GLP-1 receptor agonist as well as preparation method and application thereof

Abstract

The invention discloses a compound and application of the compound in medicine, and particularly relates to a novel compound and a medicine composition containing the compound. The invention also relates to a method for preparing the compound, and application of the compound or the pharmaceutical composition in preparation of drugs for treating GLP-1 receptor agonist mediated diseases and / or symptoms, and application of the compound or the pharmaceutical composition in preparation of drugs for treating GLP-1 receptor agonist mediated diseases and / or symptoms. The invention relates to the field of medicines, in particular to the application in preparing medicines for treating diabetes mellitus, non-alcoholic fatty liver disease, obesity, myocardial infarction, heart failure, diabetic nephropathy, Parkinson's disease and Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a GLP-1 receptor agonist and a preparation method and application thereof. Background Art

[0002] Diabetes is a multi-factorial metabolic disease characterized by chronic hyperglycemia and disturbances in sugar, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative deficiency of insulin, leading to elevated blood glucose concentrations and subsequent excretion of sugar in the urine. Symptoms include polydipsia, polyuria, polyphagia, and weight loss.

[0003] Based on the pathogenesis of diabetes, diabetes can generally be divided into type 1 and type 2 diabetes. Type 1 diabetes is caused by the immune system attacking pancreatic beta cells, resulting in the loss of insulin secretion. Type 2 diabetes begins with abnormal insulin resistance, or the failure of cells to respond to insulin. Obesity is one of the main causes of insulin resistance and is therefore considered a major risk factor for type 2 diabetes. Type 2 diabetes accounts for approximately 90% of all diabetics, making it a major public health concern in developed countries with severe obesity problems and in China, where the number of obese people is rising.

[0004] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its corresponding effects by binding to its widely existing specific receptors. At present, the organs where GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system. GLP-1 receptors may be present in the liver, adipose tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also acts on α cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes. However, the response of β cells to GLP-1 after eating is defective. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Because the duration of action of the human body's own GLP-1 is very short (intravenous injection of t 1 / 2 <1.5 minutes), so the body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0005] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the effect of lowering fasting and postprandial glucose and improving blood sugar levels in patients with type 2 diabetes. However, due to the poor oral bioavailability of peptide GLP-1 and the inconvenience of administration, there is an urgent clinical need for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0006] According to the data from the "China Cardiovascular Health and Disease Report 2022": It is estimated that there are currently 330 million people suffering from CVD in my country, including 11.39 million with coronary heart disease, 13 million with stroke, 8.9 million with heart failure, and 45.3 million with peripheral arterial disease; cardiovascular death is the leading cause of death among Chinese residents, and 2 out of every 5 deaths are due to CVD, and an important feature of the CVD epidemic in China is the rapid growth of atherosclerotic cardiovascular disease (ASCVD).

[0007] The core mechanism of ASCVD is atherosclerosis. Studies have shown that GLP-1 can inhibit the formation and progression of atherosclerotic plaques through multiple mechanisms and pathways, including inhibiting oxidative stress, reducing small, dense low-density lipoproteins, reducing macrophages and foam cells in the body, improving endothelial function, etc., thereby inhibiting arteriosclerosis and myocardial cell necrosis, thereby reducing the occurrence of major cardiovascular adverse events.

[0008] In addition, since GLP-1 receptors are widely distributed in the body and can act on multiple organs and tissues, semaglutide and tilpotide are being expanded into multiple indications, including NASH, MACE, HFpEF, kidney disease, AD, etc., all of which are treatment areas with large unmet clinical needs.

[0009] Currently, researchers have conducted a number of studies in the hope of finding therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications include WO2018056453A1, WO2018109607, WO2019239319, WO2019239371, WO2020103815, WO2020207474, WO2020263695, WO2021154796, WO2021112538, WO2021096304, WO2021096284, WO2021081207, WO2021018023, WO2021254470, WO2021249492, and WO20 ... 7979, WO2022017338A1, WO2022031994, WO2022040600, WO2022068772, and WO2022116693 disclose numerous small molecule compounds that are used as GLP-1 receptor agonists for preventing or treating diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease, or dementia. However, there is still an urgent need for more and better GLP-1 receptor agonists in clinical practice. Summary of the Invention

[0010] The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a GLP-1 receptor agonist. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by stimulating the GLP-1 receptor. The present invention further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0011] Specifically:

[0012] In one aspect, the present invention relates to a compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0013]

[0014] in:

[0015] L1 is -C(=O)-, -S(=O)2- or -CR 10 R 11 -;

[0016] L2 is -NR 12 -, -C(=O)NR 13 -、-NR 14 C(=O)NR 15 -or-CR 16 R 17 -;

[0017] L3 is a key or -CR 18 R 19 -;

[0018] L4 is a key or -CR 20 R 21 -;

[0019] X1 is C, N, O or S;

[0020] X2 is C or N;

[0021] Y1, Y2, Y3 and Y4 are each independently C or N;

[0022] Z is O, S, or -NR 26 -、-CR 27 R 28 -、-O-CR 29 R 30 -、-S-CR 31 R 32 -、-NR26 -CR 33 R 34 -or-CR 27 R 28 -CR 35 R 36 -;

[0023] R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace;

[0024] R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio,

[0025] C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6

[0026] Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0027] R 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl,

[0028] 3-8 membered heterocyclic groups, phenyl groups and 5-10 membered heteroaryl groups may be independently and optionally replaced by 1, 2 or 3 R 2a replace;

[0029] R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0030] R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0031] or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl;

[0032] R 3 is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace;

[0033] R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0034] R 4 for

[0035] R 5 and R 6 Each independently is H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6The cycloalkyl and 3-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent;

[0036] or R 5 and R 6 Together with the carbon atoms to which they are attached, they can form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 1-3 substituted by an alkylamino substituent;

[0037] Each R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 and R 36 are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino or nitro;

[0038] or R 27 and R 28 、R 27 and R 35 independently and optionally together with the carbon atom to which they are attached may form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 substituted by an alkylamino substituent;

[0039] R 9 H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 substituted by a cycloalkyl substituent;

[0040] Each R 12 、R 13 、R 14 、R 15 and R 26 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0041] In some embodiments, for

[0042] In some embodiments, R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace;

[0043] R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0044] R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace;

[0045] R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0046] R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0047] or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl;

[0048] R 3 is a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace;

[0049] R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

[0050] In some embodiments, R 1 Phenyl, The phenyl group, Can be optionally replaced by 1, 2 or 3 R 1a replace;

[0051] R 1ais D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0052] R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R 2a replace;

[0053] R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c , methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the ... 2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro;

[0054] R2b and R 2c each independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0055] or R 2b and R 2c Together with the phosphorus atoms to which they are attached, they can form

[0056] R 3 is oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, The oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, Can be optionally replaced by 1, 2 or 3 R 3a replace;

[0057] R 3a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, ethyl , n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

[0058] In some embodiments, R 5 and R 6 Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro and C3-6 substituted by a cycloalkyl substituent;

[0059] or R 5 and R 6 Together with the carbon atom to which they are attached, they may form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino;

[0060] Each R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 and R 36 are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein the methyl , ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro;

[0061] or R 27 and R 28 、R 27 and R 35 independently and optionally together with the carbon atom to which they are attached can form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino;

[0062] R 9 is H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, Methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently and optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0063] Each R 12 、R 13 、R 14 、R 15 and R 26and 1-3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxy, amino, and nitro.

[0064] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0072] In one aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

[0073] In some embodiments, the disease mediated by the GLP-1 receptor agonist of the present invention is diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease or dementia.

[0074] In some embodiments, the diabetes described in the present invention is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of adults.

[0075] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0076] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0077] Definitions and General Terms

[0078] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0079] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference.

[0080] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0081] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.The substituents may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C (=O) O-alkyl, -alkylene-S (=O) 2 -alkyl, -alkylene-S (=O) 2 -amino, -S (=O) 2 -alkyl, -S (=O) 2 -amino, -S (=O) 2 OH, -O-alkylene-C (=O) O-alkyl, -O-alkylene-S (=O) 2 -alkyl, -O-alkylene -S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, - N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C (=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and the like.

[0082] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t- -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0083] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in still other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0084] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0085] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0086] The term "heteroatom" means one or more of O, S, N, P and Si, including C, N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl); or in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0087] The term "halogen" refers to F, Cl, Br or I.

[0088] The term "deuterium" refers to heavy hydrogen, D.

[0089] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0090] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups; examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, etc., and the alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0091] The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 Alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, etc., and the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0092] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a nitrogen atom. In some embodiments, the alkylamino group is C 1-4 Alkylamino groups; examples thereof include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups. The alkylamino groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0093] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, a cycloalkyl group contains 3-10 carbon atoms; in another embodiment, a cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, a cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0094] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, never including aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0095] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0096] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0097] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,2,3 ... oxadiazole, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic rings, but are in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0098] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0099] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0100] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. Examples include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0101] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0102]

[0103] As described herein, a ring system formed by a linker attached to a ring (e.g., Formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0104]

[0105] As described herein, the group "-O-(CR m R n ) p -" has two connection sites that can be connected to the rest of the molecule, and the connection methods of the two connection sites can be interchanged. For example, formula f represents the group -O-(CR m R n ) p - can be linked to the rest of the molecule via the E-terminus or the E'-terminus. For example, EO-(CR m R n ) p -E' or E'-O-(CR m R n ) p -E.

[0106]

[0107] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0108] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0109] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0110] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described herein, or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits similar activity in vivo or in vitro as the compound of formula (I). The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0111] The definitions and conventions of stereochemistry used herein are generally those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, or (+), (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0112] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of bonding electrons.

[0113] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with an amino group, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0114] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0115] The "solvate" of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0116] "Esters" herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.

[0117] The "nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (e.g., dichloromethane), by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0118] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form. Other prodrug forms include phosphates, such as these phosphate compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0119] Unless otherwise indicated herein or the context clearly indicates a contrary meaning, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural.

[0120] The term "GLP-1 receptor agonist" as used herein refers to a substance that can agonize the activity of the GLP-1 receptor.

[0121] General synthesis process

[0122] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0123] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified. The following reaction schemes and examples are provided to further illustrate the present invention.

[0124] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0125] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Myrel Chemical Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. and used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Ocean Chemical Factory.

[0126] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, and methanol were of analytical grade.

[0127] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0128] The silica gel column was purchased from Tianjin Bona Aijieer Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0129] 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 solvents (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0130] Low-resolution mass spectrometry (MS) data were collected using an Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL / min). Mobile phase: 0%-95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0131] Compounds were purified using Cheetah Pro medium-pressure rapid purification preparative chromatography (Tianjin Bona Aijieer Technology Co., Ltd.) at 210 nm / 254 nm with UV detection.

[0132] The following abbreviations are used throughout this disclosure:

[0133] DETAILED DESCRIPTION

[0134] The present invention is described below with reference to specific examples. It should be noted that these examples are merely illustrative and do not limit the present invention in any way.

[0135] Example 1 Synthesis of 3-(1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 1)

[0136]

[0137] Step 1: Synthesis of tert-butyl (S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylate

[0138] Dissolve (3-cyclopropyl-4-fluorophenyl)hydrazine (275 mg, 1.65 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxoazepane-1-carboxylate (500 mg, 1.99 mmol) in ethanol (10 mL). Add dioxane hydrochloride (0.45 mL) under a nitrogen atmosphere, and heat to 80°C for 1.5 hours. Stop the reaction, add saturated brine (20 mL), and extract with ethyl acetate (15 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and purify by silica gel column chromatography (eluent: EA:PE (v / v) = 20-40%) to obtain the title compound.

[0139] LC-MS(ESI):[M+H] + =401.4.

[0140] Step 2: Synthesis of tert-butyl (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylate

[0141] To a reaction flask was added tert-butyl (S)-3-amino-2-(3-cyclopropene-4-fluorophenyl)-4-methyl-2,6,7,8-hydropyrazolo[4,3-c]azepane-5(4H)-carboxylate (500 mg, 1.25 mmol), DIEA (810 mg, 6.24 mmol), and tetrahydrofuran (10 mL). Phenyl chloroformate (250 mg, 1.62 mmol) was added dropwise with stirring. After reacting at room temperature for 1 hour, 2,2-dimethoxyethane-1-amine (530 mg, 4.99 mmol) was added to the system. Stirring was continued for 1 hour to stop the reaction. Saturated brine was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20-40%) to obtain the title compound.

[0142] LC-MS(ESI):[M+H] + =532.4.

[0143] Step 3: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylic acid tert-butyl ester

[0144] To a solution of tert-butyl (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylate (470 mg, 0.88 mmol) in tetrahydrofuran (6 mL) was added methanesulfonic acid (70 mg, 0.71 mmol). The mixture was heated to 60°C for 1 hour, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 20-50%) to obtain the title compound.

[0145] LC-MS(ESI):[M+H] + =468.4.

[0146] Step 4: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylic acid tert-butyl ester

[0147] (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylic acid tert-butyl ester (313 mg, 0.87 mmol), 5-bromo-4-fluoro-1-methyl-1H-indole (199 mg, 0.87 mmol), cuprous iodide (68 mg, 0.33 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (48 mg, 0.33 mmol) were added to NMP (10 mL) and the temperature was raised to 130 ° C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 20-50%) to obtain the title compound.

[0148] LC-MS(ESI):[M+H] + =616.4.

[0149] Step 5: Synthesis of (S)-1-(2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepan-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one

[0150] (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,6,7,8-tetrahydropyrazolo[4,3-c]azepane-5(4H)-carboxylic acid tert-butyl ester (430 mg, 0.7 mmol) and 4 M hydrochloric acid dioxane solution (1.7 mL) were mixed and reacted at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the title compound.

[0151] LC-MS(ESI):[M+H] + =516.4.

[0152] Step 6: Synthesis of 1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropane-1-carbonitrile

[0153] To a solution of (S)-3-(1-cyanocyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizine-2-carboxylic acid (100 mg, 0.3 mmol), (S)-1-(2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepan-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazol-2-one (184 mg, 0.3 mmol) and HATU (169 mg, 0.44 mmol) in DMF (10 mL) was added DIEA (764 mg, 5.91 mmol), and the mixture was reacted at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (eluent EA:PE (v / v) = 40-80%) afforded the title compound.

[0154] LC-MS(ESI):[M+H] + =836.5.

[0155] Step 7: Synthesis of (Z)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximide

[0156] To 1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran To a solution of (150 mg, 0.18 mmol) of (4-(2-indolizin-3-yl)cyclopropane-1-carbonitrile (150 mg, 0.18 mmol) in DMSO (10 mL) was added sodium bicarbonate (301 mg, 3.59 mmol) and hydroxylamine hydrochloride (249 mg, 3.59 mmol). The mixture was reacted at 60°C for 16 hours. The mixture was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound was obtained by separation and purification via silica gel column chromatography (eluent: EA:PE (v / v) = 40-80%).

[0157] LC-MS(ESI):[M+H]+ =869.6.

[0158] Step 8: Synthesis of 3-(1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)cyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0159] Compound (Z)-1-(2-((S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-5-carbonyl)-7-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)indolizin-3-yl)-N'-hydroxycyclopropane-1-carboximide (120 mg, 0.14 mmol), CDI (45 mg, 0.28 mmol) and DBU (53 mg, 0.35 mmol) were added to DMSO (10 mL) and reacted at room temperature for 2 hours. The mixture was diluted with water (15 mL), extracted with ethyl acetate (8 mL × 3), and the organic phases were combined. The organic phases were washed successively with water (10 mL × 3) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 80%-100%) to obtain the title compound.

[0160] LC-MS(ESI):[M+H] + =895.5.

[0161] 1H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.16(d,J=7.6Hz,1H),7.64(d,J=8.8Hz,1H),7.47–7.41(m,1H) ,7.36–7.21(m,3H),7.19–7.04(m,1H),6.97–6.77(m,2H),6.72(d,J=7.4Hz,1H),6.37(d,J=7.6Hz,1H ),5.30(d,J=41.5Hz,1H),3.72(d,J=8.6Hz,3H),3.30–3.18(m,2H),2.98–2.91(m,1H),2.10–2.06(m, 1H),1.74–1.65(m,6H),1.60–1.46(m,4H),1.32–1.20(m,12H),1.07–0.98(m,4H),0.67–0.61(m,2H).

[0162] Experimental Example 1 In vitro cell activity test

[0163] 1. Materials

[0164] (1) Cell lines

[0165] The cell line was constructed by Shanghai WuXi AppTec Co., Ltd., as shown in Table 1 below.

[0166] Table 1

[0167] Target host cells GLP-1 HEK293

[0168] (2) Reagents are shown in Table 2 below.

[0169] Table 2

[0170]

[0171]

[0172] (3) Instruments are shown in Table 3 below.

[0173] Table 3

[0174] name model factory microplate reader envision2014 PerkinElmer cell counter <![CDATA[Vi-CELL TM XR Cell Viability Analyzer]]> Beckman Automatic pipetting workstation Bravo V11 Agilent Liquid Handlers ECHO 555 Labcyte centrifuge <![CDATA[Allegra TM 25R Centrifuge]]> Beckman

[0175] (4) Compound information

[0176] Prepare the compound solution in DMSO at a working concentration of 100 μM or 10 μM. Perform 10 4-fold dilutions (maximum concentration after dilution is 1000 nM or 100 nM) using an automated pipetting workstation.

[0177] 2. Methods

[0178] (1) Experimental materials

[0179] The experimental buffer is shown in Table 4 below.

[0180] Table 4

[0181] Reagents Final concentration HBSS 1x HEPES 5mM 10% BSA 0.1％ IBMX 0.5mmol / L

[0182] The final concentrations of the detection reagents are shown in Table 5 below.

[0183] Table 5

[0184] Reagents Final concentration Lysate ≈1x D2-cyclic adenosine monophosphate solution 1x Cyclic AMP Antibody Solution 1x

[0185] (2) Experimental methods

[0186] (a) Preparation of compound plates:

[0187] The test compound was diluted 4-fold at 10 points with a starting concentration of 100 μM. The dilution was completed by the automatic pipetting workstation.

[0188] (b) Transfer compounds:

[0189] (i) Use a liquid handler to transfer 100 nL of 100x compound to a 384-well plate.

[0190] (ii) Centrifuge the 384-well plate at 1000 rpm for 5 seconds.

[0191] (c) Preparation of cell suspension

[0192] (i) Thaw a cryopreserved tube of HEK293 cells expressing hGLP-1R in 37°C warm water immediately.

[0193] (ii) Transfer the cell suspension to a 15 mL centrifuge tube and gently rinse with 10 mL of HBSS.

[0194] (iii) Centrifuge the tube at 1000 rpm at room temperature for 1 minute.

[0195] (iv) Discard the supernatant.

[0196] (v) Gently rinse with 10 ml of HBSS, pellet the cells by centrifugation, and resuspend the cells in assay buffer.

[0197] (vi) Measure cell density and activity using a cell counter.

[0198] (vii) Dilute the GLP-1R cell concentration to 1.0*10 5 / mL.

[0199] (viii) Transfer 10 μL of the diluted cell suspension into a 384-well plate.

[0200] (ix) Incubate at room temperature for 30 minutes.

[0201] (d) Detection:

[0202] (i) Add 10 μL of 800 nM serially diluted cAMP standard to empty wells of a 384-well plate.

[0203] (ii) Add 10 μL of cAMP detection reagent.

[0204] (iii) After incubation at room temperature for 60 minutes, the plate was read on a microplate reader.

[0205] Results and Discussion: The compounds of the present invention exhibited superior agonist ability on GLP-1 receptor.

[0206] Experimental Example 2: Pharmacokinetic Study of the Compounds of the Invention in Mice

[0207] 1. Experimental Materials

[0208] C57BL / 6 mice: male, 6-8 weeks old, weighing 20-30 g, were purchased from Weitonglihua (Beijing) Laboratory Animal Technology Co., Ltd.

[0209] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0210] Instrument: AB LCMS-5500 tandem mass spectrometer

[0211] 2. Experimental methods

[0212] The compound was weighed and dissolved in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate system. All formulations were clear solutions and administered intravenously or orally to mice. Blood samples were collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. At each PK sampling point, 30 μL of whole blood was collected into an EDTA-K2 anticoagulant blood collection tube and centrifuged at 4°C within 30 minutes to obtain plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or frozen until analysis.

[0213] Approximately 1 mg of compound was weighed and dissolved in DMSO, vortexed, and sonicated to obtain a 1 mg / mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile in water to obtain standard working solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL. Quality control working solutions at concentrations of 10, 20, 500, and 8,000 ng / mL were prepared using the same dilution method. Three μL of the standard working solutions at concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) were added to 30 μL of blank C57BL / 6 mouse plasma to obtain a total volume of 33 μL of standard curve samples with concentrations ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Quality control samples with concentrations of (1 ng / ml (low-1) and 2 ng / ml (low-2), 50 ng / ml (medium), 800 ng / ml (high)) were prepared separately.

[0214] Proteins were precipitated by adding 200 μL of acetonitrile containing the internal standard (dexamethasone) to 33 μL of standard sample, 33 μL of quality control sample, or 33 μL of unknown sample (30 μL of plasma and 3 μL of blank solution). The samples were then vortexed for 30 seconds and centrifuged at 4000 g at 4°C for 15 minutes. The supernatant was diluted threefold with water, and 10 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis using the following detection conditions:

[0215] Chromatographic column: Raptor Biphenyl 2.7μm 2.1×50mm

[0216] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), gradient elution according to the table below.

[0217]

[0218] 3. Data processing

[0219] Using Phoenix™ Pharmacokinetic data were analyzed using a non-compartmental model using the software.

[0220] Results and discussion: The compounds of the present invention were well absorbed orally in mice and had high exposure and bioavailability.

[0221] Experimental Example 3: Stability in Human Liver Microsomes

[0222] 1. Experimental Materials

[0223] Liver microsome species supplier people Corning

[0224] 2. Experimental methods

[0225] Preparation of compound working solution: Prepare high concentration stock solution of test substance and control drug verapamil powder with DMSO, and dilute with DMSO to 100 μM working solution before use. The final concentration of test substance and verapamil is 1 μM.

[0226] Preparation of phosphate buffer (100 mM, pH 7.4): Weigh 7.098 g of disodium hydrogen phosphate and add it to 500 mL of pure water, then sonicate to dissolve it. This is Solution A. Weigh 3.400 g of potassium dihydrogen phosphate and add it to 250 mL of pure water, then sonicate to dissolve it. This is Solution B. Add Solution B to Solution A, and the pH will be 7.4.

[0227] Preparation of 10mM NADPH: Before the experiment, weigh an appropriate amount of NADPH and prepare a working solution with a concentration of 10mM using phosphate solution.

[0228] Preparation of incubation system: The incubation system was prepared according to the table below and preheated in a 37°C water bath for 10 minutes before use.

[0229] Element Stock solution concentration volume Final concentration of the system Phosphate buffered saline 100mM 216.25μL 100mM microsomes 20 mg / mL 6.25 μL 0.5mg / mL

[0230] Transfer 25 μL of NADPH or phosphate buffered saline to the above incubation system and add 2.5 μL of 100 μM test substance or verapamil. Prepare duplicates for samples with NADPH; prepare single replicates for samples without NADPH.

[0231] At 0.5, 5, 15, 30, and 60 minutes, 30 μL of the suspension was collected, and the reaction was terminated by adding 150 μL of acetonitrile containing the internal standard and vortexing for 10 minutes.

[0232] Protein precipitation was then performed by centrifugation at 3220 g for 40 minutes. 100 μL of the supernatant was transferred to a sample plate and mixed with 100 μL of pure water for UPLC-MS / MS analysis.

[0233] 3. Data processing

[0234] All data calculations were performed using Microsoft Excel. Peak areas were determined by extracting ion spectra. The in vitro half-life (t 1 / 2 ).

[0235] In vitro half-life (t 1 / 2 ) is calculated by slope: t 1 / 2 =0.693 / k

[0236] The in vitro clearance (unit: μL / min / mg) was calculated using the following formula:

[0237] CL int =0.693 / t 1 / 2 *(Incubation system volume (μL) / Protein content (mg))

[0238] Results and Discussion: The compounds of the present invention exhibited good stability.

[0239] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in: L1 is -C(=O)-, -S(=O)2- or -CR 10 R 11 -; L2 is -NR 12 -, -C(=O)NR 13 -、-NR 14 C(=O)NR 15 -or -CR 16 R 17 -; L3 is a key or -CR 18 R 19 -; L4 is a key or -CR 20 R 21 -; X1 is C, N, O or S; X2 is C or N; Y1, Y2, Y3 and Y4 are each independently C or N; Z is O, S, -NR 26 -, -CR 27 R 28 -, -O-CR 29 R 30 -, -S-CR 31 R 32 -, -NR 26 -CR 33 R 34 - or -CR 27 R 28 -CR 35 R 36 -; R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace; R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl; R 3 is a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-8 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace; R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 4 for R 5 and R 6 Each independently is H, D, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent; or R 5 and R 6 Together with the carbon atoms to which they are attached, they can form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio and C 1-3 substituted by an alkylamino substituent; Each R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 and R 36 are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino or nitro; or R 27 and R 28 、R 27 and R 35 independently and optionally together with the carbon atom to which they are attached may form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 substituted by an alkylamino substituent; R 9 H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the phenyl, C 2-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 substituted by a cycloalkyl substituent; Each R 12 、R 13 、R 14 、R 15 and R 26 Independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

2. The compound according to claim 1, wherein for 3. The compound according to claim 1, wherein R 1 is phenyl or 5-10 membered heteroaryl, and the phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 1a replace; R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c 、C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c Each independently is C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 2b and R 2c Together with the phosphorus atom to which they are attached, they may form a 5-6 membered heterocyclic group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl and ethyl; R 3 is a 3-6 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-6 membered heterocyclic group and the 5-10 membered heteroaryl group may be independently and optionally replaced by 1, 2 or 3 R 3a replace; R 3a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

4. The compound according to claim 1, wherein R 1 Phenyl, The phenyl group, Can be optionally replaced by 1, 2 or 3 R 1a replace; R 1a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R 2a replace; R 2a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, -P(=O)R 2b R 2c , methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the ... 2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro; R 2b and R 2c are each independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R 2b and R 2c Together with the phosphorus atoms to which they are attached, they can form R 3 is oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, The oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, Can be optionally replaced by 1, 2 or 3 R 3a replace; R 3a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, the methyl, ethyl , n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino and nitro.

5. The compound according to any one of claims 1 to 4, wherein R 5 and R 6 Each is independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro and C 3-6 substituted by a cycloalkyl substituent; or R 5 and R 6 Together with the carbon atom to which they are attached, they may form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, which may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxy, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino; Each R 7 、R 8 、R 10 、R 11 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 and R 36 are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl, wherein the methyl , ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro; or R 27 and R 28 、R 27 and R 35 independently and optionally together with the carbon atom to which they are attached can form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl being independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, hydroxyl, cyano, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino and N-ethylamino; R 9 is H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the phenyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, Methyl, ethyl, n-propyl, isopropyl, -CHF2, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may independently and optionally be substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Each R 12 、R 13 、R 14 、R 15 and R 26 and 1-3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxy, amino, and nitro.

6. The compound according to claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

9. The use according to claim 8, wherein The GLP-1 receptor agonist-mediated disease is diabetes, diabetic complications, non-alcoholic fatty liver disease, obesity, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, stroke, coronary heart disease, myocardial infarction, congestive heart failure, arrhythmia, cerebral infarction, diabetic nephropathy, Parkinson's disease, Alzheimer's disease or dementia.

10. The use according to claim 9, wherein The diabetes mellitus is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of the adult.

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