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. A pyridine solution (150 mL) containing compound A-5 (15 g, 38.86 mmol) was added to the residue. The reaction solution was stirred at 40 °C for 16 hours. Water (250 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with water (300 mL) and saturated brine (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 (petroleum ether / ethyl acetate = 3 / 1) to give compound A-6. MS m / z (ESI): 518.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.19 (dd, J=7.2, 4.0Hz, 1H), 7.04-6.94 (m, 2H), 5.15 (s, 1H), 4.50-4.17 (m, 2H), 3.33 (d, J=3.6Hz, 6H), 3.13 (d,J=12.0Hz,2H),2.71(s,2H),2.12-2.05(m,1H),,1.93-1.73(m,1H),1.61-1.26(m,12H),1.04-0.89(m,2H),0.79-0.65(m,2H).

[0284] Step 6: Synthesis of compound A-7

[0285] Methylsulfonic acid (2.51 g, 26.11 mmol) was added to a tetrahydrofuran solution (200 mL) of compound A-6 (15 g, 29.01 mmol). The reaction mixture was stirred at 60 °C for 4 hours. After cooling to room temperature, triethylamine (5.86 g, 58.02 mmol) and di-tert-butyl dicarbonate (1.58 g, 7.25 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (150 mL), extracted with ethyl acetate (150 mL × 3), and the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound A-7. MS m / z (ESI): 454.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.11-7.04(m,1H),6.94(t,J=9.2Hz,1H),6.89-6.81(m,1H),6.28(s,1H),6.03(s,1H),5.36-5.02(m,1H),4.50-4.1 6(m,1H),3.16-2.93(m,1H),2.81-2.62(m,2H),2.05-1.99(m,1H),1.42(s,9H),1.23-1.19(m,3H),0.91-0.85(m,2H),0.64-0.48(m,2H).

[0286] Step 7: Synthesis of compound A-9

[0287] Compound A-7 (2.15 g, 7.28 mmol), potassium carbonate (2.74 g, 19.9 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (470 mg, 3.31 mmol), and cuprous iodide (252 mg, 1.32 mmol) were added to a solution of compound A-8 (3 g, 6.62 mmol) in N-methylpyrrolidone (40 mL). The reaction mixture was stirred at 130 °C for 4 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound A-9. MS m / z (ESI): 669.4 [M+H] + .

[0288] Step 8: Synthesis of Compound A

[0289] To a 2 mL solution of dichloromethane containing 60 mg (0.09 mmol) of compound A-9, 1 mL of 4 M dioxane hydrochloride solution was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain crude compound A, which was used directly in the next step. MS m / z (ESI): 569.3 [M+H] + .

[0290] Example B: Preparation of Compound B

[0291] Compound B was obtained by replacing compound A-2 in Example A with 4-fluoro-3,5-dimethylaniline and following the preparation method of compound A in Example A.

[0292] Compound B: MS m / z (ESI): 557.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.65(d,J=8.0Hz,1H),7.37(d,J=3.2Hz,1H),7.34-7.27(m,2H ),7.14(d,J=6.4Hz,2H),6.94(d,J=3.2Hz,1H),4.58(d,J=7.2Hz,1H),4.05(dt,J=11.6 ,5.6Hz,2H),3.83(dt,J=11.2,5.2Hz,2H),3.62(d,J=11.2Hz,1H),3.08-2.95(m,2H), 2.21(d,J=2.2Hz,6H),1.73(t,J=5.4Hz,3H),1.38(d,J=6.4Hz,3H),1.31-1.20(m,2H).

[0293] Example 1a: Preparation of compound 1a

[0294] Step 1: Synthesis of Compounds 1-2

[0295] Sodium bicarbonate (24.4 g, 291 mmol) was added to a solution of compound 1-1 (25.0 g, 145 mmol) and ethyl 3-bromopyruvate (42.5 g, 272 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 1-2. MS m / z (ESI): 267.9, 269.9 [M+H] + .

[0296] Step 2: Synthesis of compounds 1-3

[0297] To a mixed solution of compounds 1-2 (2.0 g, 7.46 mmol) and 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.13 g, 8.95 mmol) in dioxane (30 mL) and water (3 mL), potassium carbonate (2.06 g, 14.92 mmol) and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (0.55 g, 0.75 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compounds 1-3. MS m / z(ESI): 300.1 [M+H] + .

[0298] Step 3: Synthesis of compounds 1-4

[0299] Palladium on carbon (10%) (750 mg) was added to a methanol (30 mL) solution of compounds 1-3 (1.43 g, 4.78 mmol). The reaction mixture was stirred for 16 hours under hydrogen balloon protection at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compounds 1-4. MS m / z (ESI): 302.1 [M+H] + .

[0300] Step 4: Synthesis of compounds 1-5

[0301] Under ice bath conditions, ferrous sulfate heptahydrate (0.99 g, 3.57 mmol), sodium iodide (1.07 g, 7.13 mmol), and hydrogen peroxide (5.35 g, 47.22 mmol) were added to a solution of compounds 1-4 (2.15 g, 7.13 mmol) and bromoacetonitrile (0.94 g, 7.85 mmol) in dimethyl sulfoxide (45 mL). The reaction mixture was stirred under nitrogen atmosphere in an ice bath for 20 minutes. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compounds 1-5. MS m / z (ESI): 341.1 [M+H] + . 1HNMR (400MHz, CDCl3) δ7.75-7.73(m,1H),7.15-7.14(m,1H),6.74(d,J=0.8Hz,1H),6.60-6.58(m,1H),4.47(s,2H),4.33-4.28( m,2H),3.83-3.70(m,2H),2.85-2.77(m,1H),1.73-1.67(m,2H),1.52-1.49(m,2H),1.26(s,3H),1.22(s,3H),1.22-1.17(m,3H).

[0302] Step 5: Synthesis of compounds 1-6

[0303] Under ice bath conditions, bis(trimethylsilylaminolithium) (3.54 g, 21.15 mmol) was added to a solution of compounds 1-5 (800 mg, 2.35 mmol) and vinyl sulfate (875 mg, 7.05 mmol) in N,N-dimethylpropenylurea (16 mL). The reaction mixture was stirred for 1 hour under a nitrogen atmosphere in an ice bath. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compounds 1-6. MS m / z (ESI): 367.2 [M+H] + .

[0304] Step 6: Synthesis of compounds 1-7

[0305] Sodium hydroxide (170 mg, 4.22 mmol) was added to a mixed solution of compounds 1-6 (309 mg, 0.84 mmol) in methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH 5 with dilute hydrochloric acid (2 M), diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give compounds 1-7. MS m / z (ESI): 337.1 [M + H] + .

[0306] Step 7: Synthesis of compounds 1-8a and 1-8b

[0307] Compounds 1-7 (130 mg, 0.38 mmol) were purified by SFC (Separation column: ChiralPak AD, 100 × 4.6 mm ID, 3 μm; Mobile phase: A for CO2 and B for Methanol (0.1% DEA), 5-45%, 4 min; Flow rate: 3.0 mL / min; Column temperature: 40 °C; ABPR: 2000 psi) to obtain the first peak (retention time 4.48 min), which was compound 1-8a. MS m / z (ESI): 337.1 [M+H] + The second peak (retention time 5.29 min) was obtained for compound 1-8b. MS m / z (ESI): 337.1 [M+H] + .

[0308] Step 8: Synthesis of compounds 1-9a

[0309] At room temperature, N,N-diisopropylethylamine (60 mg, 0.46 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (88 mg, 0.23 mmol) were added to a solution of compounds 1-8a (52 mg, 0.15 mmol) and compound A (92 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude compounds 1-9a, which were used directly in the next reaction. MS m / z (ESI): 889.3 [M+H] + .

[0310] Step 9: Synthesis of compounds 1-10a

[0311] At room temperature, N,N-diisopropylethylamine (95 mg, 0.73 mmol) and hydroxylamine hydrochloride (51 mg, 0.73 mmol) were added to an ethanol (4 mL) solution of compound 1-9a (130 mg, 0.15 mmol). The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 1-10a, which was used directly in the next reaction. MS m / z (ESI): 922.3 [M+H] + .

[0312] Step 10: Synthesis of compound 1a

[0313] At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (45 mg, 0.29 mmol) and N,N'-carbonyldiimidazole (48 mg, 0.29 mmol) were added to a 2 mL solution of dimethyl sulfoxide (DMSO) containing 135 mg of compound 1-10a. The reaction mixture was stirred at room temperature for 1 hour. The filtrate obtained after filtration was purified by preparative HPLC (ASA-AZZOTA—C18-7μm-30*150mm, A: 0.1% FA / H2O, B: ACN, gradient: 65%) to obtain compound 1a. MS m / z (ESI): 948.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ12.05(s,1H),8.12(d,J=8.4Hz,1H),7.67(d,J=8.0Hz,1H),7.40-7.39(m,2H),7.29-7.04( m,5H),6.92-6.69(m,2H),6.38(d,J=9.6Hz,1H),5.63(d,J=6.8Hz,1H),4.98–4.81(m,1H),4.07-4.04(m,3H),3. 85-3.82(m,2H),3.71(d,J=8.0Hz,2H),3.13(d,J=28.4Hz,3H),2.93-2.90(m,1H),2.80-2.66(m,2H),2.07-2.04 (m,1H),1.75-1.44(m,11H),1.30-1.25(m,6H),1.18(d,J=6.4Hz,4H),0.98(d,J=7.2Hz,2H),0.62-0.59(m,2H).

[0314] Example 1b: Preparation of compound 1b

[0315] Compound 1b was obtained by replacing compounds 1-8a in Example 1a with compounds 1-8b, and by referring to the preparation method of compound 1a in Example 1a.

[0316] Compound 1b: MS m / z (ESI): 948.4 [M+H] + . 1H NMR (400MHz, CD3OD) δ12.04(s,1H),8.13(d,J=7.6Hz,1H),7.67(d,J=8.0Hz,1H),7.40-7.39(m,2H),7.29-7.04( m,5H),6.92-6.69(m,2H),6.38(d,J=9.6Hz,1H),5.63(d,J=6.8Hz,1H),4.98–4.81(m,1H),4.07-4.04(m,3H),3. 85-3.82(m,2H),3.71(d,J=8.0Hz,2H),3.13(d,J=28.4Hz,3H),2.93-2.90(m,1H),2.80-2.66(m,2H),2.07-2.04 (m,1H),1.75-1.44(m,11H),1.30-1.25(m,6H),1.18(d,J=6.4Hz,4H),0.98(d,J=7.2Hz,2H),0.62-0.59(m,2H).

[0317] Example 2b: Preparation of compound 2b

[0318] Compound 2b is obtained by replacing compounds 1-8a in Example 1a with compounds 1-8b, replacing compound A in Example 1a with compound B, and following the preparation method of compound 1a in Example 1a.

[0319] Compound 2b: MS m / z (ESI): 936.3 [M+H] + . 1 H NMR (400MHz, CD3OD) δ12.00(s,1H),8.13(d,J=7.2Hz,1H),7.67(d,J=7.6Hz,1H),7.37-7.33(m,2H),7 .29-7.26(m,1H),7.15-7.02(m,4H),6.72-6.70(m,1H),6.39(d,J=12.8Hz,1H),5.64(d,J=7.2Hz,1H), 4.98-4.79(m,1H),4.07-4.04(m,3H),3.85-3.82(m,2H),3.71(d,J=8.4Hz,2H),3.16(s,2H),3.08(s, 1H),2.93-2.90(m,1H),2.68-2.66(m,2H),2.22-2.18(m,6H),1.76-1.44(m,11H),1.31-1.18(m,10H).

[0320] Example 3a: Preparation of compound 3a

[0321] Step 1: Synthesis of compound 3-2

[0322] Under nitrogen protection and at 0°C, (triphenylphosphine)acetonitrile (160 g, 532 mmol) was added to a solution of compound 3-1 (90.0 g, 484 mmol) in dichloromethane (1000 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, and then at 25°C for 17 hours. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (1000 mL), and extracted with dichloromethane (1000 mL × 2). The combined organic phases were washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 3-2. MS m / z (ESI): 209.0, 211.0 [M+H] + .

[0323] Step 2: Synthesis of compound 3-3

[0324] Sodium borohydride (7.3 g, 191.3 mmol) was added to a methanol (200 mL) mixture of compound 3-2 (20.0 g, 95.7 mmol) at room temperature. After the addition was complete, nickel chloride hexahydrate (2.28 g, 9.61 mmol) was added in portions, and the reaction was stirred at 0°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (400 mL), and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 3-3. MS m / z (ESI): 211.0, 213.0 [M+H] + .

[0325] Step 3: Synthesis of compounds 3-4

[0326] At 0°C, sodium bicarbonate (7.9 g, 94.7 mmol) was added to a solution of compound 3-3 (5.0 g, 23.7 mmol) in 1,2-dichloroethane (10 mL). After the addition was complete, ethyl 3-bromopyruvate (6.9 mL, 54.5 mmol) was added dropwise. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compound 3-4. MS m / z (ESI): 307.0, 309.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.66(dd,J=1.6,0.8Hz,1H),8.12(s,1H),7.17(d,J=9.2Hz,1H) ,6.99(dd,J=9.6,1.6Hz,1H),4.31(q,J=7.2Hz,2H),4.26(s,2H),1.34(t,J=7.2Hz,3H).

[0327] Step 4: Synthesis of compounds 3-5

[0328] Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (430 mg, 0.6 mmol) was added to a mixed solvent of compounds 3-4 (1.4 g, 4.6 mmol), potassium carbonate (1.62 g, 11.7 mmol), 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (1.7 g, 7.1 mmol), 1,4-dioxane (20 mL), and water (4 mL). After purging with nitrogen three times, the mixture was heated to 100 °C and stirred for 10 hours. The reaction solution was diluted in water (100 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give compounds 3-5. MS m / z (ESI): 339.2 [M + H] + .

[0329] Step 5: Synthesis of compounds 3-6

[0330] To a solution of compounds 3-5 (1.3 g, 3.84 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), 10% palladium on carbon (0.2 g, 1.88 mmol) was added, purging with hydrogen three times. The reaction mixture was stirred at 25°C for 18 hours. After diatomaceous earth filtration, the filtrate was washed three times with ethyl acetate, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compounds 3-6. MS m / z (ESI): 341.2 [M + H] + .

[0331] Step 6: Synthesis of compounds 3-7

[0332] Under nitrogen protection and at 0°C, lithium bis(trimethylsilyl)amino (28 mL, 28.0 mmol, 1.0 M) was added dropwise to a solution of compounds 3-6 (1.2 g, 3.5 mmol) and vinyl sulfate (1.5 g, 12.3 mmol) in N,N-dimethylpropenylurea (20 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, then heated to 25°C and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 3-7. MS m / z (ESI): 367.2 [M+H] + .

[0333] Step 7: Synthesis of compounds 3-8

[0334] Sodium hydroxide (164 mg, 4.1 mmol) was added to a methanol (4 mL) and water (1 mL) solution of compound 3-7 (0.5 g, 1.36 mmol) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then heated to 50°C and stirred for 2 hours. The pH of the reaction mixture was adjusted to approximately 3 with 2 M dilute hydrochloric acid. The mixture was filtered, and the filter cake was washed three times with water and concentrated under reduced pressure to obtain compound 3-8. MS m / z (ESI): 339.2 [M+H] + .

[0335] Step 8: Synthesis of compounds 3-9a and 3-9b

[0336] Compounds 3-8 (0.45 g, 1.23 mmol) were separated by SFC (ChiralPak AD 250 × 30 mm ID, 5 μm column; mobile phase: A for CO2 and B for Methanol (0.1% DEA); flow rate: 3 mL / min; column temperature: 35 °C; ABPR: 2000 psi), yielding the first peak (retention time 4.070 min) belonging to compound 3-9a. MS m / z (ESI): 339.2 [M+H] + The second peak (retention time 4.749 min) was obtained as compound 3-9b. MS m / z (ESI): 339.2 [M+H] + .

[0337] Step 9: Synthesis of compound 3-10a

[0338] To a solution of compound 3-9a (35.0 mg, 0.1 mmol) and compound A (58.8 mg, 0.1 mmol) in N,N-dimethylacetamide (1 mL), N,N-diisopropylethylamine (27 mg, 0.2 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (47 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in water (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 3-10a. MS m / z (ESI): 889.4 [M+H] + .

[0339] Step 10: Synthesis of compound 3-11a

[0340] To a 1 mL ethanol solution of compound 3-10a (40.0 mg, 11.3 mmol) and hydroxylamine hydrochloride (16 mg, 0.22 mmol), N,N-diisopropylethylamine (58 mg, 0.45 mmol) was added, and the mixture was purged with nitrogen three times. The reaction mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the mixture was diluted with 10 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 3-11a. MS m / z (ESI): 922.4 [M+H] + .

[0341] Step 11: Synthesis of compound 3a

[0342] At 25°C, N,N'-carbonyldiimidazole (14 mg, 0.09 mmol) was added to a dimethyl sulfoxide (1 mL) solution of compound 3-11a (40.0 mg, 0.04 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (20 mg, 0.13 mmol), purged with nitrogen three times, and the reaction mixture was stirred at 25°C for 2 hours. The filtrate was then subjected to preparative HPLC (ASA-AZZOTA—C18-7μm-30*150mm, A: 0.1% FA / H2O, B: ACN, gradient: 60%) to obtain compound 3a. MS m / z (ESI): 948.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.04-8.01(m,1H),7.65-7.41(m,3H),7.33-7.11(m,4H ),7.11-6.62(m,4H),5.84-5.07(m,1H),4.22-4.07(m,2H),3.92-3.81(m,4H) ,3.54-3.47(m,1H),3.23-3.12(m,3H),2.94-2.86(m,3H),2.18-2.09(m,1H), 1.85-1.57(m,9H),1.48-1.15(m,13H),0.97-0.89(m,2H),0.66-0.65(m,2H).

[0343] Example 3b: Preparation of compound 3b

[0344] Compound 3b was obtained by replacing compounds 3-9a in Example 3a with compounds 3-9b, and by referring to the preparation method of compound 3a in Example 3a.

[0345] Compound 3b: MS m / z (ESI): 948.4 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.04-8.03(m,1H),7.61-7.51(m,3H),7.35-7.15(m,4H),6. 97-6.10(m,4H),5.84-5.10(m,1H),4.28-4.19(m,2H),3.92-3.77(m,4H),3.54-3. 47(m,1H),3.23-3.12(m,3H),2.93-2.89(m,3H),2.12-2.09(m,1H),1.85-1.57(m, 9H),1.44-1.45(m,3H),1.33-1.21(m,10H),0.97-0.89(m,2H),0.66-0.65(m,2H).

[0346] Example 4a: Preparation of compound 4a

[0347] Compound 4a was obtained by replacing compound ethylene sulfate in Example 1a with compound (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, replacing compound A in Example 1a with compound B, and by referring to the preparation method of compound 1a in Example 1a.

[0348] Compound 4a: MS m / z (ESI): 950.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.15-8.10(m,1H),7.62-6.71(m,9H),6.57-6.49(m,1H),5.32-5.82(m,1H),4.35-4.12(m,3H),3.98-3.76(m,4H) ,3.59-3.53(m,1H),3.23-3.12(m,4H),3.02-2.87(m,2H),2.26-2.17(m,6H),1.88-1.75(m,5H),1.73-1.47(m,7H),1.38-1.17(m,11H).

[0349] Example 4b: Preparation of compound 4b

[0350] Compound 4b was prepared by replacing compound vinyl sulfate in Example 1a with compound (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, replacing compound A in Example 1a with compound B, and following the preparation method of compound 1b in Example 1b.

[0351] Compound 4b: MS m / z (ESI): 950.4 [M+H]+ . 1 H NMR (400MHz, CD3OD) δ8.15-8.10(m,1H),7.62-6.71(m,9H),6.57-6.49(m,1H),5.32-5.82(m,1H),4.35-4.12(m,3H),3.98-3.76(m,4H) ,3.59-3.53(m,1H),3.23-3.12(m,4H),3.02-2.87(m,2H),2.26-2.17(m,6H),1.88-1.75(m,5H),1.73-1.47(m,7H),1.37-1.19(m,11H).

[0352] Example 5b: Preparation of compound 5b

[0353] Compound 5b was obtained by replacing compound A in Example 3a with compound B, and by referring to the preparation method of compound 3b in Example 3b.

[0354] Compound 5b: MS m / z (ESI): 936.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.03-8.00(m,1H),7.64-7.20(m,4H),7.14-7.13(m,3H ),7.01-6.49(m,3H),5.86-5.10(m,1H),4.22-4.16(m,2H),3.92-3.81(m,4H) ,3.62-3.49(m,1H),3.31-3.15(m,3H),3.02-2.82(m,3H),2.23-2.19(m,6H) ,1.84-1.80(m,6H),1.67-1.55(m,3H),1.49-1.44(m,4H),1.37-1.18(m,9H).

[0355] Example 6: Preparation of Compound 6

[0356] Compound 6 was obtained by replacing compound A in Example 3a with compound B, and replacing 2-(3,6-dihydro-2H-pyran-4-boronic acid pinacol ester in Example 3a with 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane with compound 3,6-dihydro-2H-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane with compound 3a in Example 3a.

[0357] Compound 6: MS m / z (ESI): 908.4 [M+H] + .1 H NMR(400MHz,CD3OD)δ8.05-8.01(m,1H),7.65-7.47(m,3H),7.31-7.29(m,1H),7.17-6.57(m,6H),5.86-5.10(m,1H),4 .21-3.91(m,6H),3.59-3.55(m,3H),3.23-3.13(m,4H),2.93-2.70(m,3H),2.24(d,J=7.6Hz,6H),1.84-1.25(m,15H).

[0358] Example 7a: Preparation of compound 7a

[0359] Compound 7a was obtained by replacing compound A in Example 3a with compound B, replacing compound vinyl sulfate in Example 3a with compound (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, and following the preparation method of compound 3a in Example 3a.

[0360] Compound 7a: MS m / z (ESI): 950.4 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.08(brs,1H),7.68-7.04(m,8H),6.96-6.77(m,2H),5.95-5.29(m,1H),4.25-4.13(m,2H),3.98-3.75(m,4H),3.26-3.21 (m,2H),3.04-2.90(m,2H),2.28-2.09(m,7H),2.08-1.98(m,2H),1.89- 1.71(m,6H),1.50-1.44(m,2H),1.37-1.25(m,11H),1.06-0.86(m,5H).

[0361] Example 7b: Preparation of compound 7b

[0362] Compound 7b was obtained by replacing compound A in Example 3a with compound B, replacing compound vinyl sulfate in Example 3a with compound (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, and following the preparation method of compound 3b in Example 3b.

[0363] Compound 7b: MS m / z (ESI): 950.4 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.08(brs,1H),7.68-7.04(m,8H),6.96-6.77(m,2H),5.95-5.29(m,1H),4.25-4.13(m,2H),3.98-3.75(m,4H),3.26-3.21 (m,2H),3.04-2.90(m,2H),2.28-2.09(m,7H),2.08-1.98(m,2H),1.89- 1.71(m,6H),1.50-1.44(m,2H),1.37-1.25(m,11H),1.06-0.86(m,5H).

[0364] Example 8: Preparation of Compound 8

[0365] Compound 8 was obtained by replacing compound A in Example 3a with compound B, replacing compound vinyl sulfate in Example 3a with compound (4S)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, and replacing compound 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester in Example 3a with compound 3,6-dihydro-2H-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane with compound 3,6-dihydro-2H-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, and following the preparation method of compound 3a in Example 3a.

[0366] Compound 8: MS m / z (ESI): 922.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.97 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.46 (s, 1H), 7.33-7.27 (m, 3H), 7.14-7.10(m,3H),6.85-6.73(m,2H),5.74-5.11(m,1H),4.22-4.17(m,2H),4.08-4.02(m, 2H),3.96-3.92(m,2H),3.64-3.52(m,4H),3.35-3.21(m,4H),2.68-2.59(m,2H),2.23(d,J =2.0Hz,6H),2.05-2.01(m,2H),1.93-1.72(m,10H),1.43-1.37(m,3H),1.28-1.22(m,2H).

[0367] Example 9: Preparation of Compound 9

[0368] Compound 9 was obtained by replacing compound A in Example 3a with compound B, replacing compound vinyl sulfate in Example 3a with compound (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide, and replacing compound 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-boronic acid pinacol ester in Example 3a with compound 3,6-dihydro-2H-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane with compound 3,6-dihydro-2H-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, and following the preparation method of compound 3a in Example 3a.

[0369] Compound 9: MS m / z (ESI): 922.4 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.01-7.94(m,1H),7.67-7.42(m,3H),7.31-7.09(m,5H),6. 88-6.78(m,2H),5.84-5.16(m,1H),4.59-4.57(m,2H),4.19-3.90(m,6H),3.61-3 .47(m,5H),3.36-3.34(m,1H),3.24(s,2H),3.16-3.11(m,2H),2.76-2.64(m,2H) ,2.24(d,J=10.8Hz,6H),2.06-2.02(m,1H),1.87-1.73(m,6H),1.47-1.22(m,6H).

[0370] Example 10a: Preparation of compound 10a

[0371] Step 1: Synthesis of Compound 10-2

[0372] Under nitrogen protection and at 0°C, (triphenylphosphine)acetonitrile (82.29 g, 236.45 mmol) was added to a solution of compound 10⁻¹ (40.0 g, 197.04 mmol) in dichloromethane (600 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, and then at 25°C for 17 hours. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (500 mL), and extracted with dichloromethane (600 mL × 3). The combined organic phases were washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 10⁻². MS m / z (ESI): 227.0, 229.0 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.62-8.37(m,1H),7.64-7.27(m,2H),6.61-5.66(m,1H).

[0373] Step 2: Synthesis of compound 10⁻³

[0374] Sodium borohydride (10.05 g, 318.58 mmol) was added to a mixed solution of compound 10⁻² (36.0 g, 159.29 mmol) in tetrahydrofuran (300 mL) and methanol (100 mL) at room temperature. After the addition was complete, nickel chloride hexahydrate (3.79 g, 15.93 mmol) was added in portions, and the reaction was stirred at 0°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (400 mL), and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 10⁻³. MS m / z (ESI): 229.0, 231.0 [M + H] + .

[0375] Step 3: Synthesis of compound 10⁻⁴

[0376] Under nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.85 g, 5.26 mmol) was added to a mixed solvent of compound 10-3 (12.0 g, 52.63 mmol), potassium carbonate (18.16 g, 131.58 mmol), 2-(3,6-dihydro-2,2-dimethyl-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (18.79 g, 78.95 mmol), 1,4-dioxane (150 mL), and water (15 mL). After purging with nitrogen three times, the mixture was heated to 90°C and stirred for 16 hours. The reaction solution was diluted in water (150 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 10⁻⁴. MS m / z (ESI): 261.2 [M + H] + . 1H NMR (400MHz, CDCl3) δ8.34(s,1H),7.28(ddd,J=10.8,5.2,1.6Hz,1H),6.09(dt,J=51.2,1.6Hz,1H),4.29(q,J=2.8Hz,1H),3.88(t,J=5. 2Hz, 1H), 3.12 (td, J = 7.2, 1.6Hz, 2H), 2.79 (t, J = 7.2Hz, 2H), 2.34 (td, J = 5.2, 1.6Hz, 1H), 2.27 (d, J = 1.6Hz, 1H), 1.26 (d, J = 13.2Hz, 6H).

[0377] Step 4: Synthesis of compound 10-5

[0378] Sodium bicarbonate (11.63 g, 138.48 mmol) was added to a solution of compound 10⁻⁴ (9.0 g, 34.62 mmol) in 1,2-dichloroethane (90 mL) at 0 °C. After the addition was complete, ethyl 3-bromopyruvate (16.88 g, 86.55 mmol) was added dropwise. The reaction mixture was stirred at 90 °C for 18 hours. The reaction mixture was concentrated, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compound 10⁻⁵. MS m / z (ESI): 357.1 [M + H] + .

[0379] Step 5: Synthesis of compound 10-6

[0380] To a solution of compound 10⁻⁵ (700 mg, 1.97 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), 10% palladium on carbon (700 mg, 1.97 mmol) was added, and hydrogen gas was purged three times. The reaction mixture was stirred at 25°C for 16 hours. After diatomaceous earth filtration, the filtrate was washed three times with ethyl acetate, diluted with water (100 mL), and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give compound 10⁻⁶. MS m / z (ESI): 359.2 [M + H] + . 1H NMR (400MHz, CDCl3) δ7.75(d,J=2.0Hz,1H),7.44(s,1H),6.33(d,J=12.8Hz,1H),4.33(q,J=7.2Hz,2H),4.20( s, 2H), 3.84-3.66 (m, 2H), 2.83-2.70 (m, 1H), 1.72-1.52 (m, 4H), 1.35 (t, J = 7.2Hz, 3H), 1.23 (d, J = 9.2Hz, 6H).

[0381] Step 6: Synthesis of compound 10-7

[0382] Under nitrogen protection and at 0°C, lithium bis(trimethylsilyl)amino (5.02 mL, 5.02 mmol, 1.0 M) was added dropwise to a solution of compound 10⁻⁶ (200 mg, 0.56 mmol) and vinyl sulfate (207 mg, 1.67 mmol) in N,N-dimethylpropenylurea (6 mL). After the addition was complete, the mixture was stirred at 0°C for 1 hour, then heated to 25°C and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (30 mL), diluted with water (30 mL), and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 10⁻⁷. MS m / z (ESI): 385.2 [M + H] + .

[0383] Step 7: Synthesis of compound 10-8

[0384] Sodium hydroxide (65 mg, 1.63 mmol) was added to a methanol (4 mL) and water (1 mL) solution of compound 10⁻⁷ (125 mg, 0.33 mmol) at 25°C. The reaction mixture was stirred at 50°C for 2 hours. The pH of the reaction mixture was adjusted to approximately 3 with 2M dilute hydrochloric acid. The mixture was filtered, and the filter cake was washed three times with water and concentrated under reduced pressure to obtain compound 10⁻⁸. MS m / z (ESI): 357.2 [M+H] + .

[0385] Step 8: Synthesis of compounds 10⁻⁹a and 10⁻⁹b

[0386] Compound 10⁻⁸ (110 mg, 0.31 mmol) was separated by SFC (Separation column: ChiralPak AD 250 × 30 mm ID, 5 μm; Mobile phase: A for CO₂ and B for Methanol (0.1% DEA); Flow rate: 3 mL / min; Column temperature: 35 °C; ABPR: 2000 psi). The first peak (retention time 3.727 min) was observed, indicating compound 10⁻⁹a. MS m / z (ESI): 357.2 [M + H]⁺. The second peak (retention time 4.194 min) was observed, indicating compound 10⁻⁹b. MS m / z (ESI): 357.2 [M + H]⁺. + .

[0387] Step 9: Synthesis of compound 10-10a

[0388] To a solution of compound 10-9a (50.0 mg, 0.14 mmol) and compound A (70.4 mg, 0.14 mmol) in N,N-dimethylacetamide (2 mL), N,N-diisopropylethylamine (54.4 mg, 0.42 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (80.0 mg, 0.21 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted in water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 10-10a. MS m / z (ESI): 907.3 [M+H] + .

[0389] Step 10: Synthesis of compound 10-11a

[0390] To a 4 mL ethanol solution of compound 10-10a (115 mg, 0.14 mmol) and hydroxylamine hydrochloride (47.6 mg, 0.68 mmol), N,N-diisopropylethylamine (88.5 mg, 0.68 mmol) was added, and the mixture was purged with nitrogen three times. The reaction solution was stirred at 60 °C for 3 hours. After cooling to room temperature, the solution was diluted with 50 mL of water and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 10-11a. MS m / z (ESI): 922.4 [M+H] + .

[0391] Step 11: Synthesis of compound 11a

[0392] At 25°C, N,N'-carbonyldiimidazole (48 mg, 0.30 mmol) was added to a dimethyl sulfoxide (1 mL) solution of compound 10-11a (95 mg, 0.10 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (45 mg, 0.30 mmol), purged with nitrogen three times, and the reaction mixture was stirred at 25°C for 1 hour. The filtrate was filtered and subjected to preparative HPLC (Nouryon-Kromasil-C18-10 μm-25*250 mm; Mobile: phase A: 10 mM NH4HCO3 / H2O; B: ACN; Gradient; 10% to 95%) to give compound 10a. MS m / z (ESI): 966.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.92-7.88(m,1H),7.68-7.53(m,2H),7.34-7.26(m,2H),7.18-6.94 (m,4H),6.81-6.70(m,1H),6.64-6.60(m,1H),5.85-4.97(m,1H),4.23-4.20(m,3H),3.97- 3.82(m,4H),3.57-3.50(m,1H),3.26-3.15(m,3H),2.98-2.80(m,3H),2.13-2.09(m,1H),1 .87-1.76(m,6H),1.66-1.39(m,8H),1.36-1.27(m,7H),1.06-0.99(m,2H),0.68(brs,2H).

[0393] Example 10b: Preparation of compound 10b

[0394] Compound 10b was obtained by replacing compound 10-9a in Example 10a with compound 10-9b, and by referring to the preparation method of compound 10a in Example 10a.

[0395] Compound 10b: MS m / z (ESI): 966.4 [M+H] + . 1H NMR(400MHz,CD3OD)δ7.92-7.88(m,1H),7.70-7.54(m,2H),7.34-7.27(m,2H),7.19-6.97 (m,4H),6.81-6.69(m,1H),6.62-6.54(m,1H),5.87-4.97(m,1H),4.23-4.20(m,3H),3.95- 3.83(m,4H),3.55-3.49(m,1H),3.26-3.14(m,3H),2.98-2.81(m,3H),2.13-2.09(m,1H),1 .87-1.76(m,6H),1.64-1.40(m,8H),1.36-1.27(m,7H),1.01-0.92(m,2H),0.68(brs,2H).

[0396] Example 11b: Preparation of compound 11b

[0397] Compound 11b was obtained by replacing compound A in Example 10a with compound B, and by referring to the preparation method of compound 10b in Example 10b.

[0398] Compound 11b: MS m / z (ESI): 954.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ7.89-7.85(m,1H),7.62-7.52(m,2H),7.30-7.26(m,1H),7 .15-7.11(m,3H),6.90-6.52(m,3H),5.86-5.11(m,1H),4.58(s,2H),4.21-4.18( m,2H),3.92-3.80(m,4H),3.57-3.48(m,1H),3.23-3.17(m,3H),2.95-2.66(m,3 H),2.24-2.19(m,6H),1.85-1.81(m,5H),1.59-1.56(m,3H),1.49-1.25(m,12H).

[0399] Other compounds in this application can be prepared by referring to the preparation methods of the compounds in the foregoing embodiments (with appropriate modifications if necessary).

[0400] Experimental Example 1: Determination of the ability of compounds to stimulate cAMP production in human GLP-1 receptor-stabilized cell lines

[0401] The purpose of this test case was to evaluate the ability of the compound to activate the human GLP-1 receptor on the cell surface. EC50 values ​​of cAMP generated after activation characterized the compound's activation ability on the human GLP-1 receptor.

[0402] Cell culture: A cell line stably expressing human GLP-1R (H_GLP-1R CHO-K1 Cell Line, purchased from Jimon Biotechnology, GM-C35369) was used in the experiment. Cells were maintained in F12K medium (ATCC-30-2004) supplemented with 10% fetal bovine serum (Corning-35-081-CV) and 4 μg / mL puromycin (Gibco-A1113803).

[0403] cAMP assay: When the cell density approaches 80%, remove the culture medium and gently rinse the culture flask with PBS. Add non-enzymatic cell lysis buffer (Sigma-C5914) and incubate at 37°C and 5% CO2 for 5–10 minutes until cells detach. Centrifuge the cell suspension at 1000 rpm for 5 minutes to remove the supernatant. Resuspend the cell pellet in assay buffer (F12K medium containing 0.1% BSA and 0.5 mM IBMX (MCE-HY-12318)) and adjust the cell density to 750 cells / 10 μL / well in white Proxiplate-384 plates (PerkinElmer-6007290) containing serial dilution buffer of the assay compound (maximum concentration 25 μM, 5-fold serial dilution, 12 spots). Centrifuge at 1000 rpm for 1 minute, vortex to mix, and incubate at 37°C and 5% CO2 for 30 minutes. The assay was performed using the Cisbio cAMP-Gs Dynamic Kit (Revvity-62AM4PEB). cAMP-d2 (5 μL, 1x) and Anti-cAMP-Cryptate (5 μL, 1x) were added, and the mixture was incubated at room temperature for 1 hour. HTRF signals were read using an Envision microplate reader with excitation at 320 nm and emission at 620 nm and 665 nm.

[0404] The signal ratio (665nm / 620nm*10,000) was calculated, and the EC50 value was obtained by nonlinearly fitting the signal ratio and sample concentration using a four-parameter equation in GraphPad Prism. Some test results are shown in Table 1.

[0405] Table 1 EC50 of compounds used in in vitro cAMP signal activation experiments 50

[0406] Experimental results show that the compound of this invention can significantly increase the accumulation of cAMP in hGLP-1R CHO-K1 cells.

Claims

1. A GLP-1R agonist, which is a compound with the structure shown in formula (I), or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts: in, X1, X2, X4, X5, X6, X7, and X9 are each independently selected from C or N; X3 is selected from C, N, O, or S; Y1, Y3, Y4, and Y5 are each independently selected from C or N; Y2 is selected from CR e O, S, NR e Or N; Ring Z1 is selected from a benzene ring or a 6-membered heteroaromatic ring; Ring Z2 is selected from 5-membered heteroaryl rings; Ring Z3 is selected from 5-membered heterocyclic aromatic rings; R e Selected from hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Deuterated alkyl groups; R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Substitution of aryl or 5-10 heteroaryl groups; wherein, the C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 The aryl and 5-10 heteroaryl groups are optionally coated with one or more elements selected from deuterium, halogen, hydroxyl, cyano, amino, C. 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; R 6a and R 6b Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl or C 1-6 Halogenated alkyl, or R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three atoms selected from deuterium, halogen, OH, NH2, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, the C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2 is optionally surrounded by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, said C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 cycloalkyl, 4-7 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by one or more radicals selected from deuterium, halogen, hydroxyl, cyano, amino, C. 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; R 10 Selected from C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl; the C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 aryl groups are optionally surrounded by 1, 2, 3, 4 or 5 R groups. 10a replace; R 10a Independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2、-NH(C 1-6 Halogenated alkyl), -N(C) 1-6 (halogenated alkyl) 2, hydroxyl C 1-6 Alkyl-, cyano-C 1-6 Alkyl-, amino C 1-6 Alkyl group, or two R atoms attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 aryl, 13-18-membered heteroaryl, wherein the 13-18-membered heterocyclic group, C 13-18 The aryl group and the 13-18 heteroaryl group may be optionally substituted by one or more substituents, each independently selected from group A; Group A: a) Deuterium; b) Oxo (=O); c) Halogens; d)OH; e) Cyano group; f) Among them, R 0 Selected from H, C 1-6 alkyl; g)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 Alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups; h)-C(=O)R C1 , where R C1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups; i)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 The alkoxy group and the 3-12 membered heterocyclic group are substituents, wherein the 3-12 membered heterocyclic group is optionally replaced by one or more independently selected from C. 1-6 Alkyl substituents; j)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; k) 3-12 membered heterocyclic groups, wherein the 3-12 membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; l) 5-10 heteroaryl groups, wherein the 5-10 heteroaryl groups are optionally selected independently by one or more deuterium, halogen, hydroxyl group, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N5 R N6 Substituents of R, wherein R N5 and R N6 Independently selected from H and C 1-6 Alkyl; or m)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, NH2, CN, C. 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; Among them, when for hour, Not for Or when for hour, Not for 2. The compound according to claim 1, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, Selected from in, Ring Z1 is selected from a benzene ring or a 6-membered heteroaromatic ring; Ring Z2 is selected from 5-membered heteroaryl rings; Preferably, ring Z1 is selected from a benzene ring or a 6-membered nitrogen-containing heteroaromatic ring; Preferably, ring Z2 is selected from a 5-membered nitrogen-containing heteroaromatic ring, a 5-membered sulfur-containing heteroaromatic ring, or a 5-membered oxygen-containing heteroaromatic ring.

3. The compound according to claim 2, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The Selected from: (Preferred) )； Preferably, the Selected from:

4. The compound according to any one of claims 1-3, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, Selected from in, Represents a single bond or a double bond; Among them, Y4 and Y5 are selected from C; Preferably, Y2 is selected from CH or N; Preferably, the Selected from More preferably, the Selected from 5. The compound according to any one of claims 1-4, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formula (I-1):

6. The compound according to any one of claims 1-5, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The R 1 Selected from C 6-10 Aryl or 5-10 heteroaryl; the C 6-10 The aryl or 5-10 heteroaryl group is optionally surrounded by 1, 2, 3, 4, or 5 independently selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from phenyl or 5-6 heteroaryl groups; wherein the phenyl or 5-6 heteroaryl group is optionally selected by 1, 2, 3, 4 or 5 independently from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups; Preferably, R 1 Selected from phenyl or pyridyl; wherein the phenyl or pyridyl group is optionally selected by 1, 2, 3, 4 or 5 independently from deuterium, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substituents of cycloalkyl groups; More preferably, R 1 Selected from phenyl; the phenyl group is optionally selected independently by 1, 2, 3 or 4 halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substituents of cycloalkyl groups; More preferably, the R 1 Selected from:

7. The compound according to any one of claims 1-6, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The R 10 Selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the C 3-8 Cycloalkyl, 4-7 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, optionally bound by 1, 2, 3, 4 or 5 R groups. 10a replace; Preferably, R 10 Selected from C 3-8 Cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl; the C 3-8 Cycloalkyl, 4-7-membered heterocyclic, and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace; Preferably, R 10 Selected from 6-membered heterocyclic groups, C 5-7 cycloalkyl, 5-6 membered heteroaryl; the 6 membered heterocyclic group, C 5-7 Cycloalkyl groups and 5-6-membered heteroaryl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace; More preferably, R 10 Selected from tetrahydropyranyl, morpholinyl, cyclohexyl, and pyridyl; wherein the tetrahydropyranyl, morpholinyl, cyclohexyl, and pyridyl groups are optionally surrounded by 1, 2, 3, 4, or 5 R groups. 10a replace; Among them, R 10a Independently selected from deuterium, halogens, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups, or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl or 4-7 membered heterocyclic groups; Preferably, R 10a Selected from deuterium, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy groups or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; Preferably, R 10a Selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkoxy groups or two R groups attached to the same carbon atom 10a Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; Preferably, the R 10 Selected from The The land can be optionally divided by 1, 2, 3, 4 or 5 Rs. 10a replace; More preferably, the R 10 Selected from (Preferred) )、 (Preferred) )、 (Preferred) )、 (Preferred) )、 8. The compound according to any one of claims 1-7, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts. in: R 6a and R 6b Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl; the C 3-6 The cycloalkyl group is optionally surrounded by 1, 2, or 3 elements selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Substituents of haloalkoxy groups; Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C1, C2, or C3. 1-6 Alkyl substituents; Preferably, the Selected from (For example Preferred )、 (Preferred) ); where the key marked with "#" is connected to 9. The compound according to any one of claims 1-8, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts. in: R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 alkyl; Preferably, R 3 R 4 Each element is independently selected from hydrogen, deuterium, and halogen; preferably, R 3 R 4 All are hydrogen; R 5 Selected from C 1-6 Alkyl; preferably, R 5 Selected from C 1-4 alkyl.

10. The compound according to any one of claims 1-9, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts. in: R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, and C. 1-6 alkyl; Preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, deuterium, halogen, and C. 1-4 alkyl; Preferably, R 7 R 8 R 9 and R 11 Each is independently selected from non-existent, hydrogen, and halogen.

11. The compound according to any one of claims 1-10, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, Group A is selected from: 1) Deuterium; 2) Oxygenation; 3) Halogens; 4) OH; 5) Cyano group; 6)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 alkyl; 7)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-7 membered heterocyclic groups; 8)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; 9) 3-7 membered heterocyclic groups, wherein the 3-7 membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; 10) 5-10 heteroaryl groups, wherein the 5-10 heteroaryl groups are optionally selected independently by one or more deuterium, halogen, hydroxyl group, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N5 R N6 Substituents of R, wherein R N5 and R N6 Independently selected from H and C 1-6 Alkyl; or 11)C 3-6 cycloalkyl, wherein C 3-6 The cycloalkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, NH2, CN, C. 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; Preferably, group A is selected from: 1) Deuterium; 2) Oxygenation; 3) Halogens; 4) OH; 5) Cyano group; 6)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 alkyl; 7)C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-7 membered heterocyclic groups; 8)C 1-6 Alkoxy, of which, C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; Preferably, group A is selected from: deuterium, oxo, halogen, hydroxyl, cyano, NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene-, C 1-6 Alkoxy C 1-6 Alkylene-, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkoxy-, hydroxy C 1-6 Alkyloxy-; Preferably, group A is selected from: deuterium, oxo, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Preferably, group A is selected from: deuterium, oxometalate, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Preferably, group A is selected from: deuterium, oxometalate, halogen, C 1-6 alkyl; Preferably, group A is selected from: oxo, halogen, C 1-6 alkyl.

12. The compound according to any one of claims 1-11, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The R 2 Selected from 13-18 membered heterocyclic groups and 13-18 membered heteroaryl groups; Preferably, R 2 Selected from group (1), group (2), group (3), or group (4): Group (1): in, Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl; Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl; Group (2): in, It can be a single bond or a double bond; Ring B is selected from phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocyclic group; The ring C is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered monocyclic heterocyclic group, C 5-6 Monocyclic cycloalkyl; Group (3): in, Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl; Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl; Ring D is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl; Group (4) in, Ring B is selected from 5-7 member monocyclic heterocyclic groups, C 5-7 Monocyclic cycloalkyl; Cycle C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl; Ring D is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl; In groups (1) to (4), Ring A is phenyl; R A Each is independently selected from deuterium, halogens, OH, CN, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups; n is selected from 0, 1, and 2; m is selected from 0, 1, 2, or 3; y is selected from 0, 1, 2, or 3; t is selected from 0, 1, or 2; R B R B R D Substituents are each independently selected from group A; Preferably, R A Each is independently selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups; More preferably, R A Each is independently selected from deuterium, halogens, and C. 1-6 alkyl; More preferably, R A Selected from halogens; Preferably, n is selected from 0 or 1; Preferably, m is selected from 0, 1, or 2; Preferably, y is selected from 0 or 1; Preferably, t is selected from 0; Preferably, R B Selected from deuterium, halogen, oxo, C 1-6 Alkyl; more preferably, R B Selected from oxo, C 1-6 alkyl; Preferably, R C Selected from deuterium, halogen, oxo, C 1-6 Alkyl; more preferably, R C Selected from oxo; Preferably, R D Selected from deuterium, halogen, oxo, C 1-6 alkyl.

13. The compound according to claim 12, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The group (1) Selected from: in, M2, M3, M4, M5, M6, M7, and M8 are each independently selected from C, N, O, S, or P; Between M2 and M3, between M3 and M4, between M5 and M6, between M6 and M7, and between M7 and M8, each is independently a single bond or a double bond, wherein the two adjacent chemical bonds are not simultaneously double bonds; R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl; R 21 R 22 R 31 R 32 R 41 R 42 R 51 R 52 R 61 R 62 R 71 R 72 R 81 R 82 Each is independently selected from: non-existent, hydrogen, deuterium, halogen, -C 1-6 Alkyl (preferably methyl), =O; and satisfying one of the following conditions: 1)R 21 ,R 22 The atoms connected to it form a ring C; 2)R 31 ,R 32 The atoms connected to it form a ring C; 3)R 41 ,R 42 The atoms connected to it form a ring C; 4)R 51 ,R 52 The atoms connected to it form a ring C; 5)R 61 ,R 62 The atoms connected to it form a ring C; 6)R 71 ,R 72 The atoms connected to it form a ring C; 7)R 81 ,R 82 The atoms connected to it form a ring C; Wherein, the ring C is selected from 4-7 member monocyclic heterocyclic groups, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl; the 4-7 membered monocyclic heterocyclic group, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl groups are optionally surrounded by y R C The R that was replaced C Selected from any substituent in group A; Preferably, M2, M3, M4, M5, M6, M7, and M8 are each independently selected from C, N, or O; Preferably, the 4-7 member monocyclic heterocyclic group, C 4-7 Monocyclic cycloalkyl, 6-9 membered bridged heterocyclic group, C 6-9 Bridged cycloalkyl groups are y R C The R that was replaced C Selected from the following substituents: deuterium, halogen, -C 1-6 Alkyl or =O; More preferably, the ring C is selected from 4-6 member monocyclic heterocyclic groups, C 5-6 Monocyclic cycloalkyl groups, 7-9 membered bridged heterocyclic groups; the 4-6 membered monocyclic heterocyclic groups, C 5-6 Monocyclic cycloalkyl groups and 7-9 membered bridged heterocyclic groups are optionally surrounded by y R groups. C The R that was replaced C Selected from the following substituents: deuterium, halogen, -C 1-6 Alkyl or =O; Preferably, the Selected from: Preferably, the group (1) Selected from 14. The compound according to claim 12, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The group (2) Selected from: in, R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl; M9, M 14 Each is independently selected from C, CH, N, O, or S; M 10 M 13 Each is independently selected from C, CH, or N; M 11 M 12 Each is independently selected from CH2 and CHR C C(R) C )2, O, S, NH or NR C ; M 10 With M 13 Between, M 13 With M 14 Each bond can be a single or double bond independently, but not both at the same time; R 91 R 141 Each is independently selected from: non-existent, hydrogen, deuterium, C 1-6 Alkyl (preferably methyl), halogen; R C Selected from deuterium, halogens, C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups; Preferably, M9, M 14 Each is independently selected from C or N; Preferably, M 10 M 13 Each is independently selected from C or N; Preferably, group (2) Selected from 15. The compound according to claim 12, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The group (3) Selected from: in, R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl; M 18 M 20 Each is independently selected from C, CH, N, or O; M 17 M 21 Each is independently selected from CH2 and CHR D C(R) D )2, O, S, NH or NR D ; R 17 R 18 Each is independently hydrogen, deuterium, halogen, C 1-6 Alkyl (preferably CH3) or =O; R 181 R 201 Each independently represents: non-existent, hydrogen, deuterium, halogen, and carbon. 1-6 Alkyl (preferably CH3) or =O; R D Selected from deuterium, halogens, C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups; Preferably, the group (3) Selected from 16. The compound according to claim 12, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, characterized in that, The group (4) Selected from: in, R 13 R 14 R 15 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl; M 16 It can be C, CH, N, or O; M 15 Selected from CH2, CHR D C(R) D )2, O, S, NH or NR D ; R 16 Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl (preferably CH3) or =O; R 161 Selected from non-existent, hydrogen, deuterium, halogen, C 1-6 Alkyl (preferably CH3) or =O; R D Selected from hydrogen, deuterium, halogens, and C 1-6 Alkyl; wherein, C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups and 3-12 membered heterocyclic groups; Preferably, the group (4) Selected from 17. The compound according to any one of claims 1-16, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound has the structure shown in formula (IA)-(II-G): More preferably, it has the structure shown in formula (II-A-1): Among them, K1, K2, K3, K4, and K5 are each independently selected from CH2 and CHR. C C(R) C )2, O, S, NH or NR C .

18. The compound according to any one of claims 1-17, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (X): in, Represents a single or double bond, two adjacent bonds. Not both are double bonds; R 6a R 6b R 8 R 10 R 1 X4 and X5 are as defined in any one of claims 1-17; Preferably, R 6a and R 6b Together with the carbon atoms they are attached to, they form a cyclopropyl group, which is optionally composed of one, two, or three atoms selected from C1, C2, or C3. 1-6 Alkyl substituents; preferably, the... Selected from (For example Preferred )、 The key marked with "#" is connected to Preferably, X5 is N and X4 is C; or, X5 is C and X4 is N. Preferably, R 8 Selected from hydrogen or halogens (e.g., F); Preferably, R 1 Selected from phenyl; the phenyl group is optionally selected by one, two or three independently from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Substituents of saturated cycloalkyl groups; preferably, the R 1 Selected from: Preferably, R 10 Selected from (Preferred) )、 Preferably, the formula (X) shown is as shown in formula (X-1) or (X-2): Among them, R 6a R 6b R 8 R 10 R 1 As defined above; Preferably, the formula (X) is as shown in formula (X-3) or (X-4): Among them, R 10a R 10b Each is independently selected from hydrogen or C1-4 alkyl (e.g., methyl); preferably, R 10a R 10b All are hydrogen, or R 10a R 10b All are C1-4 alkyl groups (e.g., methyl); R 6a R 6b R 8 R 1 As defined above.

19. The compound according to any one of claims 1-18, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, wherein, The compound is selected from:

20. A pharmaceutical composition comprising the compound of any one of claims 1-19, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents, or excipients.

21. The pharmaceutical composition according to claim 20, characterized in that, The pharmaceutical composition further includes another therapeutic agent, which includes an antidiabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent for treating non-alcoholic steatosis (NASH), or a combination of two or more of them. Preferably, the antidiabetic agent is selected from the group consisting of: biguanides (e.g., metformin), sulfonylureas, glitazar, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinide, sodium-glucose linker 2 (SGLT2) inhibitors, glitazone, GRP40 agonists, glucose-dependent insulinotropic peptide (GIP), insulin or insulin analogs, alpha-glucosidase inhibitors, sodium-glucose linker 1 (SGLT1) inhibitors, or combinations of two or more of these. Preferably, the anti-obesity agent is selected from the group consisting of: neuropeptide Y receptor type 2 (NPYR2) agonists, NPYR1 or NPYR5 antagonists, human proislet peptide (HIP), cannabinoid receptor type 1 (CB1R) antagonists, lipase inhibitors, melanocortin receptor 4 agonists, and farnesoid X receptors. FXR receptor agonists, phentermine, zonisamide, norepinephrine / dopamine reuptake inhibitors, GDF-15 analogs, opioid receptor antagonists, cholecystokinin agonists, serotonergic agents, methionine aminopeptidase 2 (MetAP2) inhibitors, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, sodium-glucose cotransporter 1 (SGLT-1) inhibitors, activin type 2 receptor (ActRII) inhibitors, apalinide receptor (APLNR) agonists, or combinations of two or more of these. Preferably, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or a combination of two or more thereof. Preferably, the agent for treating NASH is selected from the group consisting of: FXR agonist PF-05221304, synthetic fatty acid bile conjugates, anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, apoptosis protease inhibitor, MAPK5 inhibitor, galactoglobulin 3 inhibitor, fibroblast growth factor 21 (FGF21) agonist, niacin analog, leukotriene D4 (LTD4) receptor antagonist, acetyl-CoA carboxylase (ACC) inhibitor, hexokinase (KHK) inhibitor, ileal bile acid transporter (IBAT) inhibitor, apoptosis signal-regulated kinase 1 (ASK1) inhibitor, peroxisome proliferator-activated receptor (PPAR) agonist, diacylglycerol acyltransferase 2 (DGAT2) inhibitor, or a combination of two or more of these.

22. The use of any compound of claims 1-19, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and the use of any pharmaceutical composition of claims 20-21 in the preparation of a medicament for the prevention and / or treatment of GLP-1 receptor-mediated diseases or disorders, or for the modulation of GLP-1 receptors.

23. The application of claim 22, wherein the GLP-1 receptor-mediated disease is selected from the group consisting of: type 1 diabetes, type 2 diabetes, early-onset type 2 diabetes, idiopathic type 1 diabetes (type 1b), juvenile atypical diabetes (YOAD), young adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain due to the use of other medications, idiopathic intracranial hypertension, and Wolfram syndrome. Syndrome, gout, excessive sugar consumption, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral fat deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral artery disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attack, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial cell dysfunction, impaired vascular compliance, restenosis, thrombosis, hypertension, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, hyperglycemia, impaired glucose tolerance, diabetic complications, hypercholesterolemia, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction. Acute lipemia, postprandial hyperlipidemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, macular degeneration, cataracts, glomerulosclerosis, arthritis, osteoporosis, addiction treatment, cocaine dependence, bipolar disorder / major depressive disorder, skin and connective tissue disorders, foot ulcers, psoriasis, primary polydipsia, nonalcoholic fatty liver disease (NASH), nonalcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn's disease. Diseases such as short bowel syndrome, Parkinson's disease, Alzheimer's disease, cognitive impairment, schizophrenia, or polycystic ovary syndrome (PCOS).

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