Nitrogen-containing fused ring compound, and preparation method therefor and use thereof

Abstract

A nitrogen-containing fused ring compound as a GLP-1 receptor agonist, and a preparation method therefor and the use thereof. Specifically, provided are a compound as represented by formula (I), and the use thereof in the preparation of a drug for treating or preventing diseases mediated by GLP-1.

Description

A nitrogen-containing cyclic compound and its preparation method and use Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a nitrogen-containing cyclic compound as a GLP-1 receptor agonist and a preparation method thereof, as well as use of the compound in preparing a drug for treating or preventing GLP-1-mediated diseases. Background Art

[0002] The glucagon-like peptide-1 receptor (GLP-1R) is one of the most important therapeutic targets for type 2 diabetes. It is secreted by intestinal epithelial L cells and exerts its physiological effects by binding to its receptor. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation. In nonclinical trials, GLP-1 has been shown to promote β-cell sustainability by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell regeneration. In healthy individuals, GLP-1 plays a key role in regulating postprandial blood flow, increasing peripheral glucose absorption by stimulating glucose-dependent insulin secretion from the pancreas. GLP-1 also inhibits glucagon secretion, resulting in reduced hepatic glucose output. Furthermore, GLP-1 delays gastric emptying, slows small intestinal motility, and slows food absorption, thereby contributing to weight loss. Furthermore, GLP-1 has unique cardiovascular benefits.

[0003] GLP-1 receptor agonist-based peptide drugs such as liraglutide, exenatide, and semaglutide have been used in obese patients with type 2 diabetes, as well as those who are simply obese or overweight. They have shown significant weight loss effects, but are often accompanied by gastrointestinal adverse reactions such as nausea and vomiting. At the same time, patient compliance with peptide injection products is poor, while oral peptide drugs have low bioavailability, strict dosing procedures, high prices, and a high rate of gastrointestinal reactions. As a highly promising drug, most GLP-1 receptor agonists on the market are currently administered by injection. Therefore, the development of oral small-molecule GLP-1 receptor agonists can improve patient compliance and is the future development trend of GLP-1 receptor agonists.

[0004] Summary of the Invention

[0005] The present invention aims to provide a novel GLP-1 receptor agonist, a method for its preparation, a pharmaceutical composition containing the same, and its use in medicine. In particular, the present invention can be widely used in the preparation of drugs for treating or preventing GLP-1-mediated diseases, and is expected to be developed into a new generation of GLP-1 receptor agonists. Specifically, the present invention provides the following technical solutions:

[0006] One invention of the present invention provides a compound of formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts thereof,

[0007] in,

[0008] Ring A is selected from 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl;

[0009] X is selected from a bond, -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -, provided that, when X is selected from a bond, Z1 is selected from the following groups:

[0010] T1 and T2 are each independently selected from N and C, and at least one of T1 and T2 is N;

[0011] T3 and T4 are each independently selected from N and CH;

[0012] R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 14 R 15 The above groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15and -N(R 14 )-C(O)R 13 The above groups are optionally further substituted by one or more substituents selected from halogen, hydroxyl and C 1-6 substituted by an alkyl substituent;

[0013] R2 is selected from hydrogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy and -NR 14 R 15 ;

[0014] R3 and R4 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R3 and R4 together with the carbon atom to which they are directly attached form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from hydrogen, halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6 substituted by an alkyl substituent;

[0015] R5 is selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl being optionally further substituted by one or more selected from halogen and C 1-6 substituted by an alkyl substituent;

[0016] R6 is selected from hydrogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy and halogen substituted C 1-6 alkoxy;

[0017] R7 is selected from cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-6 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1- 6-alkyl substituted 3-6 membered heterocyclic group;

[0018] R8 and R9 are each independently selected from hydrogen, C 1-6 Alkyl, or, R8, R9 and the carbon atom to which they are directly connected together form a C 3-6 Cycloalkyl;

[0019] R10 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0020] R 11 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, or R1, R 11 Together with the carbon atom to which it is directly attached, it forms C 3-6 heterocyclic group;

[0021] Each R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, fluorine, chlorine, hydroxyl, oxo, cyano, C 1-4 Alkyl and C 1-4 substituted by an alkoxy substituent;

[0022] Z1 is selected from 5-10 membered heteroaryl, the above groups are optionally further substituted by one or more selected from halogen, =O and C 1-6 substituted by an alkyl substituent;

[0023] Z2 is selected from C 6-8 Aryl and 5-10 membered heteroaryl, the above groups are optionally further substituted by one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -P(O)R 14 R 15 、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 substituted by a substituent;

[0024] Each R 13 , each R 14 and each R 15 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogen, cyano, halogen, C 1-6 Alkyl and C 1-6substituted by an alkyl substituent;

[0025] n is selected from 0, 1, 2, 3 or 4.

[0026] As a preferred embodiment, the compound is selected from the following formula:

[0027] X is selected from -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -;

[0028] Ring A, R1, R2, R3, R4, R5, R6, R7, Z1, Z2 and n are as defined above.

[0029] As a preferred embodiment, Z1 is selected from the following groups:

[0030] As a preferred embodiment, the compound is selected from the following formula:

[0031] Ring A, R1, R7, Z2 and n are as defined above; X is selected from -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -.

[0032] As a preferred embodiment, the compound is selected from the following formula:

[0033] R1, R7, Z2 and n are as defined above; X is selected from -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -.

[0034] As a preferred embodiment, the compound is selected from the following formula:

[0035] R1 is as defined above; X is selected from -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11-、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -.

[0036] As a preferred embodiment, the compound is selected from the following formula:

[0037] R1 is as defined above; X is selected from -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -.

[0038] As a preferred embodiment, the compound is selected from the following formula:

[0039] R1, R8, R9, R 10 and R 11 As defined above.

[0040] As a further preferred embodiment, in formula (IV-1), R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0041] Preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl and 3-8 membered heterocyclic groups, and the above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0042] As a further preferred embodiment, R8 and R9 are each independently selected from hydrogen, methyl, ethyl, propyl and isopropyl, or R8, R9 together with the carbon atom to which they are directly attached form cyclopropyl, cyclobutyl and cyclopentyl;

[0043] R 10 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl;

[0044] R 11 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl and cyclopentyl, or R1, R 11 Together with the phosphorus atom to which it is directly connected, it forms

[0045] As a preferred embodiment, the compound is selected from the following formula:

[0046] Z1 is selected from

[0047] R1, R2, R3, R4, R5, R6, R7, Z2, ring A and n are as defined above.

[0048] As a preferred embodiment, the compound is selected from the following formula:

[0049] R2, R3, R4, R5, R6, R7, Z2 and n are as defined above; Z1 is as defined for compound (IB).

[0050] As a preferred embodiment, the compound is selected from the following formula:

[0051] R7, Z1, Z2 and n are as defined above.

[0052] As a preferred embodiment, the compound is selected from the following formula:

[0053] R7, Z2 and n are as defined above.

[0054] As a preferred embodiment, the compound is selected from the following formula:

[0055] R7, Z2 and n are as defined above.

[0056] As a further preferred embodiment, in formula (II-B), formula (II'-B), formula (III-B), and formula (III'-B),

[0057] R7 is selected from cyano, fluoro, chloro, bromo, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy;

[0058] Z1 is selected from

[0059] Z2 is selected from phenyl and which are optionally further substituted by one or more groups selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR 14 R15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 substituted by a substituent;

[0060] Each R 13 , each R 14 and each R 15 are each independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0061] Preferably, R7 is selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy;

[0062] Z1 is selected from

[0063] Z2 is selected from which is optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, and trifluoroethoxy;

[0064] Alternatively, Z2 is selected from phenyl, which is optionally further substituted by one or more selected from -C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 、-NR 14 R 15 , fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy substituents; each R 13 , each R 14 and each R 15 are each independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0065] n is selected from 1, 2, 3 and 4.

[0066] As a preferred embodiment, the compound is selected from the following formula:

[0067] R1, R7, Z1, Z2 and n are as defined above.

[0068] As a preferred embodiment, the compound is selected from the following formula:

[0069] R1 and Z1 are as defined above.

[0070] As a preferred embodiment, the compound is selected from the following formula:

[0071] R1 and Z1 are as defined above.

[0072] As a further preferred embodiment, in formula (III-C), formula (III-C1), and formula (III'-C1),

[0073] R1 is selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, the above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-6 substituted by a cycloalkyl substituent;

[0074] R7 is selected from cyano, fluoro, chloro, bromo, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy;

[0075] X is selected from a bond, -O-;

[0076] When X is a bond,

[0077] Z1 is selected from

[0078] When X is -O-, Z1 is

[0079] Z2 is selected from which is optionally further substituted with one or more substituents selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0080] Preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and The above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0081] R7 is selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy;

[0082] X is selected from a bond, -O-;

[0083] When X is a bond,

[0084] Z1 is selected from

[0085] When X is -O-, Z1 is

[0086] Z2 is selected from which is optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, and trifluoroethoxy;

[0087] n is selected from 1, 2, 3 and 4;

[0088] More preferably, R1 is selected from The above groups are optionally further substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0089] R7 is selected from fluoro, chloro, bromo, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy;

[0090] X is a bond, Z1 is selected from

[0091] Z2 is selected from It is optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy and trifluoroethoxy.

[0092] As a preferred embodiment, R2 is selected from hydrogen, cyano, amino, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, azetidinyl and methylamino;

[0093] R3 and R4 together with the carbon atom to which they are directly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally further substituted with one or more substituents selected from methyl, ethyl and isopropyl;

[0094] R5 is selected from the following groups:

[0095] R6 is selected from methyl, ethyl and isopropyl.

[0096] As a preferred embodiment, the compound is selected from the following formula:

[0097] in,

[0098] Each of Ra, Rb, Rc, and Rd is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 ;

[0099] Preferably, in formula IV-a,

[0100] Rb and Rd are hydrogen;

[0101] Ra and Rc are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 alkoxy;

[0102] In formula IV-b,

[0103] Ra is selected from hydrogen, cyano, -C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 ;

[0104] Rb, Rc are each independently selected from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkoxy;

[0105] Each R 13 , each R 14 and each R 15are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl;

[0106] More preferably, each of Ra, Rb, Rc, and Rd is independently the corresponding group in compound 9-25.

[0107] As a preferred embodiment, ring A is selected from C 6-8 Aryl and 5-6 membered heteroaryl; preferably, ring A is selected from phenyl, pyridyl and pyrimidinyl.

[0108] As a preferred embodiment, Z2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups:

[0109] The above groups are optionally further substituted by one or more selected from cyano, nitro, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -P(O)R 14 R 15 、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 substituted by a substituent.

[0110] As a preferred embodiment, R7 is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or is selected from the following groups:

[0111] and / or, Z2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups:

[0112] The above groups are optionally further substituted by one or more groups selected from cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -P(O)R 14 R 15、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and -NR 14 R 15 substituted by a substituent;

[0113] Each R 13 , each R 14 and each R 15 Each is independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and bicyclo[1,1,1]pentanyl, and the above groups are optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl.

[0114] As a preferred embodiment, R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, amino, phenyl, 3-8 membered heterocyclic and 5-6 membered heteroaryl, the above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and =O, and the above groups are optionally further substituted with one or more substituents selected from halogen, hydroxyl and C 1-6 substituted by an alkyl substituent;

[0115] As a further preferred embodiment, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, pyrimidinyl, thienyl, furyl and 3-8 membered heterocyclic groups, and the above groups are optionally further substituted by one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents are cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl and =O, and the above groups are optionally further substituted with one or more substituents selected from halogen, hydroxyl, C 1-6 substituted by an alkyl substituent.

[0116] As a further preferred embodiment, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, pyrimidinyl, thienyl, furyl and 3-8 membered heterocyclic group, and the above groups are optionally further substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, fluorine, chlorine, bromine, =O, phenyl, pyridyl and pyrimidinyl, and the above groups are optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl and isopropyl.

[0117] As a preferred embodiment, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, pyridyl, or the following groups:

[0118] As a preferred embodiment, the structure R1-X- is selected from the following groups:

[0119] As a preferred embodiment, R1, R2, R3, R4, R5, R6, R7, X, T1, T2, T3, T4, Z1, Z2 and n are each independently the corresponding groups in Example Compounds 1-25.

[0120] As a preferred embodiment, the compound is selected from the following:

[0121] Another aspect of the present invention provides a method for preparing the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

[0122] where R 16 Selected from C 1-6 alkyl;

[0123] R1, R2, R3, R4, R5, R6, R7, X, Z1, Z2 and n are as defined above.

[0124] Another aspect of the present invention provides a method for preparing the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

[0125] R7, Z2 and n are as defined above.

[0126] Where appropriate, the various starting materials, intermediates and compounds described herein can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. These compounds can be characterized using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance and various spectroscopic analyses.

[0127] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0128] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing diseases mediated by GLP-1 receptor agonists.

[0129] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia or hyperinsulinemia.

[0130] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0131] The present inventors have conducted extensive and in-depth research, and through extensive screening and testing, have provided a class of GLP-1 receptor agonists with novel structures, on the basis of which the present invention was completed.

[0132] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0133] As used herein, "comprising" or "including" may be open, semi-closed or closed. In other words, the term also includes "consisting essentially of" or "consisting of."

[0134] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or its various branched chain isomers, etc. “C 1- 10 "Alkyl" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1-4 The term "alkyl" refers to straight-chain and branched-chain alkyl groups having 1 to 4 carbon atoms.

[0135] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0136] "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Cycloalkyl is divided into monocyclic cycloalkyl and polycyclic cycloalkyl, preferably a cycloalkyl containing 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 12 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0137] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0138] Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spiroalkyl" refers to a polycyclic group in which the rings share a carbon atom (called a spiro atom). These may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are classified as monospiroalkyl, bispiroalkyl, or polyspiroalkyl groups based on the number of spiro atoms shared between the rings. Spiroalkyl groups include, but are not limited to:

[0139] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cycloalkyl groups include, but are not limited to:

[0140] "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0141] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0142] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2- 10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0143] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, or 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, the heterocyclic group comprises 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, a "3-6 membered heterocyclic group" refers to a ring group comprising 3 to 6 ring atoms, a "4-6 membered heterocyclic group" refers to a ring group comprising 4 to 6 ring atoms, a "4-10 membered heterocyclic group" refers to a ring group comprising 4 to 10 ring atoms, and a "3-12 membered heterocyclic group" refers to a ring group comprising 3 to 12 ring atoms.

[0144] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0145] Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the single rings share an atom (called a spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer 0, 1, or 2) with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are classified as monospiro heterocyclic groups, dispiro heterocyclic groups, or polyspiro heterocyclic groups based on the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0146] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, fused heterocyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused heterocyclic groups include, but are not limited to:

[0147] "Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged heterocyclic groups include, but are not limited to:

[0148] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:

[0149] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 .

[0150] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 5-10 or 5-8 carbon atoms, for example, "C 6-10 "Aryl" refers to an all-carbon aromatic group containing 6-10 carbon atoms, including but not limited to phenyl and naphthyl. 6-8 "Aryl" refers to an all-carbon aromatic group containing 6-8 carbon atoms, wherein the aromatic ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, including but not limited to:

[0151] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0152] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (where r is an integer of 0, 1, or 2) can also be oxidized, for example, C is oxidized to CO, and N is oxidized to N + -O - , preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, a 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, a 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, benzopyrazolyl, The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0153] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0154] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, C 2-10 Alkenyl refers to a straight or branched chain alkenyl containing 2 to 10 carbon atoms. 2-4 Alkenyl refers to a straight or branched chain alkenyl group containing 2 to 4 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0155] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0156] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, C 2-10 Alkynyl refers to a straight or branched chain alkynyl containing 2 to 10 carbon atoms. 2-4 Alkynyl refers to a straight or branched chain alkynyl group containing 2 to 4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

[0157] "Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0158] "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, C 1-4 The term "alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0159] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0160] "Cycloalkoxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkyloxy" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms. 3-6 The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 6 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0161] "Cycloalkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0162] "Heterocyclyl" refers to an -O-heterocyclyl group, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, azopentyloxy, nitrogen, oxhexyloxy, and the like.

[0163] "Heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 substituted by a substituent.

[0164] The above R9, R 10 、R 11 、R 12 、R 13 The definition of is the same as above.

[0165] "Halogen-substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl and tribromomethyl.

[0166] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0167] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0168] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, i.e., includes both substituted and unsubstituted instances. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group.

[0169] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with chemical valence theory, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated bonds (such as olefins).

[0170] "Stereoisomers," whose English name is stereoisomer, refer to isomers resulting from the different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by rotation about single bonds are called conformational stereoisomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, the presence of double bonds or rings in the molecule are called configuration stereoisomers, which are further divided into two categories. Among them, isomers caused by the inability to rotate freely around double bonds or single bonds of ring carbon atoms are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotation properties due to the lack of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations. In this invention, "stereoisomers," unless otherwise specified, are understood to include one or more of the aforementioned enantiomers, configurational isomers, and conformational isomers.

[0171] "Tautomers" refer to structural isomers of different energies that can be interconverted with a low energy barrier. For example, proton tautomers include interconversions by proton migration, and valence tautomers include interconversions by reorganization of some bonding electrons. For example and In the present invention, if the “tautomer” is not otherwise specified, all tautomeric forms of the compound are within the scope of the present invention.

[0172] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0173] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0174] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that constitute the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0175] The present invention will be further described below in conjunction with specific implementations. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0176] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0177] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0178] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0179] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0180] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures expressed in degrees Celsius (°C).

[0181] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents or instruments used, if the manufacturer is not specified, are commercially available conventional products.

[0182] The abbreviations of the compounds involved in the examples are as follows:

[0183] "NMP" means N-methylpyrrolidone;

[0184] "CDI" refers to N,N'-carbonyldiimidazole;

[0185] “DMA” refers to N,N-dimethylacetamide;

[0186] “DBAD” refers to dibenzyl azodicarboxylate;

[0187] “LiHMDS” refers to lithium bis(trimethylsilyl)amide;

[0188] "DBU" refers to 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene;

[0189] "HATU" refers to 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0190] "DMF" refers to N,N-dimethylformamide;

[0191] "DIEA" refers to N,N-diisopropylethylamine;

[0192] "BINAP" means 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;

[0193] "DMAP" refers to dimethylaminopyridine.

[0194] The reference compound A used in the present invention comes from compound 67 in patent CN109790161.

[0195] Preparation of intermediates

[0196] Synthesis of intermediate A

[0197] Intermediate A was synthesized via the following route:

[0198] Step 1: Synthesis of Compound A-2

[0199] Potassium tert-butoxide (6.26 g, 55.81 mmol) and iodomethane (3.47 mL, 55.81 mmol) were added to a solution of compound A-1 (10.0 g, 46.51 mmol) in DMF (100 mL) at room temperature, and the mixture was allowed to react for 12 h. After completion of the reaction, aqueous sodium bicarbonate (300 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (100 mL × 3). The organic phase was collected, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was then purified by normal phase purification (petroleum ether:ethyl acetate = 10:1) to obtain compound A-2 (6.5 g, 61%).

[0200] LC-MS (ESI + )m / z:228.9(M+H) + ;

[0201] 1 H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.59(dd,J=8.8,6.4Hz,1H),7.51(d,J=8.9Hz,1H),4.07(s,3H).

[0202] Step 2: Synthesis of Compound A-3

[0203] Compound A-2 (3 g, 13.1 mmol), potassium monomethyl malonate (3.1 g, 19.6 mmol), BINAP (0.5 g, 0.78 mmol), DMAP (160 mg, 1.31 mmol), and allylpalladium(II) chloride dimer (140 mg, 0.39 mmol) were added to mesitylene (30 mL) at room temperature. After nitrogen substitution, the mixture was heated at 140°C for 12 hours. After completion of the reaction, monitored by LCSM, the mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (60 mL × 3). The organic phase was collected, washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered to dryness. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1) to afford compound A-3 (1.15 g, 40%).

[0204] LC-MS (ESI + )m / z:223.0(M+H) + ;

[0205] 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.44(d,J=8.5Hz,1H),7.33(dd,J=8.5,6.9Hz,1H),4.05(s,3H),3.81(d,J=1.2Hz,2H),3.62(s,3H).

[0206] Step 3: Synthesis of Compound A-4

[0207] To a solution of compound A-3 (1.15 g, 5.18 mmol) in THF (10 mL) was added LiHMDS (7.77 mL, 7.77 mmol, 1 M in THF) at -78°C and stirred for 10 min. Bromoacetonitrile (930 mg, 7.77 mmol) was then added and allowed to react at room temperature for 1 h. After completion of the reaction as monitored by LCMS, saturated aqueous ammonium chloride (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL × 3). The organic phase was collected, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound A-4 (1.13 g, 84%).

[0208] LC-MS (ESI + )m / z:262.0(M+H) + ;

[0209] 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.53(d,J=8.7Hz,1H),7.36(dd,J=8.5,6.9H z,1H),4.51(dd,J=8.2,6.6Hz,1H),4.06(s,3H),3.63(s,3H),3.24-3.09(m,2H).

[0210] Step 4: Synthesis of Compound A

[0211] To a solution of compound A-4 (1.13 g, 4.33 mmol) in methanol (10 mL) were added ammonia in methanol (14 mL, 83.85 mmol) and Raney nickel (3 g). The mixture was then reacted at room temperature under a hydrogen atmosphere for 12 h. After completion of the reaction as monitored by LCMS, the reaction solution was filtered, and the residue was rinsed with methanol. The filtrate was concentrated, and the crude product was purified by normal phase column chromatography (0-5% methanol / dichloromethane) to obtain compound A (700 mg, 69%).

[0212] LC-MS (ESI + )m / z:234.1(M+H) +

[0213] Synthesis of intermediate B:

[0214] Intermediate B was synthesized via the following route:

[0215] Step 1: Synthesis of intermediate B-2

[0216] 3,5-Dimethyl-4-fluorobromobenzene (15 g, 73.89 mmol) was added to a 1000 mL three-necked flask. After nitrogen was displaced three times, tetrahydrofuran (150 mL) was added to dissolve the mixture and the temperature was lowered to -78°C. Then, n-butyllithium (2.5 M, 29.5 mL, 73.89 mmol) was added to the reaction system and stirred for 1 hour. Finally, a solution of di-tert-butyl azodicarboxylate (16.99 g, 73.89 mmol) dissolved in tetrahydrofuran (150 mL) was added dropwise to the reaction mixture. After addition, the mixture was cooled to -40°C and stirred for 0.5 hour. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 2 h. After completion of the reaction, ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 1), dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound B-2 (11.7 g, 45%).

[0217] 1 H NMR (400MHz, CDCl3) δ6.98 (s, 2H), 6.65 (s, 1H), 2.16 (d, J = 2.0Hz, 6H), 1.42 (s, 18H).

[0218] Step 2: Synthesis of intermediate B-3

[0219] Compound B-2 (2.02 g, 8.46 mmol) and methanesulfonic acid (1.63 g, 16.92 mmol, 2.0 eq) were dissolved in NMP (20 mL). The reaction was stirred at 80 °C for 12 h, then cooled to room temperature, toluene (10 mL) was added, and the pH was adjusted to 9 with potassium carbonate solution to obtain an organic phase. Tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (3 g, 8.46 mmol) and pyridine hydrochloride (98 mg, 0.85 mmol) were added to the above solution in sequence, and the temperature was raised to 90 °C and stirred for 1 h. After LCMS detection, the reaction was completed, water (50 mL) was added, and the pH was adjusted to 9 with NaOH solution. The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain compound B-3 (2.2 g, 69%).

[0220] LC-MS (ESI + )m / z:375.2(M+H) + .

[0221] Step 3: Synthesis of intermediate B-4

[0222] Compound CDI (38.56 g, 237.78 mmol) was added to a 2L three-necked flask. After N2 replacement, ethyl acetate (800 mL) was added to dissolve the mixture. The reaction solution was then cooled to 0°C and aminoacetaldehyde dimethyl acetal (25 g, 237.78 mmol) was slowly added dropwise. After the addition, the mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was monitored by LCMS. The mixture was washed with water (200 mL) and then with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound B-4 (23.5 g, 50%).

[0223] 1 H NMR(400MHz,DMSO-d6)δ8.70(t,J=5.5Hz,1H),8.28(s,1H),7.74-7.70(m,1H) ,7.06-7.04(m,1H),4.52(t,J=5.4Hz,1H),3.36(t,J=5.6Hz,2H),3.32(s,6H).

[0224] Step 4: Synthesis of intermediate B-5

[0225] Compounds B-3 (1.5 g, 4.01 mmol) and B-4 (1.04 g, 5.21 mmol) were dissolved in DMA (20 mL). Potassium tert-butoxide (1.35 g, 12.03 mmol) was then added to the reaction mixture and allowed to react at room temperature for 2 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford compound B-5 (2 g, 99%).

[0226] LC-MS (ESI + )m / z:506.0(M+H) + .

[0227] Step 5: Synthesis of Intermediate B-6

[0228] Methanesulfonic acid (300 mg, 3.17 mmol, 0.8 eq) was added to a solution of compound B-5 (2 g, 3.96 mmol) in toluene (20 mL), and the mixture was allowed to react at 60°C for 2 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL × 3) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase purification (petroleum ether:ethyl acetate = 1:1) to obtain compound B-6 (1.12 g, 64%).

[0229] LC-MS (ESI + )m / z:442.0(M+H)+ .

[0230] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.07(d,J=6.3Hz,2H),6.58(dd,J=11.1,8.6Hz,2H),5.05(br.s,1H),4.20(br.s,1 H),3.30(d,J=2.6Hz,1H),3.10(br.s,2H),2.70-2.60(m,2H),2.19(d,J=1.6Hz,6H),1.43(s,9H),1.13(d,J=6.3Hz,3H).

[0231] Step 6: Synthesis of Intermediate B-7

[0232] To a solution of compound B-6 (1.12 g, 2.54 mmol) in NMP (10 mL) were added 5-bromo-4-fluoro-1-methyl-1H-indazole (1.16 g, 5.08 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (180 mg, 1.27 mmol), cuprous iodide (97 mg, 0.51 mmol), and potassium carbonate (1.05 g, 7.62 mmol). The mixture was reacted at 130°C under nitrogen for 3 h. After completion of the reaction, the reaction mixture was washed with water (50 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase purification (petroleum ether:ethyl acetate = 2:1) to obtain compound B-7 (1.28 g, 86%).

[0233] LC-MS (ESI + )m / z:590.0(M+H) + .

[0234] Step 7: Synthesis of Intermediate B

[0235] To a solution of compound B-7 (1.18 g, 2.00 mmol) in ethyl acetate (10 mL) was added ethyl acetate (20 mL) and the mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was concentrated, and saturated aqueous sodium bicarbonate (20 mL) was added. The pH was adjusted to alkaline, and then ethyl acetate (20 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound B (960 mg, 98%).

[0236] LC-MS (ESI + )m / z:490.0(M+H) + .

[0237] Synthesis of intermediates C-1 and C-2

[0238] Intermediates C-1 and C-2 were synthesized via the following routes:

[0239] Step 1: Synthesis of compound C-2

[0240] To a solution of compound C-1 (25 g, 195.1 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise LDA (117 mL, 2M / THF) at -78°C under a nitrogen atmosphere. The mixture was stirred for 20 minutes. Then, a solution of N,N-bis(trifluoromethanesulfonyl)aniline (44 g, 234 mmol) in tetrahydrofuran (100 mL) was added dropwise at -70°C. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. Under an ice bath, saturated ammonium chloride solution was added dropwise. The mixture was extracted with ethyl acetate (100 mL x 3) and washed with saturated brine (100 mL x 1). The organic phase was collected, dried, and then evaporated to dryness under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to afford compound C-2 (38.2 g, 75%).

[0241] Step 2: Synthesis of compound C-4

[0242] Under a nitrogen atmosphere, a mixture of 1,4-dioxane / water (300 mL / 30 mL) containing compound C-3 (28 g, 0.104 mol), diboronic acid pinacol ester (53 g, 0.202 mol), Pd(dppf)Cl2 (3.8 g, 5.2 mmol) and potassium acetate (20.5 g, 0.21 mol) was heated to 80°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound C-4 (32.7 g, 99%).

[0243] LC-MS (ESI+) m / z: 316.2 (M+H) + .

[0244] Step 3: Synthesis of Compound C-5

[0245] Under a nitrogen atmosphere, a mixture of 1,4-dioxane / water (250 mL / 50 mL) containing compound C-4 (20 g, 63 mmol), C-2 (20 g, 76 mmol), Pd(dppf)Cl2 (2.32 g, 3.2 mmol) and potassium carbonate (26.3 g, 190 mol) was heated to 90°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound C-5 (9 g, 54%).

[0246] LC-MS (ESI+) m / z: 300.2 (M+H) + .

[0247] Step 4: Synthesis of Compound C-6

[0248] To a solution of compound C-5 (10.1 g, 33.67 mmol) in methanol (150 mL) was added Pd / C (500 mg, 10%) at room temperature. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and dried under reduced pressure. Compound C-6 (8.8 g) was used directly in the next step without purification.

[0249] LC-MS (ESI+) m / z: 302.2 (M+H) + .

[0250] Step 5: Synthesis of Compound C-7

[0251] Under an ice bath, a solution of compound C-6 (9.6 g, 31.8 mmol) in N,N-dimethylformamide (25 mL) was slowly added dropwise to a solution of NaH (1.7 g, 35 mmol) in N,N-dimethylformamide (100 mL) under a nitrogen atmosphere and stirred for 0.5 hours. Chloroacetonitrile (4.8 g, 64 mmol) was then added to the mixture, and the mixture was stirred at room temperature for 2 hours. After LCMS indicated the reaction was complete, saturated ammonium chloride solution was added for quenching. The mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 7:1) to afford compound C-7 (9.1 g, 84%).

[0252] LC-MS (ESI+) m / z: 341.1 (M+H) + .

[0253] Step 6: Synthesis of Compound C-8

[0254] Under ice bath, to a solution of compound C-7 (3.8 g, 11.16 mmol) and (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide (3.86 g, 27.91 mmol) in tetrahydrofuran (40 mL) was slowly added dropwise lithium bis(trimethylsilyl)amide (45 mL, 1 M), and the reaction was allowed to reach room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound C-8 (1.39 g, 33%).

[0255] LC-MS (ESI+) m / z: 381.3 (M+H) + .

[0256] Step 7: Synthesis of Compound C-9

[0257] An ethanol solution containing compound C-8 (1.39 g, 3.65 mmol), hydroxylamine hydrochloride (1.27 g, 18.27 mmol) and potassium carbonate (2.78 g, 20 mmol) was heated to reflux for 2 hours, filtered, and concentrated under reduced pressure to obtain compound C-9 (1.83 g), which was used directly in the next step without purification.

[0258] LC-MS (ESI+) m / z: 414.3 (M+H) + .

[0259] Step 8: Synthesis of Compound C-10

[0260] To a solution of compound C-9 (1.83 g, 4.4 mmol) in dimethyl sulfoxide (8 mL) were added N,N'-carbonyldiimidazole (1.44 g, 8.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 g, 11.1 mmol) in sequence at room temperature. The mixture was heated to 80°C and reacted for 2 hours. After the reaction was complete, water was added, extracted with dichloromethane (100 mL × 3), and washed with saturated brine (100 mL × 1). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (0-10% methanol / dichloromethane) to obtain compound C-10 (1.89 g, 97%).

[0261] LC-MS (ESI+) m / z: 440.3 (M+H) + .

[0262] Intermediate C-10 was chirally resolved to give compounds C-10a (retention time: 6.61 min) and C-10b (retention time: 7.5 min).

[0263] Chiral separation method:

[0264] Chromatographic conditions Column: IB, 10 μm, 30 x 250 mm; mobile phase A: HEX + 0.2% FA; mobile phase B: ETOH + 0.2% FA; detection wavelength: 214 nm / 254 nm; flow rate: 25 mL / min; column temperature: RT; isocratic elution program: mobile phase A: mobile phase B = 85:15 (v / v)

[0265] Step 9: Synthesis of Compound C

[0266] Under ice bath, sodium hydroxide (400 mg, 10 mmol) was added to a mixed solution of tetrahydrofuran (12 mL) and water (3 mL) containing compound C-10 (1.0 g, 2.28 mmol), and the mixture was heated to 60°C and stirred for 2 hours. After LCMS monitoring, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was collected, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound C, which was used directly in the next step without purification.

[0267] LC-MS (ESI+) m / z: 412.3 (M+H) + .

[0268] Step 10: Synthesis of intermediates C-1 and C-2

[0269] Under ice bath, sodium hydroxide (280 mg, 7 mmol) was added to a mixed solution of tetrahydrofuran (8 mL) and water (2 mL) containing compound C-10a (294 mg, 0.67 mmol) and heated to 60 ° C with stirring for 2 hours. After the reaction was complete, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, added with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound C-1, which was used directly in the next step without purification.

[0270] LC-MS (ESI + )m / z:412.3(M+H) + .

[0271] Under ice bath, sodium hydroxide (280 mg, 7 mmol) was added to a mixed solution of tetrahydrofuran (8 mL) and water (2 mL) containing compound C-10b (305 mg, 0.70 mmol) and heated to 60 ° C with stirring for 1 hour. After the reaction was complete, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was collected, added with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound C-2, which was used directly in the next step without purification.

[0272] LC-MS (ESI + )m / z:412.3(M+H) + .

[0273] Synthesis of intermediate D

[0274] Intermediate D was synthesized via the following route:

[0275] Step 1: Synthesis of compound D-1

[0276] Compound B-3 (2.2 g, 5.88 mol) and cuprous bromide (2.7 g, 18.82 mol) were added to acetonitrile (40 mL). After nitrogen substitution, isoamyl nitrite (2.24 g, 19.11 mmol) was added dropwise at room temperature. The mixture was allowed to react for one hour at room temperature. After completion of the reaction, as monitored by LCMS, the reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 9:1) to obtain compound D-1 (1.08 g, 42%).

[0277] LC-MS (ESI+) m / z: 439.9 (M+H) + .

[0278] Step 2: Synthesis of compound D-2

[0279] Compound D-1 (430 mg, 1.84 mmol), A (540 mg, 1.23 mmol), N,N-diethylsalicylamide (71 mg, 0.37 mmol), potassium phosphate (522 mg, 2.46 mmol), and cuprous iodide (47 mg, 0.25 mmol) were added to DMF (5 mL). After nitrogen substitution, the reaction was incubated at 100°C for 12 hours. After completion of the reaction, as monitored by LCMS, the reaction solution was diluted with water, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude product, which was then separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound D-2 (100 mg, 14%).

[0280] LC-MS (ESI+) m / z: 591.2 (M+H) + ;

[0281] 1 H NMR (400MHz, DMSO-d6) δ8.21-8.04(m,1H),7.56-7.39(m,1H),7.30-7.14(m,3H),5.26-5.06(m,1H),4.30-4.13(m,2H),4.07(s,3H),3.62-3 .49(m,1H),3.39-3.34(m,1H),3.32-3.28(m,1H),3.21-3.04(m,1H), 2.73-2.56(m,3H),2.31(s,6H),1.49-1.39(m,9H),1.32-1.22(m,3H).

[0282] Step 3: Synthesis of compound D-3

[0283] To a solution of compound D-2 (100 mg, 0.17 mmol) in DMF (2 mL) were added potassium tert-butoxide (23 mg, 0.20 mmol) and 18-crown-6 (67 mg, 0.26 mmol, 1.5 eq) in sequence. The mixture was then reacted at room temperature under oxygen for 1 h. After completion of the reaction, water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20 mL × 3). The organic phase was collected, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was separated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound D-3 (50 mg, 49%).

[0284] LC-MS (ESI+) m / z: 607.2 (M+H) + .

[0285] Step 4: Synthesis of Compound D

[0286] To a solution of compound D-3 (50 mg, 0.082 mmol) in DCM (1 mL) was added trifluoroacetic acid (2 mL), and the mixture was reacted at 70°C for 12 h. After completion of the reaction as monitored by LCMS, saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound B (30 mg, 75%), which was used directly in the next step without purification.

[0287] LC-MS (ESI+) m / z: 489.1 (M+H) + .

[0288] Preparation of specific compounds

[0289] Example 1: Synthesis of Compound 1

[0290] Compound 1 was synthesized via the following route:

[0291] Step 1: Synthesis of intermediate 1-2

[0292] Compound 1-1 (1.7 g, 8.28 mmol) and triphenylphosphine (2.61 g, 9.94 mmol) were added to a 100 mL three-necked flask and the atmosphere was purged with nitrogen three times. Tetrahydrofuran (50 mL) was added to dissolve the mixture, followed by the addition of tetrahydropyran-4-ol (4.23 g, 41.4 mmol). The reaction mixture was cooled to 0°C. A solution of DBAD (2.29 g, 9.94 mmol) dissolved in tetrahydrofuran (10 mL) was then added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, as monitored by LCMS, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 1-2 (1.6 g, 67%).

[0293] LC-MS (ESI + )m / z:290.2(M+H) + .

[0294] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),7.33(d,J=8.9Hz,1H),7.17-7.10(m,2H),7.01(dd,J=8.9,2.4Hz,1H),4.51-4.43(m,1H) ,4.40(q,J=7.1Hz,2H),4.06-3.96(m,2H),3.64-3.52(m,2H),2.11-1.97(m,2H),1.90-1.74(m,2H),1.41(t,J=7.1Hz,3H).

[0295] Step 2: Synthesis of intermediates 1-3

[0296] To a solution of compound 1-2 (1.2 g, 4.15 mmol) in DMF (20 mL) at 0°C was added NaH (0.22 g, 5.4 mmol) portionwise. After stirring for 0.5 h, bromoacetonitrile (0.38 mL, 5.4 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. After completion of the reaction, as monitored by LCMS, saturated ammonium chloride was added to the reaction solution for quenching. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 1-3 (0.75 g, 55%).

[0297] LC-MS (ESI + )m / z:329.0(M+H) + .

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

[0299] Compound 1-3 (0.75 g, 2.28 mmol) and (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide (0.63 g, 4.56 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL) and cooled to 0°C. 1M LiHMDS (6.84 mL, 6.84 mmol) was then added dropwise to the reaction mixture. The reaction was continued at 0°C for 3 h. After completion of the reaction, as monitored by LCMS, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 1-4 (0.5 g, 60%).

[0300] LC-MS (ESI + )m / z:369.1(M+H) + .

[0301] Step 4: Synthesis of Intermediates 1-5

[0302] To compound 1-4 (0.4 g, 1.09 mmol) dissolved in dimethyl sulfoxide (20 mL) was added a 50% aqueous solution of hydroxylamine (0.72 g, 10.9 mmol) and stirred at room temperature for 16 h. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was dissolved in dimethyl sulfoxide (4 mL). CDI (0.35 g, 2.18 mmol) and DBU (0.41 g, 2.73 mmol) were added sequentially and stirred at room temperature for 1 h. After the reaction was completed, LCMS monitoring was performed. 1 M HCl was added to the reaction solution to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 1-5 (0.3 g, 65%).

[0303] LC-MS (ESI + )m / z:428.1(M+H) + .

[0304] Step 5: Synthesis of Intermediates 1-6

[0305] To compound 1-5 (0.2 g, 0.47 mmol) dissolved in methanol (5 mL) was added lithium hydroxide (0.11 g, 4.7 mmol), and the mixture was heated to 50°C for 6 h. After completion of the reaction, the reaction solution was cooled to room temperature, 1 M HCl was added to adjust the pH to 3-4, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford compound 1-6 (170 mg, 90%), which was used directly in the next step.

[0306] LC-MS (ESI + )m / z:400.1(M+H) + .

[0307] Step 6: Synthesis of Compound 1

[0308] Compound 1-6 (67 mg, 0.17 mmol), compound B (70 mg, 0.14 mmol), and HATU (64 mg, 0.17 mmol) were dissolved in DMF (2 mL), followed by the addition of DIEA (0.06 mL, 0.35 mmol). The reaction was stirred at room temperature for 1 h. After completion of the reaction, monitored by LCMS, water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The crude product was separated and purified by Prep-HPLC (0-40% MeCN, 0.1% FA) to obtain compound 1 (48 mg, 39%).

[0309] LC-MS (ESI + )m / z:870.7(M+H) + ;

[0310] 1 H NMR(400MHz,DMSO-d6)δ11.74(br s,1H),8.44-8.07(m,1H),7.64(d,J=8.9Hz,1H),7.54-7.42(m,1H),7.40-7 .06(m,5H),7.05-6.75(m,3H),5.82-5.12(m,1H),4.80-4.30(m,2H),4.11(s ,3H),3.93-3.76(m,2H),3.70-3.41(m,3H),3.23-2.80(m,2H),2.26(s,6H), 2.02-1.92(m,2H),1.82-1.70(m,1H),1.65-1.55(m,3H),1.48-1.08(m,7H).

[0311] Compounds 2 to 5 can be obtained by referring to the preparation method of Example 1:

[0312] Example 2: Synthesis of Compound 6

[0313] Compound 6 was synthesized via the following route:

[0314] To a solution of compound D (22 mg, 0.045 mmol) in DMF (1 mL) were added intermediate C-2 (20 mg, 0.050 mmol), HATU (21 mg, 0.054 mmol), and DIEA (0.02 mL, 0.14 mmol) in sequence. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction as monitored by LCMS, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was collected, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which was then purified by HPLC to afford compound 6 (3 mg, 6%).

[0315] LC-MS (ESI+) m / z: 882.6 (M+H) + ;

[0316] 1 H NMR (400MHz, CDCl3) δ11.40-11.25(m,1H),8.29-7.99(m,2H),7.83-7.41(m,3H),7.32-7.27 (m,1H),7.19-6.96(m,3H),6.75-6.61(m,1H),5.82-5.19(m,1H),4.96-4.35(m,1H),4.24-3 .99(m,4H),3.94-3.76(m,2H),3.70-3.36(m,1H),3.22-2.96(m,3H),2.28-2.20(m,6H),1.9 3-1.69(m,4H),1.56-1.49(m,4H),1.35-1.23(m,9H),1.20-1.16(m,2H),1.12-1.01(m,1H).

[0317] Compound 7 can be obtained by referring to the preparation method of Example 2:

[0318] Biological test evaluation

[0319] 1. Determination of cAMP levels in HEK293T cells stably transfected with human GLP-1R

[0320] 1. Experimental instruments

[0321] 2. Experimental Materials

[0322] 3. Experimental Methods

[0323] Human GLP-1R stably transfected HEK293T cells were trypsinized and terminated with DMEM total (without p / S). After centrifugation, the cells were washed twice with 1X stimulation buffer. The cells were resuspended in 1X stimulation buffer (provided with the Cisbio kit) and counted. The cells were then resuspended in stimulation buffer to a 1 million / mL cell suspension. Compound powder was first prepared in DMSO to a 10 mM stock solution. The 10 mM compound stock solution was then diluted to 2 mM in DMSO. A 2X compound was then prepared in 1X stimulation buffer (provided with the Cisbio kit, with IBMX freshly added to a final concentration of 0.5 mM). The top dose final concentration was 2000 nM, and the final DMSO concentration was 0.2%. A 1:3 serial dilution was performed over 11 steps.

[0324] According to the layout, add 5µl of compound to each well; the Min well contains 100nM GLP-1, and the Max well contains 1X stimulation buffer with 0.2% DMSO. Add 5µl of cell suspension to each well, centrifuge at 300rpm for 1 minute at room temperature, and incubate at 37°C for 30 minutes. Prepare a 2X cAMP standard in 1X Stimulation buffer to a final concentration of 2.8µM. Make a 1:3 serial dilution across 12 doses, and according to the layout, add 10µl to each well. Finally, dilute d2 and the antibody 20-fold in 1X Detection buffer (buffer included with the Cisbio kit). According to the layout, add 5µl of each to each well. Centrifuge at 300rpm for 1 minute at room temperature, and incubate at room temperature for 2 hours.

[0325] 4. Data Analysis

[0326] Stimulation% was calculated based on the Min and Max readings (665nm / 615nm ratio): 100*(Ratio Max well - Ratio Test well) / (Ratio Max well - Ratio Min well). The cAMP concentration of each test well was fitted based on the cAMP curve. The data were then analyzed using GraphPad Prism 9, and a four-parameter fitting curve was drawn to calculate the EC. 50 , the formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope)). The results are shown in Table 1.

[0327] Table 1: cAMP level determination in HEK293T cells stably transfected with human GLP-1R

[0328] 2. Pharmacokinetic Analysis of Compounds in Cynomolgus Monkey Plasma

[0329] 1. Experimental Materials

[0330] Oral administration and intravenous injection: 3 cynomolgus monkeys / compound, animals were obtained from Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0331] 2. Experimental Methods

[0332] Pharmacokinetic characterization of the test compound in cynomolgus monkeys following oral (PO) or intravenous (IV) administration. The test compound was prepared as a clear solution in a vehicle consisting of 10% (v / v) DMSO, 10% (v / v) Solutol, and 80% (v / v) Saline. Three cynomolgus monkeys were given a single oral dose of 0.5 mg / kg. Blood samples were collected via the submandibular vein or other appropriate means at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Approximately 0.03 mL of blood was collected via the submandibular vein or other appropriate means, anticoagulated with heparin, and placed on ice. Three cynomolgus monkeys were also given a single intravenous dose of 0.1 mg / kg of the test compound. Blood samples were collected via the submandibular vein or other appropriate means at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Approximately 0.03 mL of blood was collected via the submandibular vein or other appropriate means, anticoagulated with heparin, and placed on ice. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2-8°C), and then analyzed for the concentration of the compound of the invention by LC-MS / MS. All samples were stored at -80°C prior to analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin. Pharmacokinetic parameter results are shown in Table 2.

[0333] Table 2: Pharmacokinetic parameters

[0334] 3. Experimental Results

[0335] Compared with the positive compound, the compound of the present invention has a higher exposure amount and better bioavailability in monkey blood and is expected to have better drug efficacy.

[0336] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, in, Indicates a double bond or a single bond; Ring A is selected from 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl; X is selected from a bond, -O-, -C(O)-, -C≡C-, -CR8R9-, -NR 10 -、-P(O)R 11 -、-S(O)2-、-S-、-N(R 10 )-C(O)- and -C(O)NR 10 -; T1 and T2 are each independently selected from N and C, and at least one of T1 and T2 is N; T3 and T4 are each independently selected from N and CH; R1 is selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-8 Aryl, 5-8 membered heteroaryl and -NR 14 R 15 The above groups are optionally further substituted with one or more selected from deuterium, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, =O, -SF5, -C(O)OR 12 、-C(O)R 13 、-OC(O)R 13 、-NR 14 R 15 、-C(=NR 14 )R 13 、-N(R 14 )-C(=NR 15 )R 13 、-C(O)NR 14 R 15 and -N(R 14 )-C(O)R 13 The above groups are optionally further substituted by one or more substituents selected from halogen, hydroxyl and C 1-6 substituted by an alkyl substituent; R2 is selected from hydrogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy and -NR 14 R 15 ; R3 and R4 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, or R3 and R4 together with the carbon atom to which they are directly attached form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from hydrogen, halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6 substituted by an alkyl substituent; R5 is selected from 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally further substituted by one or more selected from halogen and C 1-6 substituted by an alkyl substituent; R6 is selected from hydrogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy and halogen substituted C 1-6 Alkoxy; R7 is selected from cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-6 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1- 6-alkyl substituted 3-6-membered heterocyclic group; R8 and R9 are each independently selected from hydrogen, C 1-6 Alkyl, or, R8, R9 and the carbon atom to which they are directly connected together form a C 3-6 Cycloalkyl; R 10 Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 11 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, or R1, R 11 Together with the carbon atom to which it is directly attached, it forms C 3-6 Heterocyclic group; Each R 12 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, fluorine, chlorine, hydroxyl, oxo, cyano, C 1-4 Alkyl and C 1-4 substituted by an alkoxy substituent; Z1 is selected from 5-10 membered heteroaryl, the above groups are optionally further substituted by one or more selected from halogen, =O and C 1-6 substituted by an alkyl substituent; Provided that, when X is selected from a bond, Z1 is selected from the following groups: Z2 is selected from C 6-8 Aryl and 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -P(O)R 14 R 15 、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and-NR 14 R 15 substituted by a substituent; Each R 13 , each R 14 and each R 15 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogen, cyano, halogen, 1-6 Alkyl and C 1-6 substituted by an alkyl substituent; n is selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, X, Z1 are as defined in claim 1.

3. The compound according to any one of claims 1 to 2, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1 is as defined in any one of claims 1-2.

4. The compound according to any one of claims 1 to 2, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R7, Z2 and n are as defined in any one of claims 1-2.

5. The compound according to any one of claims 1 to 2 and 4, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R7, Z2 and n are as defined in any one of claims 1-2 and 4.

6. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from hydrogen, cyano, amino, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, azetidinyl and methylamino; R3 and R4 together with the carbon atom to which they are directly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally further substituted by one or more substituents selected from methyl, ethyl and isopropyl; R5 is selected from the following groups: R6 is selected from methyl, ethyl and isopropyl.

7. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from C 6-8 Aryl and 5-6 membered heteroaryl; preferably, ring A is selected from phenyl, pyridyl and pyrimidinyl.

8. The compound according to any one of claims 1 and 4-5, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: Z2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups: The above groups are optionally further substituted with one or more selected from cyano, nitro, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, -P(O)R 14 R 15 、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and-NR 14 R 15 substituted by a substituent.

9. The compound according to any one of claims 1 and 4 to 5, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R7 is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or is selected from the following groups: And / or, Z2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups: The above groups are optionally further substituted by one or more selected from cyano, nitro, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, fluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -P(O)R 14 R 15 、-S(O)2R 14 、-C(O)NR 14 R 15 、-N(R 14 )-C(O)R 13 and-NR 14 R 15 substituted by a substituent; Each R 13 , each R 14 and each R 15 Each independently selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl and bicyclo[1,1,1]pentyl, the above groups are optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl and isopropyl replaced.

10. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, amino, phenyl, 3-8 membered heterocyclic group and 5-6 membered heteroaryl, the above groups are optionally further substituted with one or more selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents are substituted by cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and =O, wherein the above groups are optionally further substituted by one or more substituents selected from halogen, hydroxyl and C 1-6 substituted by an alkyl substituent; Preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, pyrimidyl, thienyl, furanyl and 3-8 membered heterocyclic radicals, wherein the above radicals are optionally further substituted by one or more radicals selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents are substituted by cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and =O, and the above groups are optionally further substituted by one or more selected from halogen, hydroxyl, C 1-6 substituted by an alkyl substituent; More preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, oxazolyl, imidazolyl, pyrimidinyl, thienyl, furanyl and 3-8 membered heterocyclyl, and the above groups are optionally further substituted by one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, fluorine, chlorine, bromine, =O, phenyl, pyridyl and pyrimidinyl, and the above groups are optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl and isopropyl.

11. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, amino, phenyl, pyridyl, or the following groups:

12. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

13. A method for preparing the compound of claim 5, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that: The steps include: R7, Z2 and n are as defined in claim 1.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. Use of the compound according to any one of claims 1 to 12, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating and / or preventing a disease mediated by a GLP 1 receptor agonist.

16. Use of the compound according to any one of claims 1 to 12, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia or hyperinsulinemia.

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