Heterocyclic compound with GLP-1 receptor agonist effect and application thereof

Abstract

The invention relates to the field of medicine, and discloses a heterocyclic compound with a GLP-1 receptor agonist effect and application of the heterocyclic compound, the heterocyclic compound is a compound with a structure shown in a formula (I), or an isomer, an isotope labeled compound, a prodrug, or pharmaceutically acceptable salt, ester, hydrate or solvate of the compound. The obvious treatment effect is realized in the aspect of reducing blood sugar or reducing weight.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to 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 contributing to 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-1 RAs) 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 hydrolysis 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-1 R 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 saw 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 view of the above-mentioned technical status, the present invention provides an oral small molecule agonist of GLP-1R that can enhance insulin secretion and lower blood glucose levels in a glucose-dependent manner.

[0011] The GLP-1R agonist of this invention 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 derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts:

[0012] (I)

[0013] in,

[0014] X4 is selected from CH, N, O, or S;

[0015] X1, X2, X3, X5, X6, X8, and X9 are each independently selected from C or N;

[0016] X7 is selected from N, CH, NH, O, or S;

[0017] Ring M1 is selected from a benzene ring or a 6-membered heteroaromatic ring;

[0018] Ring M2 is selected from 5-membered heterocyclic aromatic rings;

[0019] Ring M3 is selected from 5-membered heterocyclic aromatic rings;

[0020] R e R f Each element is independently selected from non-existent, hydrogen, deuterium, or halogen;

[0021] R a1 and R a2 Together with the carbon atoms they are attached to, they form 7-12 membered heterocyclic groups, wherein the heteroatoms of the 7-12 membered heterocyclic groups are selected from N, S, or O, or combinations of two or more of them, and optionally are surrounded by one, two, or three atoms selected from hydrogen, deuterium, halogen, oxo group (=O), -C(O)C 1-6 Alkyl, C 1-6 Alkyl, cyano, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substitution of halogenated alkoxy and amino groups;

[0022] R b Selected from 6-15 membered heterocyclic groups, C 6-15 Aryl, 6-15 membered heteroaryl, of which 6-15 membered heterocyclic, C 6-15The aryl and 6-15-membered heteroaryl groups are optionally substituted by one or more substituents, each independently selected from group A;

[0023] Group A:

[0024] a) Deuterium;

[0025] b) Oxo (=O);

[0026] c) Halogens;

[0027] d) OH;

[0028] e) Cyano group;

[0029] f) Among them, R 0 Selected from H, C 1-6 alkyl;

[0030] 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;

[0031] h) -C(=O)R C1 , where R C1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0032] i) C 1-6 Alkyl, wherein, C 1-6 The alkyl group may be selected independently by one or more groups, including deuterium, halogen, hydroxyl, cyano, and 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;

[0033] 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;

[0034] k)-P(O)R P1 R P2 -(CH2) u -S(O)2RS1 -S(O)(=NR) S2 )R S3 , where R P1 R P2 R S1 R S2 R S3 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl, or R P1 R P2 One of them and -P(O)R P1 R P2 The adjacent connections form 5-6 membered heterocyclic groups, or R S2 With -S(O)(=NR S2 )R S3 Adjacent connections form 5-6 quinary heterocycles; where u is selected from 0, 1, or 2;

[0035] In this invention, as one embodiment, group A is selected from: deuterium, oxometalate, halogen, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkylene-, -NH(C 1-6 Alkyl), -P(O)R P1 R P2 -(CH2) u -S(O)2R S1 -S(O)(=NR) S2 )R S3 Among them, R P1 R P2 R S1 R S3 Each was independently selected from C 1-6 Alkyl or C 3-6 cycloalkyl, or R P1 R P2 One of them and -P(O)R P1 R P2 Adjacent connections form or The wavy lines in the ring represent fusion sites; R S2 Selected from H, C 1-6 Alkyl, or R S2 With -S(O)(=NR S2 )R S3 Adjacent connections form or The wavy line in the ring represents a fusion site; u is selected from 0, 1 or 2;

[0036] In this invention, as one embodiment, group A is selected from: deuterium, oxo, halogen, CH3, CD3, CH2CH3, CNCH2-, -NHCH3, -S(O)(=NH)CH3, -S(=O)(=NCH3)-CH2CH3, -(P=O)(CH3)2, -(P=O)(CH2CH3)2, -(CH2) u S(=O)2(CH3), -(CH2) u S(=O)2(CH2CH3), , , or The wavy lines in the ring represent 6-15 member heterocyclic groups, C 6-15 Fusing sites of aryl and 6-15 membered heteroaryl groups; wherein u is selected from 0, 1 or 2;

[0037] In this invention, as one embodiment, group A is selected from: deuterium, oxo, F, CH3, CD3, CH2CH3, CNCH2-, -NHCH3, , , , , , , , , , , , , , or ;

[0038] R c1 It is a 5-membered heterocyclic group or a 5-membered aromatic heterocyclic group, wherein the heteroatom of the 5-membered heterocyclic group and the 5-membered aromatic heterocyclic group is N or / and O; the 5-membered heterocyclic group is substituted with an oxo group;

[0039] R c2 Selected from hydrogen or C 1-6 alkyl;

[0040] R d1 R d2 R d3 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl or halogen, wherein C 1-6 Alkyl groups can be replaced by deuterium or halogens.

[0041] In this invention, as one embodiment, the R b Selected from 9-10 membered heteroaryl, 9-15 membered heterocyclic or C6-10 Aryl groups, including 9-10 membered heteroaryl groups, 9-15 membered heterocyclic groups, or C 6-10 The aryl group may be optionally substituted by one or more substituents, each independently selected from group A;

[0042] In this invention, as one embodiment, the R b Selected from group (1), group (2), or group (3):

[0043] (1) , where R b1 R b2 Each was independently selected from group A;

[0044] (2) ,

[0045] in,

[0046] Ring A is selected from phenyl or 6-membered heteroaryl, X 10 Selected from CH or N;

[0047] Ring B is selected from 5-6 member monoheterocyclic groups, C 5-6 Monocycloalkyl;

[0048] Cyclic C is selected from 4-6 nucleotide monoheterocyclic groups, C 4-6 Monocycloalkyl;

[0049] n0 is selected from 0, 1, and 2;

[0050] m0 is selected from 0, 1, 2, or 3;

[0051] y0 is selected from 0, 1, 2, or 3;

[0052] 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;

[0053] R B R C Each was independently selected from group A;

[0054] Preferably, ring B is selected from: , , , or ;

[0055] Preferably, ring C is selected from: , , , , , , or ;

[0056] Among them, R A11 and R A12 Connected to ring A, R B11 With R C11 Connected, R B12 With R C12 Connected;

[0057] (3) ,

[0058] Among them, R b3 R b4 R b5 R b6 R b7 Each can be independently selected from group A, optionally.

[0059] R b4 and R b5 They can form 5-6 membered heterocyclic groups together with the carbon atoms they are attached to, or

[0060] R b5 and R b6 They can form 5-6 membered heterocyclic groups together with the carbon atoms to which they are attached; the 5-6 membered heterocyclic groups may optionally be substituted by one or more substituents selected from group A.

[0061] In this invention, as one embodiment, the R a1 and R a2 Together with the carbon atoms they are attached to, they form 7-12 membered spiroheterocycles, wherein at least one heteroatom of the 7-12 membered spiroheterocycle is an oxygen atom.

[0062] In this invention, as one embodiment, X1, X2, X3, X5, and X9 are selected from C or N;

[0063] X4 is selected from CH, O, or S;

[0064] R e R f Selected from non-existent, hydrogen, or halogen;

[0065] Selected from , , , or ;

[0066] More preferably, Selected from , , , or .

[0067] In this invention, as one embodiment, the...

[0068] Selected from

[0069] Among them, Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are each independently selected from CH2, NH, O, or S;

[0070] Preferably, Y1 is selected from O, CH2, S or NH;

[0071] Y2 is selected from CH2, O, or NH;

[0072] Y3 is selected from O, CH2, or NH;

[0073] Y4 is selected from CH2, O, or NH;

[0074] Y5 is selected from CH2 or O;

[0075] Y6 is selected from O or CH2;

[0076] Y7 is selected from CH2, O, or NH;

[0077] Y8 is selected from CH2, NH, or O;

[0078] R g1 R g2 R h1 R h2 R k1 R k2 Each element is independently selected from hydrogen, deuterium, halogen, cyano, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(O)C 1-6 alkoxy, or R g1 and R g2 R h1 and R h2 R k1 and R k2 Together they form oxygen groups, which can be selectively and independently.

[0079] R g1 and R g2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups;

[0080] R h1 and R h2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups;

[0081] R k1 and R k2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups;

[0082] The 4-7 membered heterocyclic group is optionally composed of one or two elements selected from C. 1-6 Alkyl or -C(O)-C 1-6 Alkyl substituents; the 4-7 membered heterocyclic group is selected from monocyclic or spirocyclic groups;

[0083] n, t, and m are each independently selected from 0, 1, or 2;

[0084] R0, R1, and R2 are each independently selected from hydrogen, deuterium, halogen, oxo group, and C. 1-6 Alkyl; preferably, Selected from ;

[0085] Among them, v1, v2, v3, v4, v5, v6, v7, and v8 are each independently selected from 0 or 1;

[0086] q, p, s, and r are each independently selected from 0, 1, or 2;

[0087] R3, R4, R5, and R6 are each independently selected from C. 1-6 Alkyl or -C(O)-C 1-6 alkyl.

[0088] In this invention, as one embodiment, the R a1 and R a2 Together with the carbon atoms they are attached to, they form: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or Among them, R a10 The key of the identifier is connected to R a1 The ring carbon on the bonded ring M1, with R a20 The key of the identifier is connected to R a2 The cyclic carbon on the bonded ring M1.

[0089] In this invention, as one embodiment, R... b Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0090] In this invention, as one embodiment, the R c1 Selected from: or Preferred or ;

[0091] R c2 Selected from hydrogen or CH3;

[0092] R d1 R d2 R d3 Each is independently selected from hydrogen, CH3, CD3, cyclopropyl or halogen.

[0093] In this invention, as one embodiment, X6 and X8 are each independently selected from C or N; X7 is selected from N;

[0094] Preferably, the Selected from The key marked with "#" is connected to... ;

[0095] More preferably, the Selected from The key marked with "#" is connected to... .

[0096] In this invention, as one embodiment, the halogen is Cl, F, Br, or I.

[0097] In this invention, as one embodiment, the... Selected from or Preferred options are: or .

[0098] In this invention, as one embodiment, the compound is selected from:

[0099] .

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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. Xreceptor (FXR) 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 derivatives), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering a therapeutically effective amount of the above-described pharmaceutical composition to the individual; or administering a therapeutically effective amount of the above-described pharmaceutical composition to the individual in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or disorders or for modulating GLP-1 receptors.

[0115] This invention avoids the risk of hypoglycemia caused by traditional T2DM treatment drugs, and maintains 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.

[0116] In addition to its applications in diabetes and obesity, the oral small molecule agonist GLP-1R of this invention can also be used to treat a range of conditions, including non-alcoholic fatty liver disease (NASH), diabetic nephropathy (DKD), atherosclerotic cardiovascular disease (ASCVD), and Alzheimer's disease (AD), as research into these drugs continues to deepen in the fields of chronic liver disease, kidney disease, and cardiovascular and cerebrovascular diseases.

[0117] Terminology Explanation

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] The term "racemate" refers to two enantiomers existing in equal amounts in the crystal lattice, forming a homogeneous crystal.

[0123] 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 two identical or different atoms or groups are on the same side of the double bond; trans isomers are those where two identical or different atoms or groups are on opposite sides of the double bond.

[0124] 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.

[0125] The term "deuterated product" refers to a molecule obtained by replacing one or more hydrogen atoms (1H) in a molecule with deuterium atoms (D).

[0126] The term "N-oxide" refers to a binary compound composed of oxygen and nitrogen.

[0127] The term "metabolite" refers to compounds or substances produced during the metabolism of an organism.

[0128] 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.).

[0129] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, with C0 as the base group. 1-6 For example, alkyl groups are straight-chain or branched groups containing 1-6 carbon atoms, including but not limited to aliphatic alkyl groups such as 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, and 1,1,2-trimethylpropyl.

[0130] The term "alkene" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group, which can be considered as a hydrocarbon group formed by removing one or more hydrogen atoms from an olefin molecule, denoted by C. 1-6 For example, alkenyl groups are straight-chain or branched groups 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.

[0131] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, 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 group includes fused rings, spiro rings, bridged rings, and combinations thereof.

[0132] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing at least one heteroatom, such as a group 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 ring heterocyclic groups), and combinations thereof; the heterocyclic group includes monocyclic heterocyclic groups and polycyclic groups (e.g., bicyclic, tricyclic) where at least one ring is heterocyclic, such as a benzo[a]heterocyclic group.

[0133] 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, thiadiazole, 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.

[0134] The term "alkoxy" refers to -O-alkyl, where alkyl is defined as described above, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0135] 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.

[0136] The term "halogenated" refers to a group that can be replaced by any one or more F, Cl, Br, or I atoms.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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. Detailed Implementation

[0141] 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.

[0142] Example: Preparation of Compounds

[0143] The control compound LY3502970 was prepared according to patent CN109790161B; the structure of the control compound LY3502970 is as follows:

[0144]

[0145] Example 1: Preparation of compound C

[0146]

[0147] Synthesis route:

[0148]

[0149] Step 1: Synthesis of compound C-2

[0150] Under nitrogen protection at 0°C, N-bromosuccinimide (71.1 g, 399 mmol) was added dropwise to a solution of compound C-1 (50 g, 399 mmol) in N,N-dimethylformamide (500 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water, extracted with ethyl acetate (600 mL × 3), and the combined organic phases were washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound C-2. MS m / z (ESI): 203.9, 205.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.05 (t, J = 8.0 Hz, 1H), 6.29 (dd, J = 8.8, 1.2 Hz, 1H), 2.02 (d, J = 1.6 Hz, 3H).

[0151] Step 2: Synthesis of compound C-3

[0152] Compound C-2 (72 g, 353 mmol) was dissolved in acetic acid (2500 mL), and sodium nitrite (29.2 g, 423 mmol) was added in portions at room temperature. The resulting mixture was stirred at room temperature for 18 hours, then poured into ice water (4000 mL). The mixture was filtered, and the filter cake was washed with water (1000 mL × 3) and dried to give compound C-3. MS m / z (ESI): 214.9, 216.9 [M+H] + .

[0153] Step 3: Synthesis of Compound C

[0154] Potassium tert-butoxide (25 g, 224 mmol) was added to a solution of compound C-3 (48 g, 224.3 mmol) in N,N-dimethylformamide (500 mL) at 0°C. The resulting mixture was stirred for 40 minutes under nitrogen protection at room temperature. Iodomethane (22 mL, 269 mmol) was then slowly added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride (500 mL) and extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine (600 mL), 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 / 3) to give compound C. MS m / z (ESI): 229.0, 231.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.2 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.00 (dd, J= 8.8, 1.2 Hz, 1H), 4.00 (s, 3H).

[0155] Example 2: Preparation of compound D

[0156]

[0157] Synthesis route:

[0158]

[0159] Step 1: Synthesis of compound D-2

[0160] Under nitrogen protection at -78°C, n-butyllithium (197 mL, 492.5 mmol, 2.5 M) was slowly added dropwise to a tetrahydrofuran (1000 mL) solution of compound D-1 (100 g, 492.5 mmol). The reaction mixture was stirred at -78°C for 1 hour, followed by the addition of di-tert-butyl azide dicarboxylate (113.5 g, 492.5 mmol). The mixture was then heated to room temperature and stirred for 18 hours. The reaction solution was quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound D-2. MS m / z (ESI): 377.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ 9.60 (s, 1H), 7.00 (t, J = 6.8 Hz, 2H), 2.19 (d, J = 2.4 Hz, 6H), 1.42 (d, J = 6.0 Hz, 18H).

[0161] Step 2: Synthesis of compound D-4

[0162] Trifluoroacetic acid (250 mL) was added to a solution of compound D-2 (50.0 g, 141.24 mmol) in dichloromethane (500 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and evaporated to dryness. Then, an ethanol solution (500 mL) containing pyridine hydrochloride (1.65 g, 14.12 mmol) and (2S)-3-cyano-2-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (33.6 g, 141.24 mmol) was added. The reaction mixture was heated to 85°C and stirred for 2 hours. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (500 mL × 2). The organic phase was washed with saturated brine (300 mL), 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 D-4. MS m / z (ESI): 375.2 [M+H] + .

[0163] Step 3: Synthesis of compound D-5

[0164] N,N-diisopropylethylamine (5.92 g, 45.80 mmol) and p-nitrophenyl chloroformate (16.0 g, 79.38 mmol) were added to a solution of aminoacetaldehyde dimethyl acetal (12.0 g, 114 mmol) in tetrahydrofuran (160 mL). The reaction mixture was stirred at 40 °C for 6 hours under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure, and a solution of compound D-4 (5.0 g, 13.35 mmol) in pyridine (50 mL) was added. The reaction solution was stirred at 40 °C for 48 hours. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (200 mL × 2). The organic phase was washed with saturated brine (300 mL), 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 / 1) to give compound D-5. MS m / z (ESI): 506.2 [M+H] + .

[0165] Step 4: Synthesis of compound K

[0166] Methanesulfonic acid (761 mg, 7.92 mmol) was added to a tetrahydrofuran (50 mL) solution of compound D-5 (5.0 g, 9.90 mmol), and the reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, a saturated potassium phosphate solution was added to adjust the pH of the reaction mixture to approximately 9. Then, di-tert-butyl dicarbonate (864 mg, 3.96 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound K. MS m / z (ESI): 442.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.34 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 6.4 Hz, 2H), 6.57(dt, J = 16.4, 2.8 Hz, 2H), 5.05 (s, 1H), 3.30 (d, J = 2.8 Hz, 2H), 2.75 –2.56 (m, 2H), 2.20 (d, J = 2.0 Hz, 6H), 1.43 (s, 9H), 1.13 (d, J = 6.4 Hz, 3H).

[0167] Step 5: Synthesis of compound D-6

[0168] Compound C (1.04 g, 4.53 mmol), potassium carbonate (940 mg, 6.79 mmol), cuprous iodide (90 mg, 0.45 mmol), and trans-N,N'-dimethylcyclohexane-1,2-diamine (160 mg, 1.13 mmol) were added to a solution of compound K (1.0 g, 2.26 mmol) in N-methylpyrrolidone (10 mL). The reaction mixture was stirred at 130 °C for 2 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 1) to give compound D-6. MS m / z (ESI): 590.4 [M+H] + .

[0169] Step 6: Synthesis of Compound D

[0170] To a solution of compound D-6 (200 mg, 0.34 mmol) in dichloromethane (2 mL), dioxane hydrochloride (2.0 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours, and the solution was concentrated to give compound D. MS m / z (ESI): 490.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.38 (d, J = 10.0 Hz, 1H), 8.30 (d, J = 0.8 Hz, 1H), 7.63 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (dd, J =8.8, 6.8 Hz, 1H), 7.16 (d, J = 6.0 Hz, 2H), 7.07 (d, J = 3.2 Hz, 1H), 6.86(d, J = 3.2 Hz, 1H), 4.60 – 4.58 (m, 1H), 4.11 (s, 3H), 3.65 – 3.59 (m, 2H),3.40 – 3.30 (m, 1H), 3.09 – 2.94 (m, 1H), 2.25 (s, 6H), 1.42 (d, J = 6.4 Hz, 3H).

[0171] Example 3: Preparation of Compound 1

[0172]

[0173] Synthesis route:

[0174]

[0175]

[0176] Step 1: Synthesis of Compounds 1-2

[0177] Sodium hydride (36.4 g, 909 mmol) was added to a solution of diethyl malonate (125 mL, 818.18 mmol) in N,N-dimethylformamide (1.0 L) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours under nitrogen protection. Then, compound 1-1 (100 g, 454 mmol) was slowly added and stirred at room temperature for 16 hours. The mixture was diluted with saturated ammonium chloride solution (500 mL), extracted with ethyl acetate (800 mL × 3), and the combined organic phases were washed with saturated brine (3 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. Recrystallization from petroleum ether at -20°C and filtration yielded compound 1-2. MS m / z (ESI): 360.0, 362.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 8.4, 2.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 5.30 (s, 1H), 4.22 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2Hz, 6H).

[0178] Step 2: Synthesis of compounds 1-3

[0179] Compounds 1-2 (130 g, 360 mmol) were dissolved in ethanol (700 mL) at room temperature. A solution of water (700 mL) containing sodium hydroxide (57.7 g, 1443 mmol) was slowly added dropwise at 10°C. The mixture was stirred at room temperature under nitrogen protection for 16 hours. The ethanol was removed by concentration under reduced pressure. The pH of the mixture was adjusted to 2 with 2M dilute hydrochloric acid. The mixture was extracted with dichloromethane (0.7 L × 3). The combined organic phases were washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The solutions were recrystallized from dichloromethane at 0°C and filtered to give compounds 1-3. MS m / z (ESI): 259.9, 261.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.95 (s, 2H).

[0180] Step 3: Synthesis of compounds 1-4

[0181] Concentrated sulfuric acid (50 mL) was added to 500 mL of ethanol containing compounds 1-3 (50 g, 193 mmol). The reaction mixture was stirred at 80 °C for 3 hours, cooled to room temperature, and then water (500 mL) was added. The mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compounds 1-4. 1 H NMR (400 MHz, CDCl3)δ 8.39 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 8.4, 2.4 Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 1.20 (d, J = 7.2 Hz, 3H).

[0182] Step 4: Synthesis of compounds 1-5

[0183] Sodium hydride (6.25 g, 260 mmol) was added to a solution of compounds 1-4 (50 g, 173 mmol) in N,N-dimethylformamide (1.0 L) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 h under nitrogen protection. 2,2'-dibromodiethyl ether (28 mL, 226 mmol) was slowly added, and the mixture was heated to 80 °C and stirred for 18 h. The reaction solution was diluted with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate (800 mL × 3). The combined organic phases were washed with saturated brine (3 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compounds 1-5. MS m / z (ESI): 439.9 [M+H] + .

[0184] Step 5: Synthesis of compounds 1-6

[0185] Sodium hydride (2.36 g, 98.39 mmol) was added to a solution of compounds 1-5 (36 g, 81.99 mmol) in N,N-dimethylformamide (700 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours under nitrogen protection, then slowly heated to 80°C and stirred for 18 hours. The reaction solution was diluted with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate (800 mL × 3). The combined organic phases were washed with saturated brine (3 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compounds 1-6. MS m / z (ESI): 358.0, 360.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.4 Hz, 1H), 8.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.74 (dt, J = 12.0, 4.4 Hz, 2H), 2.52 – 2.42 (m,2H), 2.13 – 1.97 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H).

[0186] Step 6: Synthesis of compounds 1-7

[0187] Diisobutylaluminum hydride (134 mL, 201 mmol, 1.5 M) was slowly added dropwise to a toluene (360 mL) solution of compounds 1-6 (18 g, 50.25 mmol) at -78°C. The reaction mixture was stirred at -78°C for 2 hours under nitrogen protection, then diluted with water (50 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) and concentrated to give compounds 1-7. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.4Hz, 1H), 8.18 (dd, J = 8.8, 2.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 4.74 (t, J= 5.6 Hz, 1H), 3.95 (d, J = 5.6 Hz, 2H), 3.76 – 3.67 (m, 2H), 3.47 (ddd, J =11.6, 8.0, 3.2 Hz, 2H), 2.40 – 2.32 (m, 2H), 2.11 – 2.02 (m, 2H).

[0188] Step 7: Synthesis of compounds 1-8

[0189] To a mixed solution of compounds 1-7 (10.5 g, 33.21 mmol) in dioxane (100 mL) and water (20 mL), tris(dibenzylacetone)palladium (6.08 g, 6.64 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (3.17 g, 6.64 mmol), and potassium hydroxide (5.59 g, 99.6 mmol) were added. The reaction mixture was stirred at 100°C for 3 hours under nitrogen protection. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compounds 1-8. 1 H NMR (400 MHz, DMSO-d6) δ7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.62 – 7.53 (m, 2H), 4.66 (s, 2H), 3.90 –3.82 (m, 2H), 3.44 (dt, J = 12.0, 2.0 Hz, 2H), 2.03 – 1.89 (m, 2H), 1.68 –1.59 (m, 2H).

[0190] Step 8: Synthesis of compounds 1-9

[0191] To a solution of compounds 1-8 (7.8 g, 33.16 mmol) in methanol (160 mL), stannous chloride dihydrate (99.5 g, 99.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. A saturated sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compounds 1-9. MS m / z (ESI): 206.1 [M+H] + .

[0192] Step 9: Synthesis of compounds 1-10

[0193] Sodium nitrite (2.13 g, 30.87 mmol) was slowly added to a mixed solution of compounds 1-9 (6.4 g, 20.58 mmol) in hydrochloric acid (40 mL) and water (40 mL) under ice bath conditions. After stirring the mixture at 0°C for 1 hour, stannous chloride dihydrate (13.9 g, 61.74 mmol) was added, and the reaction mixture was reacted at room temperature for 18 hours. The mixture was filtered, and the filter cake was washed with water (50 mL) and dried to give compounds 1-10. MS m / z (ESI): 221.1 [M+H] + .

[0194] Step 10: Synthesis of compounds 1-11

[0195] Ethyl pyruvate (2.37 g, 20.37 mmol) was slowly added to a 50 mL ethanol solution of compounds 1-10 (5.5 g, 16.98 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compounds 1-11. MS m / z (ESI): 319.1 [M+H] + .

[0196] Step 11: Synthesis of compounds 1-12

[0197] Eaton reagent (4.64 g, 19.47 mmol) was added to a toluene (31 mL) solution of compound 1-11 (3.1 g, 9.74 mmol) at room temperature. The reaction mixture was stirred at 90°C for 2 hours, then poured into ice water (40 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 1-12. MS m / z (ESI): 302.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.62 – 11.48(m, 1H), 7.46 (s, 1H), 7.05 (dd, J = 2.4, 0.8 Hz, 1H), 6.71 (d, J = 0.8 Hz,1H), 4.49 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.91 – 3.83 (m, 2H), 3.44 (dt, J= 12.0, 2.0 Hz, 2H), 1.91 (dt, J = 13.2, 4.4 Hz, 2H), 1.65 – 1.58 (m, 2H),1.33 (d, J = 7.2 Hz, 3H).

[0198] Step 12: Synthesis of compounds 1-13

[0199] Sodium hydride (23.9 mg, 1.00 mmol) was added to a solution of compounds 1-12 (200 mg, 0.66 mmol) in N,N-dimethylformamide (5 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 0.5 hours under nitrogen protection. Then, bromoacetonitrile (23.9 mg, 1.33 mmol) was slowly added, followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compounds 1-13. MS m / z (ESI): 341.1 [M+H] + .

[0200] Step 13: Synthesis of compounds 1-14

[0201] (4R)-4-methyl-1,3,2-dioxathiapentane 2,2-dioxide (162 mg, 1.18 mmol) was added to a solution of compound 1-13 (100 mg, 0.29 mmol) in N,N-dimethylpropenylurea (3 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 10 min under nitrogen protection, followed by slow addition of bis(trimethylsilylaminolithium) (2.6 mL, 2.6 mmol, 1 M). The reaction mixture was then stirred at room temperature for 18 h. The reaction mixture was diluted with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 1-14. MS m / z (ESI): 381.1 [M+H] + .

[0202] Step 14: Synthesis of compounds 1-15

[0203] Lithium hydroxide (6 mg, 0.25 mmol) was added to a mixed solution of tetrahydrofuran (2 mL) and water (2 mL) of compounds 1-14 (41 mg, 0.05 mmol) under ice bath conditions. The reaction mixture was stirred at 50°C for 2 hours under nitrogen protection. The pH of the reaction solution was adjusted to 2 with 2M dilute hydrochloric acid under ice bath conditions. The mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compounds 1-15. MS m / z (ESI): 353.1 [M+H] + .

[0204] Step 15: Synthesis of compounds 1-16

[0205] Compound D (19.3 mg, 0.04 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (22.5 mg, 0.06 mmol), and N,N-diisopropylethylamine (25.5 mg, 0.20 mmol) were added to a solution of compounds 1-15 (50 mg, 0.04 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 5) to give compounds 1-16. MS m / z (ESI): 824.4 [M+H]+ .

[0206] Step 16: Synthesis of compounds 1-17

[0207] To a solution of compounds 1-16 (28 mg, 0.03 mmol) in ethanol (3 mL), hydroxylamine hydrochloride (10.4 mg, 0.15 mmol) and N,N-diisopropylethylamine (19.4 mg, 0.15 mmol) were added. The reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give compounds 1-17, and the crude product was used directly in the next step. MS m / z (ESI): 857.4 [M+H] + .

[0208] Step 17: Synthesis of Compound 1

[0209] To a solution of compounds 1-17 (29 mg, 0.03 mmol) in dimethyl sulfoxide (3 mL), N,N'-carbonyldiimidazole (12.2 mg, 0.08 mmol) and 1,8-diazabicycloundec-7-ene (11.5 mg, 0.08 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The crude product obtained by concentration of the filtrate was purified by preparative HPLC (Waters-Xbridge-C18-7µm-30*150mm A: 0.1% TFA / H2O B: ACN 35%A-65%B: Ret 1.49 min) to obtain compound 1. MS m / z (ESI): 883.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 7.51 – 7.43 (m, 2H), 7.18 (d, J = 6.4 Hz, 2H), 7.13 –7.09 (m, 1H), 6.87 (d, J = 6.4 Hz, 2H), 6.80 – 6.74 (m, 2H), 5.35 (d, J = 4.8Hz, 1H), 4.55 (s, 2H), 4.12 (s, 3H), 3.97 (d, J = 12.0 Hz, 3H), 3.59 – 3.53(m, 3H), 2.31 – 2.25 (m, 8H), 2.05 – 1.97 (m, 4H), 1.80 – 1.49 (m, 6H), 1.33 – 1.21 (m, 3H).

[0210] Experimental Example 1: Determination of the ability of the compounds of this invention to stimulate cAMP production in human GLP-1 receptor-stabilized cell lines

[0211] Purpose: The purpose of this experiment was to test the ability of the compound to activate the human GLP-1 receptor on the cell surface. Activation stimulated ECs to produce cAMP. 50 The activation ability of the compound on human GLP-1 receptor was characterized.

[0212] Cell culture The cell line stably expressing human GLP-1 R (H_GLP-1 R CHO-K1 Cell Line, purchased from Jimon Biotechnology, GM-C35369) was used in the experiment. Cells were maintained in F12K medium (ATCC-30-2004), which was supplemented with 10% fetal bovine serum (Corning-35-081-CV) and 4 μg / mL puromycin (Gibco-A1113803).

[0213] cAMP assayWhen 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 (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.

[0214] The signal ratio (665 nm / 620 nm * 10,000) was calculated, and the signal ratio was nonlinearly fitted to the sample concentration using a four-parameter equation in GraphPad Prism to obtain the EC. 50 value.

[0215] The results are shown in Table 1. The control compound was LY3502970, and compound 1 was prepared according to Example 3.

[0216] Table 1. EC5 values ​​of compounds used in in vitro cAMP signal activation experiments. 50

[0217]

[0218] Experimental results show that the compound of this invention can significantly increase the accumulation of cAMP in hGLP-1 R 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: （Ⅰ） in, X4 is selected from CH, N, O, or S; X1, X2, X3, X5, X6, X8, and X9 are each independently selected from C or N; X7 is selected from N, CH, NH, O, or S; Ring M1 is selected from a benzene ring or a 6-membered heteroaromatic ring; Ring M2 is selected from 5-membered heterocyclic aromatic rings; Ring M3 is selected from 5-membered heterocyclic aromatic rings; R e R f Each element is independently selected from non-existent, hydrogen, deuterium, or halogen; R a1 and R a2 Together with the carbon atoms they are attached to, they form 7-12 membered heterocyclic groups, wherein the heteroatoms of the 7-12 membered heterocyclic groups are selected from N, S, or O, or combinations of two or more of them, and are optionally surrounded by one, two, or three atoms selected from hydrogen, deuterium, halogen, oxo group (=O), -C(O)C 1-6 Alkyl, C 1-6 Alkyl, cyano, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substitution of halogenated alkoxy and amino groups; R b Selected from 6-15 membered heterocyclic groups, C 6-15 Aryl, 6-15 membered heteroaryl, of which 6-15 membered heterocyclic, C 6-15 The aryl and 6-15-membered heteroaryl groups are 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 selected independently by one or more groups, including deuterium, halogen, hydroxyl, cyano, and 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)-P(O)R P1 R P2 -(CH2) u -S(O)2R S1 -S(O)(=NR) S2 )R S3 , where R P1 R P2 R S1 R S2 R S3 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl, or R P1 R P2 One of them and -P(O)R P1 R P2 The adjacent connections form 5-6 membered heterocyclic groups, or R S2 With -S(O)(=NR S2 )R S3 Adjacent connections form 5-6 quinary heterocycles; where u is selected from 0, 1, or 2; Preferably, group A is selected from: deuterium, oxometalate, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, cyano C 1-6 Alkylene-, -NH(C 1-6 Alkyl), -P(O)R P1 R P2 -(CH2) u -S(O)2R S1 -S(O)(=NR) S2 )R S3 Among them, R P1 R P2 R S1 R S3 Each was independently selected from C 1-6 Alkyl or C 3-6 cycloalkyl, or R P1 R P2 One of them and -P(O)R P1 R P2 Adjacent connections form or The wavy lines in the ring represent fusion sites; R S2 Selected from H, C 1-6 Alkyl, or R S2 With -S(O)(=NR S2 )R S3 Adjacent connections form or The wavy line in the ring represents a fusion site; u is selected from 0, 1 or 2; Preferably, group A is selected from: deuterium, oxo, halogen, CH3, CD3, CH2CH3, CNCH2-, -NHCH3, -S(O)(=NH)CH3, -S(=O)(=NCH3)-CH2CH3, -(P=O)(CH3)2, -(P=O)(CH2CH3)2, -(CH2) u S(=O)2(CH3), -(CH2) u S(=O)2(CH2CH3), , , or The wavy lines in the ring represent 6-15 member heterocyclic groups, C 6-15 Fusing sites of aryl and 6-15 membered heteroaryl groups; wherein u is selected from 0, 1 or 2; Preferably, group A is selected from: deuterium, oxo, F, CH3, CD3, CH2CH3, CNCH2-, -NHCH3, , , , , , , , , , , , , , or ; R c1 It is a 5-membered heterocyclic group or a 5-membered aromatic heterocyclic group, wherein the heteroatom of the 5-membered heterocyclic group and the 5-membered aromatic heterocyclic group is N or / and O; the 5-membered heterocyclic group is substituted with an oxo group; R c2 Selected from hydrogen or C 1-6 alkyl; R d1 R d2 R d3 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 3-6 cycloalkyl or halogen, wherein C 1-6 Alkyl groups can be replaced by deuterium or halogens.

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, wherein, R b Selected from 9-10 membered heteroaryl, 9-15 membered heterocyclic or C 6-10 Aryl groups, including 9-10 membered heteroaryl groups, 9-15 membered heterocyclic groups, or C 6-10 The aryl group may be optionally substituted by one or more substituents, each independently selected from group A; R b Selected from group (1), group (2), or group (3): (1) , where R b1 R b2 Each was independently selected from group A; （2） ， in, Ring A is selected from phenyl or 6-membered heteroaryl, X 10 Selected from CH or N; Ring B is selected from 5-6 member monoheterocyclic groups, C 5-6 Monocycloalkyl; Cyclic C is selected from 4-6 nucleotide monoheterocyclic groups, C 4-6 Monocycloalkyl; n0 is selected from 0, 1, and 2; m0 is selected from 0, 1, 2, or 3; y0 is selected from 0, 1, 2, or 3; 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; R B R C Each was independently selected from group A; Preferably, ring B is selected from: , , , or ; Preferably, ring C is selected from: , , , , , , or ; Among them, R A11 and R A12 Connected to ring A, R B11 With R C11 Connected, R B12 With R C12 Connected; （3） ， Among them, R b3 R b4 R b5 R b6 R b7 Each can be independently selected from group A, optionally. R b4 and R b5 They can form 5-6 membered heterocyclic groups together with the carbon atoms they are attached to, or R b5 and R b6 They can form 5-6 membered heterocyclic groups together with the carbon atoms to which they are attached; the 5-6 membered heterocyclic groups may optionally be substituted by one or more substituents selected from group A.

3. 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, wherein, R a1 and R a2 Together with the carbon atoms they are attached to, they form 7-12 membered spiroheterocycles, wherein at least one heteroatom of the 7-12 membered spiroheterocycle is an oxygen atom.

4. 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, wherein, X1, X2, X3, X5, and X9 are selected from C or N; X4 is selected from CH, O, or S; R e R f Selected from non-existent, hydrogen, or halogen; Selected from , , , or ; More preferably, Selected from , , , , , , , , or .

5. 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, wherein, Selected from , , ; Among them, Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8 are each independently selected from CH2, NH, O, or S; Preferably, Y1 is selected from O, CH2, S, or NH; Y2 is selected from CH2, O, or NH; Y3 is selected from O, CH2, or NH; Y4 is selected from CH2, O, or NH; Y5 is selected from CH2 or O; Y6 is selected from O or CH2; Y7 is selected from CH2, O, or NH; Y8 is selected from CH2, NH, or O; R g1 R g2 R h1 R h2 R k1 R k2 Each element is independently selected from hydrogen, deuterium, halogen, cyano, amino, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(O)C 1-6 alkoxy, or R g1 and R g2 R h1 and R h2 R k1 and R k2 Together they form oxygen groups, which can be selectively and independently. R g1 and R g2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups; R h1 and R h2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups; R k1 and R k2 Together with the carbon atoms they are attached to, they form 4-7 membered heterocyclic groups; The 4-7 membered heterocyclic group is optionally composed of one or two elements selected from C. 1-6 Alkyl or -C(O)-C 1-6 Alkyl substituents; the 4-7 membered heterocyclic group is selected from monocyclic or spirocyclic groups; n, t, and m are each independently selected from 0, 1, or 2; R0, R1, and R2 are each independently selected from hydrogen, deuterium, halogen, oxo group, and C. 1-6 Alkyl; preferably, Selected from , , , , ; Among them, v1, v2, v3, v4, v5, v6, v7, and v8 are each independently selected from 0 or 1; q, p, s, and r are each independently selected from 0, 1, or 2; R3, R4, R5, and R6 are each independently selected from C. 1-6 Alkyl or -C(O)-C 1-6 alkyl.

6. The compound according to claim 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. R a1 and R a2 Together with the carbon atoms they are attached to, they form: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;in, With R a10 The key of the identifier is connected to R a1 The ring carbon on the bonded ring M1, with R a20 The key of the identifier is connected to R a2 The cyclic carbon on the bonded ring M1.

7. 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. R b Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. 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, wherein, R c1 Selected from: or Preferred or ; R c2 Selected from hydrogen or CH3; R d1 R d2 R d3 Each is independently selected from hydrogen, CH3, CD3, cyclopropyl or halogen.

9. 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, wherein, X6 and X8 are each independently selected from C or N; X7 is selected from N; Preferably, the Selected from , The key marked with "#" is connected to... ; More preferably, the Selected from , The key marked with "#" is connected to... .

10. 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, wherein, The halogens are Cl, F, Br, and I.

11. The compound according to claim 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, wherein, Selected from , or Preferred options are: or .

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, wherein, The compound is selected from: 。 13. A pharmaceutical composition comprising the compound of any one of claims 1-12, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents, or excipients.

14. The pharmaceutical composition according to claim 13, characterized in that, The pharmaceutical composition further includes another therapeutically active 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 these. 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.

15. The use of the compound of any one of claims 1-12, 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, and the pharmaceutical composition of any one of claims 13-14, 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.

16. The application of claim 15, 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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