Tetracyclic GLP-1 receptor allosteric modulator and composition, preparation and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a tetracyclic GLP-1 receptor allosteric modulator and a composition, a preparation and application thereof. Specifically, the tetracyclic GLP-1 receptor allosteric modulator has a structure as shown in a formula I, has excellent in-vitro agonistic activity on a GLP-1 receptor, can be used as a micromolecular GLP-1 receptor allosteric modulator, and has a good effect on treating GLP-1 related diseases of mammals (including human). # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the technical field of medicinal chemistry, and relates to a series of novel tetracyclic GLP-1 receptor allosteric modulators, pharmaceutical compositions and pharmaceutical preparations containing the same, and medical uses thereof. Background Art

[0002] Diabetes has become one of the major diseases that seriously threaten human health and life in modern society. This disease is a group of clinical syndromes caused by the interaction of genetic and environmental factors. Currently, two major forms of diabetes have been identified, namely type I and type II. Type I diabetics, that is, insulin-dependent diabetics, produce little or almost no insulin (a hormone used in the body to regulate glucose utilization). Type II diabetics, that is, non-insulin-dependent diabetics, have the same or higher plasma insulin levels as non-diabetic patients. However, these patients are resistant to insulin (which stimulates the glucose and lipid metabolism of major insulin-sensitive tissue cells (such as muscle, liver, adipose tissue, etc.)). Even if the plasma insulin level is increased, it is impossible to overcome the patient's significant resistance to insulin. Insulin resistance is a key factor in the occurrence and development of type II diabetes. In addition to being related to the reduction in the number of insulin receptors, it is also related to insulin receptor defects, but this mechanism has not yet been fully clarified. Insulin responsiveness resistance results in the inability of insulin to activate the uptake, oxidation, and storage of glucose in muscle tissue, and the inability to effectively inhibit the lipolysis of adipose tissue, as well as the production and secretion of glucose in the liver.

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L cells in the digestive tract. GLP-1 exerts its corresponding effects by binding to its widely existing specific receptors. At present, the organs where GLP-1 receptors (GLP-1R) are clearly present include pancreatic islet cells, stomach, intestines, lungs, brain, kidneys, hypothalamus and cardiovascular system. GLP-1 receptors may also exist in 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. In patients with type 2 diabetes, 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 (the half-life of intravenous injection is less than 1.5 minutes), the human body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0004] Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) have the effect of reducing fasting and postprandial glucose and improving blood sugar in patients with type II diabetes. However, because peptide GLP-1 receptor agonists have poor oral bioavailability and are inconvenient to take, the advent of small molecule GLP-1 receptor agonists with good oral bioavailability is highly anticipated. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] The present application aims to discover new non-peptide GLP-1 receptor allosteric modulators (especially positive allosteric modulators, or agonists), especially new compounds with good biological properties that can be safely applied to the human body; in addition, the present application also aims to provide new means for preventing and / or treating GLP-1 related diseases (especially diabetes, etc.).

[0007] Solutions for solving problems

[0008] In a first aspect, the present application provides a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance (e.g., deuterated substance) or prodrug thereof:

[0009]

[0010] in:

[0011] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 5-8 Cycloalkenyl and 5-8 membered heterocycloalkenyl;

[0012] Ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl;

[0013] If present, each R 1 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0014] R 2Selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0015] Every R 3 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more substituents; if present, each of the substituents is independently selected from hydroxy, amino, =O, =S, =NH, halogen, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0016] R 4 and R 5 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group;

[0017] X1 is O or NR 6 ;

[0018] X2 is N or CR 6 ;

[0019] X3 is N or CR 6 ;

[0020] If present, each R 6 independently selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =CH2 and =NH;

[0021] If present, each R 7 Independently selected from amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0022] m is 0, 1, 2 or 3;

[0023] n is 1, 2, 3, 4 or 5;

[0024] p is 0, 1, 2 or 3;

[0025] The heterocyclyl, heterocycloalkenyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

[0026] In a second aspect, the present application provides the following non-limiting examples of the above-mentioned compounds having the structure of Formula I:

[0027] (1) (R)-11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-7,11-dihydroimidazo[4',5':4,5]benzo[1,2-b]pyrido[3,2-d]azepine -6(5H)-ketone;

[0028] (2) (R)-10-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-1,4,6,10-tetrahydroimidazo[4,5-g]pyrano[3,4-c]quinolin-5(2H)-one;

[0029] (3) (R)-10-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-10H-imidazo[4,5-b]phenanthridin-5-amine;

[0030] (4) (R)-11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-5,11-dihydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-amine;

[0031] (5) (R)-N-(11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-5,11-dihydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-yl)acetamide;

[0032] (6) (R)-11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-N-methyl-5,11-dihydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-amine;

[0033] (7) (R)-1-(11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-5,11-dihydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-yl)urea;

[0034] (8) (R)-N-(2-amino-11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-5,11-dihydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-yl)acetamide;

[0035] (9) (R)-N-(11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-1,4,5,11-tetrahydro-2H-imidazo[4',5':4,5]benzo[1,2-b]pyrano[4,3-d]azepine -6-yl)acetamide;

[0036] (10) (R)-N-(11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-1,2,3,4,5,11-hexahydrobenzo[d]imidazo[4',5':4,5]benzo[1,2-b]azepine -6-yl)acetamide; and

[0037] (11)(R)-N-(11-(1-(2,6-dichloro-3-cyclopropylphenyl)ethyl)-3-methyl-1,2,3,4,5,11-hexahydroimidazo[4',5':4,5]benzo[1,2-b]pyrido[4,3-d]azepine -6-yl)acetamide.

[0038] In a third aspect, the present application provides a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, and at least one pharmaceutically acceptable carrier.

[0039] Preferably, in the above-mentioned pharmaceutical composition, the pharmaceutically acceptable carrier includes but is not limited to diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, olfactory agents, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, opacifiers (opacifiers), etc.

[0040] In a fourth aspect, the present application provides a pharmaceutical preparation, which is made of the above-mentioned compound having the structure of formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or is made of the above-mentioned pharmaceutical composition. Alternatively, the present application provides a pharmaceutical preparation, which contains the above-mentioned compound of formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug as an active ingredient.

[0041] In the fifth aspect, the present application provides the above-mentioned compound having the structure of formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the use of the above-mentioned pharmaceutical preparation in the preparation of a drug for preventing and / or treating GLP-1 related diseases. Alternatively, the present application provides the above-mentioned compound of formula I for preventing and / or treating GLP-1 related diseases or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation. Alternatively, the present application provides a method for preventing and / or treating GLP-1 related diseases, comprising administering the above-mentioned compound of formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation to a subject in need.

[0042] The present application provides a GLP-1 receptor allosteric modulator, the modulator comprising the compound of formula I above or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above pharmaceutical composition, or the above pharmaceutical preparation. Alternatively, the present application provides a compound of formula I above or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above pharmaceutical composition, or the above pharmaceutical preparation used as a GLP-1 receptor allosteric modulator.

[0043] Preferably, the GLP-1 related disease is selected from diabetes (especially type II diabetes), obesity, liver disease (especially non-alcoholic steatohepatitis, i.e. NASH), neurodegenerative diseases (especially Parkinson's disease, i.e. PD, and Alzheimer's disease, i.e. AD) and cardiovascular disease (especially atherosclerotic cardiovascular disease, i.e. ASCVD).

[0044] In a sixth aspect, the present application provides a drug combination form (also referred to as a "drug combination product"), which comprises the above-mentioned compound having the structure of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, and at least one additional GLP-1-related disease therapeutic agent.

[0045] Effects of the Invention

[0046] The compounds of the present application have excellent in vitro agonist activity against the GLP-1 receptor, can be used as small molecule GLP-1 receptor allosteric modulators, and have good effects on the treatment of GLP-1 related diseases in mammals (including humans). DETAILED DESCRIPTION

[0047] Before further describing the present application, it should be understood that the present application is not limited to the specific embodiments described herein; it should also be understood that the terms used herein are only used to describe and not to limit specific embodiments. In the absence of a definition, the term should be interpreted according to the meaning commonly understood by those skilled in the art.

[0048] [Definition of terms]

[0049] Unless otherwise stated, the following terms have the following meanings.

[0050] The term "pharmaceutically acceptable salt" refers to a salt of a compound having the structure of Formula I that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting the compounds of the present application with pharmaceutically acceptable inorganic acids or organic acids, which are also known as acid addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid (which can form sulfates or acid sulfates), phosphoric acid (which can form phosphates or acid phosphates), etc. Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid (which can form citric acid monosalt, disalt or trisalt), maleic acid (which can form maleic acid monosalt or disalt), fumaric acid (which can form fumaric acid monosalt or disalt), succinic acid (which can form succinic acid monosalt or disalt), tartaric acid (which can form tartaric acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), malonic acid (which can form malonic acid monosalt or disalt), malic acid (which can form malic acid monosalt or disalt), oxalic acid (which can form oxalic acid monosalt or disalt), lactic acid, pyruvic acid, salicylic acid, formic acid, acetic acid, propionic acid, benzoic acid, glycolic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Pharmaceutically acceptable salts can be synthesized by general chemical methods.

[0051] The term "hydrate" refers to a substance formed by the combination of the compound of the present application or its pharmaceutically acceptable salt with water through non-covalent intermolecular forces. Common hydrates include but are not limited to hemihydrate, monohydrate, dihydrate, trihydrate, etc.

[0052] The term "solvate" refers to a substance formed by the combination of the compound of the present application or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include but are not limited to hydrates, ethanolates, acetonates, etc. It should be understood that the present application covers all solvate forms having GLP-1 receptor allosteric modulation activity.

[0053] The term "isomers" refers to compounds that have the same number and types of atoms and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space.

[0054] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since there are asymmetric centers and other chemical structures that may cause stereoisomerism in the compounds of the present application, the present application also includes these stereoisomers and mixtures thereof. Since the compounds of the present application and their salts include asymmetric carbon atoms, they can exist in the form of a single stereoisomer, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if necessary, such compounds can be prepared or separated to obtain pure stereoisomers, i.e., single enantiomers or diastereomers, or single stereoisomer enriched (purity ≥98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%) mixtures. As described below, a single stereoisomer of a compound is prepared synthetically from an optically active starting material containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereoisomers followed by separation or recrystallization, chromatography, use of a chiral resolution agent, or direct separation of the enantiomers on a chiral chromatographic column. Starting compounds with a specific stereochemistry are either commercially available or prepared as described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomer" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise stated, all stereoisomeric forms of the compounds of the present application are within the scope of the present application.

[0055] The term "tautomer" (or "tautomeric form") refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or prototransfer tautomers) include but are not limited to mutual conversion by proton migration (for example, two tautomers actually corresponding to the compound 5 of the present application as shown below), such as keto-enol isomerization, imine-enamine isomerization (for example, two tautomers actually corresponding to the compound 11 of the present application as shown below), amide-imino alcohol isomerization (for example, two tautomers actually corresponding to the compound 1 of the present application as shown below), etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0056]

[0057] The term "cis-trans isomer" refers to stereoisomers formed by the different positions of atoms (or groups) located on both sides of a double bond or a ring system relative to a reference plane; in cis isomers, the atoms (or groups) are located on the same side of the double bond or the ring system, and in trans isomers, the atoms (or groups) are located on opposite sides of the double bond or the ring system. Unless otherwise indicated, all cis-trans isomeric forms of the compounds of the present application are within the scope of the present application.

[0058] The term "isotope-labeled compound" refers to a compound formed by replacing a specific atom in a structure with an isotope atom thereof. Unless otherwise indicated, the compounds of the present application include various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H(D), 3 H(T), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 S and 37 For example, deuterated species may be defined as a compound in which a hydrogen atom is replaced with deuterium (ie, D), and the amount of deuterium at that position greatly exceeds (eg, at least 1000 times exceeds) the abundance of deuterium that occurs naturally.

[0059] The term "prodrug" refers to a derivative compound that can directly or indirectly provide the compound of the present application after being administered to a patient. Particularly preferred derivative compounds or prodrugs are compounds that can improve the bioavailability of the compound of the present application when administered to a patient (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present application are within the scope of the present application, and various prodrug forms are well known in the art.

[0060] The term "aryl" refers to a monocyclic or fused polycyclic group with aromatic properties, whose ring atoms are all C atoms, for example, it may have 6 to 20, 6 to 14 or 6 to 12 carbon atoms (including both connecting with other fragments in a substitution manner and connecting with other fragments in a fusion manner). Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthalene. The term "C 6-10 "Aryl" refers to an aromatic group having 6 to 10 carbon atoms, C 6-10 Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthalene, and the like.

[0061] The term "heteroaryl" refers to a monocyclic or fused polycyclic group with aromaticity, wherein at least one (e.g., 1, 2, 3, or 4) ring atom is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C, for example, a 5- to 10-membered ring, especially a 5- to 9-membered ring, a 5- to 8-membered ring (including both substitution and fusion with other fragments). Non-limiting examples of heteroaryl include, but are not limited to

[0062] The term "5- to 10-membered heteroaryl" refers to a heteroaryl group having 5 to 10 (e.g., 5, 6, 7, 8, 9 or 10) ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P. Non-limiting examples of 5- to 10-membered heteroaryl groups include, but are not limited to, furanyl, pyrrolyl, thienyl, pyridyl, indolyl and quinolyl, etc.

[0063] The term "heterocycloalkyl" refers to a fully saturated monocyclic group, the term "heterobridged cycloalkyl" refers to a fully saturated bridged ring group, and the term "heterospirocycloalkyl" refers to a fully saturated spirocyclic group, wherein: at least one (e.g. 1, 2, 3 or 4) ring atoms are heteroatoms selected from N, O, S and P, and the remaining ring atoms are C, for example, it can be a 3- to 14-membered ring, or even a 3- to 6-membered ring (including both connection to other fragments by substitution and connection to other fragments by fusion).

[0064] The term "heterocycloalkenyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 double bonds) monocyclic group, the term "heterobridged cycloalkenyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 double bonds) bridged ring group, and the term "heterospirocycloalkenyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 double bonds) spirocyclic group, wherein: at least one (for example 1, 2, 3 or 4) ring atoms are heteroatoms selected from N, O, S and P, and the remaining ring atoms are C, for example, it can be a 3- to 14-membered ring (such as a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered ring), or even a 3- to 6-membered ring (including both connection to other fragments in a substitution manner and connection to other fragments in a fusion manner).

[0065] The term "heterocycloalkynyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 triple bonds) monocyclic group, the term "heterobridged cycloalkynyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 triple bonds) bridged ring group, and the term "heterospirocycloalkynyl" refers to a partially unsaturated (but not fully unsaturated, for example, having 1 or 2 triple bonds) spirocyclic group, wherein: at least one (for example 1, 2, 3 or 4) ring atoms are heteroatoms selected from N, O, S and P, and the remaining ring atoms are C, for example, it can be a 3- to 14-membered ring (such as a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered ring), or even a 3- to 6-membered ring (including both connection to other fragments in a substitution manner and connection to other fragments in a fusion manner).

[0066] The term "heterocyclyl" refers to a fully saturated or partially unsaturated (but not fully unsaturated, for example, having 1 or 2 double bonds) monocyclic, bridged or spirocyclic group, wherein at least one (for example, 1, 2, 3 or 4) ring atoms are heteroatoms selected from N, O, S and P, and the remaining ring atoms are C. For example, it can be a 3- to 14-membered ring (such as a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered ring), or even a 3- to 6-membered ring (including both connection with other fragments in a substitution manner and connection with other fragments in a fusion manner), including but not limited to heterocycloalkyl (or heteromonocycloalkyl), heterocycloalkenyl (or heteromonocycloalkenyl), heterocycloalkynyl (or heteromonocycloalkynyl), heterobridged cycloalkyl, heterobridged cycloalkenyl, heterobridged cycloalkynyl, heterospirocycloalkyl, heterospirocycloalkenyl and heterospirocycloalkynyl, etc. The term "3- to 14-membered heterocyclyl" refers to a heterocyclyl group having 3 to 14 ring atoms, which may contain 1 to 4 heteroatoms selected from N, O, S and P; the term "3- to 6-membered heterocyclyl" refers to a heterocyclyl group having 3 to 6 ring atoms, which may contain 1 or 2 heteroatoms selected from N, O, S and P; the term "5- to 15-membered heterocyclyl" refers to a heterocyclyl group having 5 to 15 ring atoms, which may contain 1 to 5 heteroatoms selected from N, O, S and P.

[0067] Non-limiting examples of saturated 3-membered heterocyclic groups include, but are not limited to, oxirane, thioethane, cyclonitroethane, etc.; non-limiting examples of saturated 4-membered heterocyclic groups include, but are not limited to, azetidinyl, oxadidinyl, thiadidinyl, etc.; non-limiting examples of saturated 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, etc.; non-limiting examples of saturated 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, Tetrahydrothiopyranyl, cyclopentylsulfoxide, cyclopentylsulfone, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, 1,4-diphospholinyl, 1,4-azaphospholinyl, 4-oxy-1,4-azaphospholinyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and the like; non-limiting examples of saturated 7-membered heterocyclic groups include, but are not limited to, azepanyl, oxacycloheptyl, thiacycloheptyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, and the like.

[0068] Non-limiting examples of partially unsaturated heterocyclic groups include, but are not limited to

[0069] wait.

[0070] The term "alkyl" refers to a linear or branched monovalent hydrocarbon group containing no unsaturation.1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. 1-6 "Alkyl" refers to an alkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms, C 1-6 Non-limiting examples of alkyl groups include, but are not limited to, methyl (-CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), sec-butyl (-CH(CH3)CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), neopentyl (-CH2C(CH3)3), and the like.

[0071] The term "alkoxy" refers to an "-O-alkyl" group, wherein the "alkyl" portion has the meaning defined above.

[0072] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 (e.g., 2, 3, 4, 5 or 6) carbon atoms; the term "C 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, butenyl, 2-methyl-2-buten-1-yl, pentenyl, hexenyl, and the like.

[0073] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds, for example, having 2 to 20 carbon atoms. 2-6 "Alkynyl" refers to an alkynyl group having 2 to 6 (e.g., 2, 3, 4, 5 or 6) carbon atoms; the term "C 2-4 "Alkynyl" refers to an alkynyl group having 2 to 4 carbon atoms. 2-6 Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.

[0074] The term "haloalkyl" refers to a linear or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a halogen atom, and does not contain unsaturation. 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms; the term "C 1-4 "Haloalkyl" refers to a haloalkyl group having 1 to 4 carbon atoms. 1-6Non-limiting examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, and the like.

[0075] The term "hydroxyalkyl" refers to a linear or branched monovalent group formed by replacing at least one hydrogen atom in an alkyl group with a hydroxyl group, and contains no unsaturation. 1-6 "Hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms; the term "C 1-4 "Hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 4 carbon atoms. 1-6 Non-limiting examples of hydroxyalkyl include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and the like.

[0076] The term "cycloalkyl" refers to a fully saturated monocyclic or polycyclic (eg, spirocyclic, fused, or bridged) monovalent cyclic hydrocarbon group, for example, having 3 to 20, 3 to 12, 3 to 6, or 5 to 6 carbon atoms. 3-14 "Cycloalkyl" refers to a cycloalkyl group having 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms; the term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms. 3-14 Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like; polycyclic C 3-14 Cycloalkyl groups include, but are not limited to, decahydronaphthyl, adamantyl, and the like.

[0077] The term "cycloalkenyl" refers to a monovalent cyclic hydrocarbon group having one or more carbon-carbon double bonds, such as a spirocyclic, fused or bridged ring, but not an aromatic ring, and having, for example, 3 to 20, 3 to 12, 3 to 6 or 5 to 6 carbon atoms. 3-14 The term "cycloalkenyl" refers to a cycloalkenyl group having 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms. 3-14 Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

[0078] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in Group VII of the Periodic Table of Elements. The term "hydroxyl" refers to the -OH group. The term "amino" refers to the -NH2 group. In some cases, amino can also mean that at least one of the H atoms in the structure is further replaced by an alkyl group (e.g., C1-6 The term "nitro" refers to a -NO2 group. The term "cyano" refers to a -CN group. The term "carboxyl" refers to a -C(=O)OH group. The term "oxo" refers to a =O group attached to a carbon atom, while the term "oxido" refers to a =O group attached to a sulfur atom or a phosphorus atom.

[0079] The term "single bond" refers to a chemical bond between atoms used to connect or interact with each other, such as an ionic bond, a covalent bond, a coordination bond, etc.; in the molecular structure of an organic compound, a single bond is usually a covalent bond.

[0080] In this article, Respectively represent R 1 and R 3 The substitution may be carried out at any substitutable position of Ring A and Ring B, and multiple R 1 Can be the same or different, multiple R 3 Can be the same or different.

[0081] The term "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. When referring to a group as "optionally substituted", this means that the group is substituted or unsubstituted. For example, a heterocyclic group is "optionally" substituted with halogen, which means that the heterocyclic group may be unsubstituted, or may be monosubstituted, polysubstituted or fully substituted with halogen atoms. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced. The term "independently" means that when one or more substituents are selected from a number of possible groups, the groups corresponding to these substituents may be the same or different.

[0082] The term "one or more" means 1 or more than 1, for example 1-5, 1-4, 1-3 or 1-2.

[0083] In this application, the terms "include", "comprises", and "contains" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents, and vice versa. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0084] Unless otherwise specified, in this article, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0085] The term "subject" encompasses mammals, such as humans, non-human primates (eg, rhesus monkeys), pigs, cows, horses, sheep, dogs, rabbits, mice, and the like.

[0086] For the purpose of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents.

[0087] [Tetracyclic GLP-1 receptor allosteric modulators]

[0088] The present application provides a series of novel tetracyclic GLP-1 receptor allosteric modulators or their pharmaceutically acceptable forms, such as salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotope labels (e.g., deuterated substances) or prodrugs of such compounds.

[0089] In one embodiment of the present application, the structure of the compound is as shown in Formula I:

[0090]

[0091] in:

[0092] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 5-8 Cycloalkenyl and 5-8 membered heterocycloalkenyl;

[0093] Ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl;

[0094] If present, each R 1 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0095] R 2 Selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0096] Every R 3 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more substituents; if present, each of the substituents is independently selected from hydroxy, amino, =O, =S, =NH, halogen, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl;

[0097] R 4 and R 5 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group;

[0098] X1 is O or NR 6 ;

[0099] X2 is N or CR 6 ;

[0100] X3 is N or CR 6 ;

[0101] If present, each R 6 independently selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =CH2 and =NH;

[0102] If present, each R 7 Independently selected from amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino;

[0103] m is 0, 1, 2 or 3;

[0104] n is 1, 2, 3, 4 or 5;

[0105] p is 0, 1, 2 or 3;

[0106] The heterocyclyl, heterocycloalkenyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

[0107] In one embodiment of the present application, ring A in formula I is selected from C 6-10 Aryl, 6-10 membered heteroaryl, C 6-8 In one embodiment of the present application, ring A in formula I is selected from C 6-10Aryl, 6-10 membered heteroaryl containing 1-3 N, O or S, C 6-8 Cycloalkenyl and 6-8 membered heterocycloalkenyl containing 1-3 N or O or S. In some embodiments of the present application, the ring A is selected from C 6-10 Aryl and 6-10 membered heteroaryl containing 1-3 N. In some preferred embodiments of the present application, the ring A is selected from phenyl and pyridyl.

[0108] In a specific embodiment of the present application, ring A in formula I is C 6-10 Aryl.

[0109] In a more specific embodiment of the present application, Ring A in Formula I is selected from phenyl and naphthyl, preferably phenyl.

[0110] In another specific embodiment of the present application, Ring A in Formula I is a 6-10 membered heteroaryl group, for example a 6-10 membered heteroaryl group containing 1-2 N atoms.

[0111] In another more specific embodiment of the present application, Ring A in Formula I is selected from pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, preferably pyridinyl.

[0112] In another specific embodiment of the present application, ring A in formula I is C 6-8 Cycloalkenyl.

[0113] In yet another more specific embodiment of the present application, Ring A in Formula I is selected from cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptatrienyl, preferably cyclohexenyl.

[0114] In yet another specific embodiment of the present application, Ring A in Formula I is a 6-8 membered heterocycloalkenyl group, for example, a 6-8 membered heterocycloalkenyl group containing 1-3 N, O or S.

[0115] In yet another more specific embodiment of the present application, Ring A in Formula I is selected from dihydropyridinyl, tetrahydropyridinyl, pyranyl and dihydropyranyl, preferably tetrahydropyridinyl and dihydropyranyl.

[0116] In one embodiment of the present application, p in Formula I is 0, 1 or 2.

[0117] In a specific embodiment of the present application, p in Formula I is 0, that is, ring A is not substituted by R 1 replace.

[0118] In another specific embodiment of the present application, p in Formula I is 1, that is, Ring A is substituted by 1 substituent R 1 substituted, and the substituent R 1 Substitution is performed at any substitutable position of Ring A.

[0119] In one embodiment of the present application, each R in Formula I 1 are independently selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group. Alternatively, each R in Formula I 1 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, C 1-5 Alkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group containing 1-3 N, O or S atoms.

[0120] In a specific embodiment of the present application, each R in Formula I 1 independently selected from hydrogen, amino, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group. Alternatively, each R in Formula I 1 independently selected from hydrogen, deuterium, tritium, amino, C 1-5 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group containing 1-3 N, O or S atoms.

[0121] In a more specific embodiment of the present application, each R in Formula I 1 independently selected from deuterium, tritium, amino and C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 alkyl), preferably amino, methyl, ethyl, n-propyl and isopropyl, more preferably amino and methyl.

[0122] In one embodiment of the present application, R in Formula I 2 Selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group. 2 Selected from hydrogen, deuterium, tritium, amino, halogen, cyano, C 1-5 Alkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group containing 1-3 N, O or S atoms.

[0123] In a specific embodiment of the present application, R in Formula I 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl. Alternatively, R 2 Selected from deuterium, tritium, C 1-5 Alkyl and C 3-6 Cycloalkyl.

[0124] In a more specific embodiment of the present application, R in Formula I 2 Selected from C 1-4 Alkyl (or, R 2 Selected from deuterium, tritium, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 alkyl), preferably methyl, ethyl, n-propyl and isopropyl, more preferably methyl.

[0125] In one embodiment of the present application, ring B in formula I is selected from C 6-10 aryl, 6-10 membered heteroaryl and 6-8 membered heterocyclyl. Alternatively, ring B is selected from C 6-10 Aryl, 6-10 membered heteroaryl containing 1-3 N, O or S, and 6-8 membered heterocyclic group containing 1-3 N, O or S (e.g. 6-8 membered heterocycloalkenyl).

[0126] In a specific embodiment of the present application, ring B in formula I is C 6-10 Aryl.

[0127] In a more specific embodiment of the present application, Ring B in Formula I is selected from phenyl and naphthyl, preferably phenyl.

[0128] In one embodiment of the present application, n in Formula I is 1, 2 or 3.

[0129] In a specific embodiment of the present application, n in Formula I is 1, that is, ring B is substituted by 1 substituent R 3 substituted, and the substituent R 3 Substitution is performed at any substitutable position of Ring B.

[0130] In another specific embodiment of the present application, n in Formula I is 2, that is, Ring B is substituted by 2 substituents R which are the same or different from each other. 3 Substituted, and the two substituents R 3 Substitution is independently performed at any substitutable position of Ring B.

[0131] In another specific embodiment of the present application, n in Formula I is 3, that is, Ring B is substituted by 3 substituents R which are the same or different from each other. 3 Substituted, and the three substituents R 3Substitution is independently performed at any substitutable position of Ring B.

[0132] In one embodiment of the present application, each R in Formula I 3 are independently selected from amino, halogen, cyano, carboxyl, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 6-10 membered heteroaryl. Alternatively, each R in Formula I 3 are independently selected from amino, halogen, cyano, carboxyl, nitro, C 1-5 Alkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S, C 6-10 Aryl and 6-10 membered heteroaryl containing 1-3 N, O or S atoms.

[0133] In a specific embodiment of the present application, each R in Formula I 3 are independently selected from halogen, cyano, C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 Alkyl) and C 3-6 Cycloalkyl (e.g. C 3-5 Cycloalkyl, C 3-4 cycloalkyl).

[0134] In a more specific embodiment of the present application, each R in Formula I 3 Independently selected from fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, preferably fluorine, chlorine, bromine, cyclopropyl and cyclobutyl, more preferably chlorine and cyclopropyl.

[0135] In one embodiment of the present application, R in Formula I 4 and R 5 are independently selected from hydrogen, amino, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group. Alternatively, R in Formula I 4 and R 5 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, nitro, C 1-5 Alkyl, C 1-5 Alkoxy, C 3-6Cycloalkyl and 3-6 membered heterocyclic group containing 1-3 N, O or S atoms.

[0136] In a specific embodiment of the present application, R in Formula I 4 and R 5 are independently selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy. Alternatively, R in Formula I 4 and R 5 are independently selected from hydrogen, deuterium, tritium, amino, halogen, cyano, C 1-5 Alkyl and C 1-5 Alkoxy.

[0137] In a more specific embodiment of the present application, R in Formula I 4 and R 5 are independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy, preferably hydrogen. Alternatively, R in formula I 4 and R 5 independently selected from hydrogen, deuterium, tritium, C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 Alkyl) and C 1-5 Alkoxy (e.g. C 1-4 Alkoxy, C 1-3 alkoxy), preferably hydrogen, deuterium or tritium.

[0138] In one embodiment of the present application, X1 in Formula I is O or NR 6 .

[0139] In a specific embodiment of the present application, X1 in Formula I is O, and the structure of the compound of Formula I is as shown in Formula IA or Formula IA':

[0140]

[0141] Among them: Ring A, Ring B, m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , X2 and X3 are as defined in Formula I.

[0142] In another specific embodiment of the present application, X1 in Formula I is NR 6 , in this case, the structure of the compound of formula I is as shown in formula IB or formula IB':

[0143]

[0144] Among them: Ring A, Ring B, m, n, p, R1 , R 2 , R 3 , R 4 , R 5 , R 6 , X2 and X3 are as defined in Formula I.

[0145] In one embodiment of the present application, X2 in Formula I is N or CR 6 .

[0146] In a specific embodiment of the present application, X2 in Formula I is N.

[0147] In another specific embodiment of the present application, X2 in Formula I is CR 6 .

[0148] In one embodiment of the present application, X3 in Formula I is N or CR 6 .

[0149] In a specific embodiment of the present application, X3 in Formula I is N.

[0150] In another specific embodiment of the present application, X3 in Formula I is CR 6 .

[0151] In one embodiment of the present application, each R 6 are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted by one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl, 6-10 membered heteroaryl, =O, =CH2 and =NH. Alternatively, each R 6 independently selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, C 1-5 Alkyl, C 1-5 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-5 Alkyl, C 1-5 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each optionally independently selected from halogen, C1-5 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 The alkylene group is substituted with one or more substituents selected from aryl, 6-10 membered heteroaryl, =O, =CH2 and =NH.

[0152] In a specific embodiment of the present application, each R 6 are independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and -C(=O)R 7 , wherein the C 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, =O, =CH2 and =NH. Alternatively, each R 6 independently selected from hydrogen, deuterium, tritium, C 1-5 Alkyl, C 3-6 Cycloalkyl and -C(=O)R 7 , wherein the C 1-5 Alkyl and C 3-6 The cycloalkyl groups are each optionally independently selected from halogen, C 1-5 Alkyl, C 3-6 The alkyl group is substituted with one or more substituents selected from the group consisting of cycloalkyl, =O, =CH2 and =NH.

[0153] In a more specific embodiment of the present application, each R 6 are independently selected from hydrogen, C 1-4 Alkyl and -C(=O)R 7 , wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 cycloalkyl, =O, =CH2 and =NH. Alternatively, each R 6 independently selected from hydrogen, deuterium, tritium, C 1-5 Alkyl and -C(=O)R 7 , wherein the C 1-5 Alkyl is optionally independently selected from halogen, C 1-5 Alkyl, C 3-6 The alkyl group is substituted with one or more substituents selected from the group consisting of cycloalkyl, =O, =CH2 and =NH.

[0154] In an even more specific embodiment of the present application, each R 6 are independently selected from hydrogen, C 1-4 Alkyl and -C(=O)R 7(Or, each R 6 independently selected from hydrogen, deuterium, tritium, C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 alkyl) and -C(=O)R 7 ), preferably hydrogen, methyl, ethyl, n-propyl, isopropyl and -C(=O)R 7 , more preferably hydrogen, methyl and -C(=O)R 7 .

[0155] In one embodiment of the present application, each R 7 Independently selected from amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are each optionally substituted by one or more halogen, hydroxyl or amino groups. 7 Independently selected from amino, C 1-5 Alkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-5 Alkyl, C 1-5 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted with one or more halogen, hydroxy or amino.

[0156] In a specific embodiment of the present application, each R 7 Independently selected from amino, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are each optionally substituted with one or more halogen, hydroxyl or amino groups. 7 Independently selected from amino, C 1-5 Alkyl, C 1-5 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-5 Alkyl, C1-5 Alkoxy and C 3-6 The cycloalkyl groups are each optionally substituted with one or more halogen, hydroxy or amino groups.

[0157] In a more specific embodiment of the present application, each R 7 are independently selected from amino and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more halogen, hydroxyl or amino groups. 7 are independently selected from amino and C 1-5 Alkyl, wherein the C 1-5 The alkyl group is optionally substituted with one or more halogen, hydroxy or amino groups.

[0158] In an even more specific embodiment of the present application, each R 7 are independently selected from amino and C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 alkyl), preferably amino, methyl, ethyl, n-propyl and isopropyl, more preferably amino and methyl.

[0159] In one embodiment of the present application, m in Formula I is 0, 1 or 2.

[0160] In a specific embodiment of the present application, m in Formula I is 0, and the structure of the compound of Formula I is as shown in Formula I-1:

[0161]

[0162] Among them: Ring A, Ring B, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2 and X3 are as defined in Formula I.

[0163] In another specific embodiment of the present application, m in Formula I is 1, and the structure of the compound of Formula I is as shown in Formula I-2:

[0164]

[0165] Among them: Ring A, Ring B, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2 and X3 are as defined in Formula I.

[0166] In another specific embodiment of the present application, m in Formula I is 2, and the structure of the compound of Formula I is as shown in Formula I-3:

[0167]

[0168] Among them: Ring A, Ring B, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2 and X3 are as defined in Formula I.

[0169] In one embodiment of the present application, in the compound of formula I, formula IA, formula IA', formula IB, formula IB', formula I-1, formula I-2 or formula I-3 The fragment is Among them: Ring B, n, R 2 , R 3 , R 4 and R 5 As defined in Formula I.

[0170] In a specific embodiment of the present application, the compound of formula I, formula IA, formula IA', formula IB, formula IB', formula I-1, formula I-2 or formula I-3 The fragment is Among them: Ring B, n, R 2 and R 3 As defined in Formula I.

[0171] In a more specific embodiment of the present application, the compound of formula I, formula IA, formula IA', formula IB, formula IB', formula I-1, formula I-2 or formula I-3 The fragment is Where: n, R 2 and R 3 As defined in Formula I.

[0172] In an even more specific embodiment of the present application, in the compound of formula I, formula IA, formula IA', formula IB, formula IB', formula I-1, formula I-2 or formula I-3 The fragment is Where: R 2 and R 3 As defined in formula I; preferably, The fragment is More preferably, The fragment is Even more preferably, The fragment is

[0173] In one embodiment of the present application, heterocyclyl, heterocycloalkenyl and heteroaryl each contain 1 to 5 heteroatoms selected from N, O and S as ring atoms.

[0174] In a specific embodiment of the present application, heterocyclyl, heterocycloalkenyl and heteroaryl each contain 1 to 3 heteroatoms selected from N, O and S as ring atoms.

[0175] In a more specific embodiment of the present application, heterocyclyl, heterocycloalkenyl and heteroaryl each contain 1 or 2 heteroatoms selected from N, O and S as ring atoms, preferably each contain 1 or 2 heteroatoms selected from N and O as ring atoms.

[0176] In some specific embodiments of the present application, the compound of formula I is:

[0177]

[0178] Among them, ring A, ring B, n, p, R 1 , R 2 , R 3 , R 4 , R 5 and X1 are as defined in Formula I.

[0179] In some embodiments of the present application, the compound of formula I is:

[0180]

[0181] Wherein, the ring A is selected from C 6-10 Aryl and 6-10 membered heteroaryl containing 1-3 N (preferably ring A is phenyl and pyridyl);

[0182] Every R 3 Independently selected from halogen (preferably fluorine, chlorine);

[0183] X1 is O or NR 6 , each R 6 are independently selected from hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 alkyl) and -C(=O)R 7 , R 7 Selected from C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 alkyl).

[0184] In some embodiments of the present application, the compound of formula I is:

[0185]

[0186] Among them, each R 3 Independently selected from halogen (preferably fluorine, chlorine);

[0187] R 6 are independently selected from hydrogen, C 1-6 Alkyl (e.g. C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 alkyl) and -C(=O)R 7 , R 7 Selected from C 1-5 Alkyl (e.g. C 1-4 Alkyl, C 1-3 alkyl).

[0188] Specifically, the tetracyclic GLP-1 receptor allosteric modulators of the present application include but are not limited to the following compounds:

[0189]

[0190]

[0191] In a specific embodiment of the present application, the compound of formula I does not contain

[0192] [Drug composition]

[0193] The term "pharmaceutical composition" refers to a composition that can be used as a medicament, which comprises a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.

[0194] The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the active ingredient of the drug and is harmless to the subject, including but not limited to one or more of a diluent (or filler), a binder, a disintegrant, a lubricant, a wetting agent, a thickener, a glidant, a flavoring agent, an olfactory agent, a preservative, an antioxidant, a pH adjuster, a solvent, a cosolvent, a surfactant, a light-shielding agent (opacifying agent), etc.

[0195] The present application provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof.

[0196] In one embodiment of the present application, the above-mentioned pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0197] [Drug preparations]

[0198] The term "pharmaceutical preparation" refers to a finished drug prepared in a certain form for use by patients.

[0199] The present application provides a pharmaceutical preparation, which is made of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition. Alternatively, the present application provides a pharmaceutical preparation, which contains the compound of formula I above or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug as an active ingredient.

[0200] In one embodiment of the present application, the above-mentioned pharmaceutical preparation can be a solid preparation for oral administration, including but not limited to pharmaceutically acceptable capsules, tablets, pills, powders, granules, etc. The solid preparation can be coated or microencapsulated with a coating or shell material (such as an enteric coating or other materials known in the art). The solid preparation can contain an opacifying agent, and the active ingredient therein can be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be adopted are polymeric substances and wax substances. In addition, the active ingredient can also form a microcapsule form with one or more of the above-mentioned carriers.

[0201] In another embodiment of the present application, the above-mentioned pharmaceutical preparation may be a liquid dosage form for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.

[0202] In another embodiment of the present application, the above-mentioned pharmaceutical preparations may be dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions.

[0203] In yet another embodiment of the present application, the above-mentioned pharmaceutical preparation may be a dosage form for topical administration, including but not limited to ointments, powders, suppositories, drops, sprays, inhalants, and the like.

[0204] [Medical Use]

[0205] Whether it is the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation, it can show activity on the GLP-1 receptor. Therefore, the present application provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug, or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation in the preparation of a drug for preventing and / or treating GLP-1 related diseases.

[0206] In one embodiment of the present application, the above-mentioned GLP-1 related diseases include but are not limited to diabetes, obesity, liver disease, neurodegenerative diseases and cardiovascular diseases. In a specific embodiment of the present application, the above-mentioned GLP-1 related diseases are diabetes, especially type II diabetes. In another specific embodiment of the present application, the above-mentioned GLP-1 related diseases are obesity. In another specific embodiment of the present application, the above-mentioned GLP-1 related diseases are liver diseases, especially non-alcoholic fatty hepatitis (NASH) (or metabolic fatty liver disease, i.e. MAFLD). In another specific embodiment of the present application, the above-mentioned GLP-1 related diseases are neurodegenerative diseases, especially Parkinson's disease (PD) or Alzheimer's disease (AD). In another specific embodiment of the present application, the above-mentioned GLP-1 related diseases are cardiovascular diseases, especially atherosclerotic cardiovascular disease (ASCVD).

[0207] The present application also provides the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation, which is used for preventing and / or treating GLP-1 related diseases.

[0208] The present application also provides a method for preventing and / or treating GLP-1 related diseases, which comprises administering a preventive and / or therapeutically effective amount of the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation to an individual in need thereof.

[0209] Herein, the preventive and / or therapeutically effective amount refers to an amount sufficient to prevent, improve, inhibit, delay, or slow down the progression of GLP-1-related diseases or related symptoms, which can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, sex, weight, etc., and can be administered through conventional routes of administration in the art. For example, the compound described herein or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label, or prodrug, or the above-mentioned pharmaceutical composition, or the above-mentioned pharmaceutical preparation can be administered through parenteral, oral, subcutaneous, intravenous, intraperitoneal, and other routes.

[0210] [Combination medication]

[0211] The present application provides a drug combination form, which comprises the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation, and at least one additional GLP-1-related disease therapeutic agent.

[0212] In one embodiment of the present application, the above-mentioned compound or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug or the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation can be administered alone or in combination with other GLP-1-related disease therapeutic agents. The combined treatment can be achieved by administering different GLP-1-related disease therapeutic agents simultaneously, sequentially or separately.

[0213] The technical solutions in this application will be further described below in conjunction with specific examples. Unless otherwise specified, the reagents, materials, instruments, etc. used in the following examples can be obtained by conventional commercial means, and the experimental methods used are all conventional methods in the art.

[0214] Example 1: Preparation of Compound 1

[0215] (1) Synthesis route of compound 1-1

[0216]

[0217] Under nitrogen protection, compound 1-1a (20 g, 88.5 mmol, 1.0 eq.), potassium cyclopropyltrifluoroborate (17.03 g, 115.09 mmol, 1.3 eq.), Xantphos (5.12 g, 8.85 mmol, 0.1 eq.), potassium carbonate (36.71 g, 265.59 mmol, 3.0 eq.) and Pd(OAc)2 (0.99 g, 4.43 mmol, 0.05 eq.) were added to the reaction flask in sequence, and toluene (300 mL) and water (100 mL) were added; after the addition, the reaction was carried out at 85°C for 16 h; after the reaction was completed, the temperature was cooled to room temperature, ethyl acetate (200 mL) was added, and the organic phase was washed with 1 M hydrochloric acid (50 mL) and saturated sodium chloride aqueous solution (50 mL) in sequence, the organic phase was concentrated, and purified by silica gel column chromatography (eluent: pure petroleum ether) to obtain compound 1-1b (16 g, 96.0%).

[0218] Under nitrogen protection, diisopropylamine (16.91 g, 167.11 mmol, 2 eq.) and THF (85 mL) were added to the reaction bottle in sequence, and then the temperature was lowered to 0°C, and n-butyl lithium (1.6 M, 104 mL, 167.11 mmol, 2.0 eq.) was slowly added dropwise under temperature control; after the addition, the reaction was kept warm for 1 h, and then the temperature was lowered to -78°C, and a solution of compound 1-1b (15.54 g, 83.55 mmol, 1.0 eq.) in THF (78 mL) was slowly added dropwise; after the addition, the reaction was kept warm for 1 h. The reaction was maintained at -78°C for 1 h, and DMF (13.43 g, 183.82 mmol, 2.2 eq.) was slowly added; after the addition, the reaction was maintained at -78°C for 2 h; after the reaction was completed, saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (200 mL) was added for extraction, and the organic phase was washed with saturated aqueous sodium chloride solution (50 mL), the organic phase was spin-dried, and purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 30 / 1, v / v) to obtain compound 1-1c (13.85 g, 77.0%).

[0219] Under nitrogen protection, compound 1-1c (13.85 g, 64.72 mmol, 1.0 eq.), dichloromethane (140 mL), cesium carbonate (42.17 g, 129.44 mmol, 2.0 eq.) and S-tert-butylsulfenamide (7.84 g, 64.72 mmol, 1.0 eq.) were added to the reaction bottle in sequence; after the addition, the reaction was refluxed for 3 h; after the reaction was completed, the temperature was cooled to room temperature, the system was filtered, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 10 / 1, v / v) to obtain compound 1-1d (18.16 g, 88.5%); MS: m / z 317.8 [M+H] + .

[0220] Under nitrogen protection, compound 1-1d (18.16 g, 57.28 mmol, 1.0 eq.), copper bromide (640 mg, 2.86 mmol, 0.05 eq.) and dichloromethane (180 mL) were added to the reaction bottle in sequence. After the system was cooled to 0-5 ° C, methylmagnesium bromide (3.0 M, 28.6 mL, 85.92 mmol, 1.5 eq.) was slowly added; after the addition, the temperature was controlled to react for 2 h; after the reaction was completed, the system was quenched with saturated aqueous ammonium chloride solution (30 mL), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL), the organic phase was concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, v / v) to obtain compound 1-1e (13.64 g, 71.5%), MS: m / z 333.8 [M+H] + .

[0221] Compound 1-1e (13.64 g, 40.92 mmol, 1.0 eq.) and methanol (20 mL) were added to the reaction flask in sequence, and then the temperature was lowered to 0-5°C, and 4M hydrochloric acid dioxane solution (20 mL) was added; after the addition was completed, the reaction was continued for 30 min, the system was spin-dried, ethyl acetate (50 mL) and water (30 mL) were added to the system, the organic phase was washed once with water (30 mL), the aqueous phases were combined, the pH was adjusted to 9-10 with 1M NaOH solution, the aqueous phase was extracted with ethyl acetate (50 mL×2), and concentrated to obtain compound 1-1 (9.0 g, 96.0%); MS: m / z 229.8[M+H] + .

[0222] (2) Synthesis route of compound 1-2

[0223]

[0224] Under nitrogen protection, compound 1-2a (22 g, 96 mmol, 1.0 eq.) and THF (330 mL) were added to the reaction bottle. After cooling to -78°C, LiHMDS (1 M, 124 mL, 125 mmol, 1.3 eq.) was slowly added; after the addition was completed, the reaction was kept warm for 1 h, and then iodomethane (7.7 mL, 120 mmol, 1.25 eq.) was slowly added dropwise; after the addition was completed, the temperature was raised to -20°C and the reaction was carried out for 1 h; the system was quenched with saturated aqueous ammonium chloride solution (30 mL), the organic phase was washed with saturated aqueous sodium chloride solution (30 mL), the organic phase was concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 10 / 1, v / v) to obtain compound 1-2b (21.9 g, 93.8%).

[0225] Under nitrogen protection, compound 1-2b (1.55 g, 6.38 mmol, 1.0 eq.), bipyralidin (2.43 g, 9.57 mmol, 1.5 eq.), Pd(dppf)Cl2 (260 mg, 0.32 mmol, 0.05 eq.), KOAc (1.25 g, 12.7 mmol, 2.0 eq.) and 1,4-dioxane (16 mL) were added to the reaction bottle in sequence, and then heated to 90 ° C for 6 h; after the reaction was completed, ethyl acetate (30 mL) was added to the system, the organic phase was concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 10 / 1, v / v) to obtain compound 1-2 (1.46 g, 78.6%); MS: m / z 290.8 [M+H] + .

[0226] (3) Synthesis route of compound 1

[0227]

[0228] Compound 1a (500.0 mg, 1.89 mmol, 1.0 eq.), tetrahydrofuran (10 mL), compound 1-1 (519.8 mg, 2.27 mmol, 1.2 eq.) and triethylamine (270.7 mg, 5.68 mmol, 3.0 eq.) were added to the reaction bottle and reacted at room temperature for 3 h. After the reaction was completed, the system was quenched with water (10 mL), extracted three times with ethyl acetate (40 mL), the organic phases were combined, washed with water (50 mL), and then washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1, v / v) to obtain compound 1b (0.85 g, 94.9%); MS: m / z 474.0 [M+H] + .

[0229] Compound 1b (500.0 mg, 1.06 mmol, 1.0 eq.), acetic acid (2 mL) and triethyl orthoformate (10 mL) were added to the reaction flask, heated to 80°C for reaction for 10 min, iron powder (455.9 mg, 8.14 mmol, 7.7 eq.) was added, and the temperature was raised to 90°C for reaction for 10 h; the system was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed twice with ethyl acetate (10 mL); water was added to the mother liquor, adjusted to a weak base with saturated sodium carbonate solution, and extracted three times with ethyl acetate (40 mL); the organic phase was washed with water (50 mL), then with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, spin-dried, and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, v / v) to obtain compound 1c (360 mg, 75.2%); MS: m / z 454.0 [M+H] + .

[0230] Compound 1c (360.0 mg, 0.79 mmol, 1.0 eq.), ethanol (10 mL) and stannous chloride (898.8 mg, 4.74 mmol, 6.0 eq.) were added to the reaction bottle and heated to 80°C for 4 h; the system was spin-dried, ethyl acetate (20 mL) was added to dissolve, saturated sodium carbonate aqueous solution was used to adjust to weak base, and filtered through diatomaceous earth; the mother liquor was separated, the organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain compound 1d (280 mg, 83.3%); MS: m / z 424.0 [M+H] + .

[0231] Under nitrogen protection, compound 1d (100.0 mg, 0.24 mmol, 1.0 eq.), compound 1-2 (137.2 mg, 0.48 mmol, 2.0 eq.), Pd(PPh3)4 (40.9 mg, 0.035 mmol, 0.15 eq.), sodium carbonate (75.2 mg, 0.71 mmol, 3.0 eq.), dioxane (3 mL) and water (1 mL) were added to the reaction bottle, and microwave heating was performed at 100 ° C for 2 h; water (10 mL) was added to the system, and then ethyl acetate (20 mL) was added for extraction three times; the organic phase was washed with water (20 mL), then washed with a saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, spin-dried, and chromatographed on a reversed-phase silica gel column (Shim-pack GIS C 18 20*250mm, 5μm; 0.01% formic acid-water / acetonitrile) to obtain compound 1 (2.93mg, 2.6%); MS: m / z 476.1[M+H] + .

[0232] Example 2: Preparation of Compound 2

[0233] (1) Synthesis route of compound 2-1

[0234]

[0235] Under nitrogen protection, compound 2-1a (500 mg, 2.17 mmol, 1.0 eq.), bipyralidin (830 mg, 3.26 mmol, 1.5 eq.), Pd(dppf)Cl2 (78.7 mg, 0.11 mmol, 0.05 eq.), KOAc (426 mg, 4.34 mmol, 2.0 eq.) and 1,4-dioxane (5 mL) were added to the reaction bottle in sequence, and then heated to 90 ° C for 6 h; after the reaction was completed, ethyl acetate (30 mL) was added to the system, the organic phase was concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / dichloromethane = 10 / 1, v / v) to obtain compound 2-1 (120 mg, 20%); MS: m / z 278.1 [M+H] + .

[0236] (2) Synthesis route of compound 2

[0237]

[0238] The synthesis method was similar to that of compound 1 in Example 1, except that compound 1-2 was replaced by compound 2-1, to obtain compound 2 (white solid, 1.70 mg, 6.5%); MS: m / z 463.1 [M+H] + .

[0239] Example 3: Preparation of Compound 3

[0240] (1) Synthesis route of compound 3-1

[0241]

[0242] Compound 3-1a (0.5 g, 1.0 eq.) was weighed and placed in a round-bottom flask, and dichloromethane (5.0 mL) and DIPEA (1.2 eq.) were added in sequence. The reaction system was cooled to -10°C-0°C, and trifluoromethanesulfonic anhydride (1.0 eq.) was added dropwise to the above reaction system, and stirring was continued overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added, and the organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude compound 3-1b, which was purified by silica gel column chromatography to obtain compound 3-1b (0.6 g, 65.4%).

[0243] Under nitrogen protection, compound 3-1b (500 mg, 1.0 eq.), bipyralidin (1.5 eq.), Pd(dppf)Cl2 (0.05 eq.), KOAc (2.0 eq.) and 1,4-dioxane (5 mL) were added to the reaction bottle in sequence, and then heated to 90 ° C for 6 h; after the reaction, ethyl acetate (30 mL) was added to the system, the organic phase was concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1, v / v) to obtain compound 3-1 (300 mg, 64.9%); MS: m / z 269.1 [M+H] + .

[0244] (2) Synthesis route of compound 3

[0245]

[0246] The synthesis method was similar to that of compound 1 in Example 1, except that compound 1-2 was replaced by compound 3-1, to obtain compound 3 (white solid, 4.87 mg, 20.1%). MS: m / z 454.1 [M+H] + .

[0247] Example 4: Preparation of Compound 4

[0248]

[0249] The synthesis method was similar to that of compound 1 in Example 1, except that compound 1-2 was replaced by compound 4-1, to obtain compound 4 (white solid, 33.7 mg, 39.9%). MS: m / z 447.1 [M+H] + .

[0250] Example 5: Preparation of Compound 5

[0251]

[0252] The synthesis method was similar to that of compound 1 in Example 1, except that compound 1-2 was replaced by compound 5a, to obtain compound 5 (white solid, 20.5 mg, 51.2%). MS: m / z 461.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.13(s,1H),8.06(s,1H),7.82-7.80(m,1H),7.68-7.57(m,2H),7.47-7.38(m,2H),7.35-7.33(m,1H),7.2 7-7.24(m,1H),6.89(q,J=7.0Hz,1H),3.61(s,2H),2.33(d,J=7.0Hz,3H),2.20-2.09(m,1H),1.09-0.93(m,2H),0.67-0.65(m,2H).

[0253] Example 6: Preparation of Compound 6

[0254]

[0255] Compound 5 (20 mg, 1.0 eq.), triethylamine (3.0 eq.) and dichloromethane (2 mL) were added to the reaction flask, and the mixture was cooled to 0°C in an ice-water bath, and acetyl chloride (1.5 eq.) was slowly added dropwise. After the addition was complete, the reaction was allowed to react for 4 h. After the reaction was complete, the reaction system was directly concentrated to obtain a crude product, which was purified by silica gel thin layer chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain compound 6 (15.0 mg, 68.7%); MS: m / z 503.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.13(s,1H),8.06(s,1H),7.80-7.7.78(m,1H),7.68-7.57(m,2H),7.46-7.37(m,2H),7.35-7.33(m,1H),7.27-7. 24(m,1H),6.89(q,J=7.0Hz,1H),3.62(s,2H),2.33(d,J=7.0Hz,3H),2.25(s,3H),2.20-2.09(m,1H),1.09-0.93(m,2H),0.67-0.65(m,2H).

[0256] Example 7: Preparation of Compound 7

[0257]

[0258] Compound 5 (20 mg, 1.0 eq.), triethylamine (3.0 eq.), iodomethane (2.0 eq.) and dichloromethane (2 mL) were added to the reaction flask, and the temperature was raised to 60 ° C for 6 h; after the reaction was completed, the reaction system was directly concentrated to obtain a crude product, which was purified by silica gel thin layer chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain compound 7 (13 mg, 63.1%); MS: m / z 475.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.13(s,1H),8.06(s,1H),7.80-7.7.78(m,1H),7.68-7.57(m,2H),7.46-7.37(m,2H),7.35-7.33(m,1H),7.27-7. 24(m,1H),6.89(q,J=7.0Hz,1H),3.62(s,2H),3.31(s,3H),2.33(d,J=7.0Hz,3H),2.20-2.09(m,1H),1.09-0.93(m,2H),0.67-0.65(m,2H).

[0259] Example 8: Preparation of Compound 8

[0260]

[0261] Under nitrogen protection, compound 5 (50.0 mg, 1.0 eq.), DIPEA (N,N-diisopropylethylamine) (3.0 eq.), CDI (carbonyldiimidazole) (1.0 eq.) and DMF (N,N-dimethylformamide, 2 mL) were added to the reaction bottle and reacted at room temperature for 1 h. After the reaction was completed, a DMF solution of compound 8a was obtained, which was directly carried out to the next step without purification.

[0262] Ammonia water (5.0 eq.) was added to the reaction system, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the reaction solution was poured into water. The mixed solution was extracted three times with dichloromethane, and the organic phase was washed five times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol=10 / 1, v / v) to obtain compound 8 (10.2 mg, total yield of two steps 18.3%); MS: m / z 504.1 [M+H] + .

[0263] Example 9: Preparation of Compound 9

[0264]

[0265] The fuming nitric acid was cooled to -10°C, compound 5a (2.0 g, 1.0 eq.) was added, and the reaction was continued at this temperature until compound 5a was completely consumed; water was added to quench the reaction, the pH was adjusted to neutral with potassium hydroxide, and then extracted with dichloromethane (100 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate=10 / 1, v / v) to obtain compound 9a (0.8 g, 33.7%); MS: m / z 289.1[M+H] + .

[0266] Synthesis method: Refer to the preparation of compound 1 in Example 1 to obtain compound 9b (208 mg, 40.3%); MS: m / z 506.1 [M+H] + .

[0267] The synthesis method was referred to Example 6 to obtain compound 9c (80 mg, 72.6%); MS: m / z 548.1 [M+H] + .

[0268] Compound 9c (80 mg, 1.0 eq.) was dissolved in a mixed solution of ethanol and water (3 mL ethanol and 1 mL water), and ammonium chloride (55.3 mg, 7.0 eq.) and iron powder (65.5 mg, 5.0 eq.) were added in sequence, and the mixture was heated to 85°C and refluxed for 3 h. After the reaction, the reaction solution was filtered while hot, concentrated under reduced pressure, extracted with dichloromethane (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel thin layer chromatography (eluent: dichloromethane / methanol=15 / 1, v / v) to obtain compound 9 (31.0 mg, 39.7%); MS: m / z 518.1[M+H] + .

[0269] Example 10: Preparation of Compound 10

[0270]

[0271] Compound 10a (2.0 g, 1.0 eq.) and tetrahydropyrrole (1.1 eq.) were dissolved in toluene (20 mL) and heated under reflux until compound 10a was completely consumed. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude compound 10b, which was directly used for the next step without purification. MS: m / z 154.1 [M+H] + .

[0272] Under nitrogen protection, the crude compound 10b (2.9 g, 1.0 eq.) was dissolved in anhydrous 1,4-dioxane, and then chloroacetonitrile (1.5 eq.) was added at once with a syringe, and the temperature was raised to 110°C and refluxed until the compound 10b was completely converted; after cooling, water was added and the reflux was continued for 30-60 min; after cooling to room temperature, it was concentrated under reduced pressure, and ethyl acetate (100 mL) and 2N hydrochloric acid (20 mL) were added to the obtained residue, and the aqueous phase was extracted four times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1, v / v) to obtain compound 10c (0.8 g, 28.8%); MS: m / z 140.0 [M+H] + .

[0273] The synthesis method was based on the synthesis route of compound 3-1 in Example 3 to obtain compound 10d (0.8 g, 51.3%); MS: m / z 272.0 [M+H] + and compound 10e (0.6 g, 81.6%); MS: m / z 250.1 [M+H] + .

[0274] The synthesis method was similar to that of compound 1 in Example 1 to obtain compound 10f (50 mg, 41.3%); MS: m / z 467.1 [M+H] + .

[0275] The synthesis method was referred to Example 6 to obtain compound 10 (30 mg, 55.0%); MS: m / z 509.1 [M+H] + .

[0276] Example 11: Preparation of Compound 11

[0277]

[0278] Except that compound 11a (cyclohexanone) was used to replace compound 10a (tetrahydropyran-4-one), other conditions were the same as those in Example 10 to obtain compound 11 (42 mg, 65.3%); MS: m / z 507.2 [M+H] + .

[0279] Example 12: Preparation of Compound 12

[0280]

[0281] Except that compound 12a (N-methylpiperidin-4-one) was used to replace compound 10a (tetrahydropyran-4-one), other conditions were the same as those in Example 10 to obtain compound 12 (36 mg, 58.2%); MS: m / z 522.2 [M+H]+ .

[0282] Experimental Example 1: Activity test of GLP-1 receptor allosteric modulators

[0283] In Flp-In-293-Human GLP-1R cells that stably overexpress the GLP-1 receptor, the cyclic adenosine monophosphate (cAMP) content was detected by homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) method to determine the activity of GLP-1 receptor allosteric modulators. The EC of GLP-1(7-36) 50 The value is approximately 200,000 times that of GLP-1(9-36)NH2. When the screening analysis was performed, all compounds were within the EC value of the orthosteric ligand GLP-1(9–36). 20 The test was performed at 1000 nM concentration to better evaluate the putative allosteric activity. The highest concentration of the test compound was 1000 nM, and a 4-fold gradient dilution was performed step by step, with a total of 10 points.

[0284] 1.1 Experimental Materials

[0285] 1.1.1 Reagents and consumables

[0286]

[0287] 1.1.2 Instruments

[0288] EnVision multi-function microplate reader (manufacturer: Perkin Elmer, model: 2105).

[0289] 1.2 Experimental process

[0290] 1.2.1 Cell culture and reagent preparation

[0291] 1) Cell line: Flp-In-293-Human GLP1R;

[0292] 2) Complete culture medium: DMEM + 10% fetal bovine serum + 1X penicillin-streptomycin + 200 μg / mL hygromycin;

[0293] 3) Experimental buffer: 1X HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX;

[0294] 1.2.2 Determination of the activity of test compounds on Human GLP1R

[0295] 1) Dissolve the test compound in DMSO to prepare a 10 mM stock solution;

[0296] 2) Digest the cells, resuspend them in the experimental buffer, and inoculate them into 384 cell culture plates at a density of 2000 cells / well and an inoculation volume of 15 μL / well;

[0297] 3) The stock solution of the test compound was diluted 25-fold with DMSO, then diluted 4-fold (starting concentration was 400 μM), and then diluted 100-fold with experimental buffer (the test compound wells contained 240 nM GLP-1 (9-36), and the positive control wells did not contain 240 nM GLP-1 (9-36)) to obtain the test compound dilution solution;

[0298] 4) Add 5 μL of the test compound dilution in step 3) to each well and incubate at 37°C for 30 min;

[0299] 5) Freeze-thaw Eu-cAMP tracer and Ulight-anti-cAMP, and dilute them with the lysis buffer in the cAMP kit;

[0300] 6) Add 10 μL of diluted Eu-cAMP tracer to the experimental wells, and then add 10 μL of diluted Ulight-anti-cAMP to the experimental wells;

[0301] 7) The reaction plate in step 6) was centrifuged at 200 g for 30 seconds at room temperature, allowed to stand at 25° C. for 1 hour, and then data was collected using EnVision.

[0302] 1.3 Data Analysis

[0303] 1.3.1 Activity % calculation formula

[0304] Activity% = 100-(Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC )×100;

[0305] Among them: Signal cmpd Indicates the signal value of the test compound well; Signal Ave_PC Signal represents the average signal of the negative control well (no drug was added but only the solvent DMSO was added); Ave_VC It represents the average signal of the positive control wells, i.e. 0.1 nM GLP-1 (7-37).

[0306] 1.3.2 Calculation of EC of compounds using GraphPad nonlinear fitting formula 50

[0307] The log value of compound concentration was used as the X-axis and Activity% as the Y-axis. The log(agonist) vs. response-Variable slop of the analysis software GraphPad was used to fit the dose-effect relationship, thereby obtaining the allosteric regulatory activity of each compound on the GLP-1 receptor.

[0308] Fitting formula: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope));

[0309] Among them: Top represents the activity percentage at the top platform, and the Top of the curve is generally between 80% and 120%; Bottom represents the activity percentage at the bottom platform, and the Bottom of the curve is generally between -20% and 20%, and HillSlope represents the slope of the activity percentage curve.

[0310] 1.4 In vitro activity test results (EC 50 As shown in Table 1)

[0311] Table 1. Results of the allosteric regulation of the compounds of the present application on the GLP-1 receptor

[0312] Compound <![CDATA[EC 50 (nM)]]> 1 83.1 2 34.4 5 14.9 6 2.5 7 39.5

[0313] As can be seen from Table 1, the compounds of the present application have excellent in vitro agonist activity on the GLP-1 receptor, making it possible to be used as a small molecule GLP-1 receptor allosteric modulator, which has the effects of reducing fasting and postprandial glucose and improving diabetes (such as type II diabetes), obesity, liver diseases (such as non-alcoholic fatty hepatitis), neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease) and cardiovascular diseases (such as atherosclerotic cardiovascular disease).

[0314] Although the present application has been described by way of specific examples above, it should not be construed as being limited thereto, but rather the present application encompasses the general aspects previously disclosed and may be modified and have various embodiments without departing from the spirit and scope of the present application.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, in: Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl, C 5-8 Cycloalkenyl and 5-8 membered heterocycloalkenyl; Ring B is selected from C 6-10 Aryl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl; If present, each R 1 are independently selected from hydrogen, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino; R 2 is selected from hydrogen, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino; Every R 3 are independently selected from hydrogen, amino, halogen, cyano, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl and 5-10 membered heteroaryl groups are each optionally substituted with one or more substituents; if present, each of the substituents is independently selected from hydroxy, amino, =O, =S, =NH, halogen, carboxyl, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)-C 1-6 Alkyl and -C(=O)OC 1-6 alkyl; R 4 and R 5 are independently selected from hydrogen, amino, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic group; X1 is O or NR 6 ; X2 is N or CR 6 ; X3 is N or CR 6 ; If present, each R 6 are independently selected from hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, =CH2 and =NH; If present, each R 7 Independently selected from amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino; m is 0, 1, 2 or 3; n is 1, 2, 3, 4 or 5; p is 0, 1, 2 or 3; The heterocyclyl, heterocycloalkenyl and heteroaryl groups each contain one or more heteroatoms selected from N, O and S as ring atoms.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Ring A is selected from C 6-10 Aryl, 6-10 membered heteroaryl, C 6-8 Cycloalkenyl and 6-8 membered heterocycloalkenyl; Preferably, ring A is C 6-10 Aryl, preferably phenyl and naphthyl, more preferably phenyl; or Preferably, ring A is a 6-10 membered heteroaryl group, preferably pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, more preferably pyridinyl; or, Preferably, ring A is C 6-8 Cycloalkenyl, preferably cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptatrienyl, more preferably cyclohexenyl; or, Preferably, ring A is a 6-8 membered heterocycloalkenyl group, preferably a dihydropyridyl group, a tetrahydropyridyl group, a pyranyl group and a dihydropyranyl group, more preferably a tetrahydropyridyl group and a dihydropyranyl group.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: p is 0, 1, or 2; Preferably, p is 0; or, Preferably, p is 1; and / or n is 1, 2 or 3; Preferably, n is 3.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: If present, each R 1 are independently selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; Preferably, each R 1 independently selected from hydrogen, amino, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; More preferably, each R 1 are independently selected from amino and C 1-4 As the alkyl group, amino, methyl, ethyl, n-propyl and isopropyl are preferred, and amino and methyl are more preferred.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 2 Selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; Preferably, R 2 Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl; More preferably, R 2 Selected from C 1-4 The alkyl group is preferably a methyl group, an ethyl group, a n-propyl group and an isopropyl group, and more preferably a methyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Ring B is selected from C 6-10 Aryl, 6-10 membered heteroaryl and 6-8 membered heterocyclyl; Preferably, ring B is C 6-10 Aryl; More preferably, ring B is selected from phenyl and naphthyl, preferably phenyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: Every R 3 are independently selected from amino, halogen, cyano, carboxyl, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 6-10 membered heteroaryl; Preferably, each R 3 are independently selected from halogen, cyano, C 1-4 Alkyl and C 3-6 Cycloalkyl; More preferably, each R 3 Independently selected from fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, preferably fluorine, chlorine, bromine, cyclopropyl and cyclobutyl, more preferably chlorine and cyclopropyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: R 4 and R 5 are independently selected from hydrogen, amino, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group; Preferably, R 4 and R 5 are independently selected from hydrogen, amino, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy; More preferably, R 4 and R 5 are independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy, preferably hydrogen.

9. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The structure of the compound is shown in Formula IA or Formula IA': Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , X2, X3, m, n and p are as defined in claim 1; Alternatively, the structure of the compound is as shown in Formula IB or Formula IB': Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X2, X3, m, n and p are as defined in claim 1.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: X2 is N or CR 6 ; Preferably, X2 is N.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: X3 is N or CR 6 ; Preferably, X3 is N.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: If present, each R 6 are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C(=O)R 7 , wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted by one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, 6-10 membered heteroaryl, =O, =CH2 and =NH; Preferably, each R 6 are independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl and -C(=O)R 7 , wherein the C 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted with one or more substituents; if present, each of said substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, =O, =CH2 and =NH; More preferably, each R 6 are independently selected from hydrogen, C 1-4 Alkyl and -C(=O)R 7 , wherein the C 1-4 The alkyl group is optionally substituted with one or more substituents; if present, each of the substituents is independently selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, =O, =CH2 and =NH; Further preferably, each R 6 are independently selected from hydrogen, C 1-4 Alkyl and -C(=O)R 7 , preferably hydrogen, methyl, ethyl, n-propyl, isopropyl and -C(=O)R 7 , more preferably hydrogen, methyl and -C(=O)R 7 .

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: If present, each R 7 Independently selected from amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are each optionally substituted by one or more halogen, hydroxyl or amino; Preferably, each R 7 Independently selected from amino, C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, wherein the C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 The cycloalkyl groups are each optionally substituted with one or more halogen, hydroxy or amino groups; More preferably, each R 7 are independently selected from amino and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with one or more halogen, hydroxy or amino groups; Further preferably, each R 7 are independently selected from amino and C 1-4 As the alkyl group, amino, methyl, ethyl, n-propyl and isopropyl are preferred, and amino and methyl are more preferred.

14. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The structure of the compound is shown in Formula I-1: Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2, X3, n and p are as defined in claim 1; Alternatively, the structure of the compound is as shown in Formula I-2: Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2, X3, n and p are as defined in claim 1; Alternatively, the structure of the compound is as shown in Formula I-3: Among them, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , X1, X2, X3, n and p are as defined in claim 1.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The fragment is Best Preferably, The fragment is Best More preferred More preferably, The fragment is Best 16. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein: The compound of formula I is: Preferably, the compound of formula I is: Wherein, the ring A is selected from C 6-10 Aryl and 6-10 membered heteroaryl containing 1-3 N; Every R 3 independently selected from halogen; X1 is O or NR 6 , each R 6 are independently selected from hydrogen, C 1-6 Alkyl and -C(=O)R 7 , R 7 Selected from C 1-5 alkyl; More preferably, the compound of formula I is: Among them, each R 3 independently selected from halogen; R 6 are independently selected from hydrogen, C 1-6 Alkyl and -C(=O)R 7 , R 7 Selected from C 1-5 alkyl.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof, wherein the compound is selected from:

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug thereof; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

19. A pharmaceutical preparation, which is made of the compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the pharmaceutical composition according to claim 18; Preferably, the pharmaceutical preparation is a solid preparation or a liquid dosage form for oral administration, or a dosage form for parenteral injection, or a dosage form for topical administration.

20. Use of the compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled substance or prodrug, or the pharmaceutical composition according to claim 18, or the pharmaceutical preparation according to claim 19 in the preparation of a medicament for preventing and / or treating a GLP-1-related disease; Preferably, the GLP-1 related diseases include diabetes, obesity, liver disease, neurodegenerative disease and cardiovascular disease; More preferably, the diabetes is type II diabetes; or, More preferably, the liver disease is non-alcoholic steatohepatitis; or, More preferably, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease; or, More preferably, the cardiovascular disease is atherosclerotic cardiovascular disease.

21. A pharmaceutical combination comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-labeled form or prodrug thereof, or a pharmaceutical composition according to claim 18, or a pharmaceutical preparation according to claim 19, and at least one additional therapeutic agent for a GLP-1-related disease.

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