GLP-1 receptor agonists and methods for preparing and using same

Abstract

The present invention discloses GLP-1 receptor agonists and their preparation methods and uses. Specifically, the present invention discloses compounds represented by formula (I) and can be used to prepare medicaments for treating or preventing GLP-1 receptor-mediated diseases.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, in particular to GLP-1 receptor agonist compounds and methods for preparing them, and the use of said compounds in the preparation of medicaments for treating or preventing GLP-1 receptor-mediated diseases. [Background technology]

[0002] Obesity is a highly prevalent chronic disease in modern society and is associated with numerous medical problems, including hypertension, hypercholesterolemia, coronary heart disease, etc. Currently, the only treatment that effectively eliminates obesity is weight loss surgery, which is expensive and carries high risks. Pharmacological interventions are usually less effective and associated with side effects. Therefore, there is a clear need for more effective pharmacological interventions that have fewer side effects and are easier to administer.

[0003] Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted by intestinal epithelial L cells and exerts its physiological effects by binding to its receptor. The GLP-1 receptor (GLP-1R) belongs to the G protein-coupled receptor subfamily, and its reciprocal binding to the GLP-1 receptor induces a series of biological effects. Research has shown that GLP-1 promotes insulin secretion in a glucose-dependent manner. That is, when blood glucose levels in the body increase, GLP-1 stimulates pancreatic cells to increase insulin secretion and lower blood glucose. GLP-1 receptor agonists are novel hypoglycemic drugs that not only effectively control blood glucose levels without causing hypoglycemia, but also increase satiety, delay gastric emptying, regulate appetite, slow small intestinal motility to delay food absorption, and reduce fat accumulation, thereby effectively reducing body weight and achieving weight loss goals.

[0004] GLP-1 receptor agonist-based polypeptide drugs such as liraglutide, exenatide, and semaglutide have been used in obese patients with type II diabetes and simply obese or overweight patients. Although they all show obvious weight loss effects, they often suffer from gastrointestinal side effects such as nausea and vomiting. At the same time, patient compliance with the use of polypeptide injection products is low, and oral polypeptide drugs have low bioavailability, strict dosage regulations, high prices, and still high incidence of gastrointestinal reactions. Therefore, it is necessary to develop new compounds with good biological properties, excellent compliance, and safety. Summary of the Invention [Problem to be solved by the invention]

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

[0006] One aspect of the present invention provides a compound of formula (I), its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof: [ka] where: Ring A is a 3- to 12-membered heterocyclic group, C 6-10 selected from an aryl group and a 5- to 10-membered heteroaryl group; R1 is a cyano group, a halogen, or C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, halogen-substituted C 1-10 Alkyl group, halogen-substituted C 3-12Cycloalkyl groups, halogen-substituted 3- to 12-membered heterocyclic groups, halogen-substituted C 1-10 Alkoxy group, halogen-substituted C 1-10 Alkylthio group, C 1-6 Alkyl-substituted C 3-12 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 12-membered heterocyclic groups; R2 is hydrogen, cyano group, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, halogen-substituted C 1-10 Alkoxy groups and -NR 12 R 13 is selected from R3 is C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl groups and 5- to 10-membered heteroaryl groups, which may optionally further comprise halogen, cyano, nitro, azide, C 1-10 Alkyl groups, halogenated C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more substituents selected from R4 and R5 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, or C 1-10 Alkyl groups, halogenated C 1-10Alkyl group, C 1-10 Alkoxy and halogenated C 1-10 or R4 and R5 together with the carbon atoms to which they are directly attached form a C 3-12 Forming a cycloalkyl group, 3-12 The cycloalkyl group may optionally further comprise hydrogen, halogen, amino, hydroxy, C 1-10 Alkyl groups, halogenated C 1-10 Alkyl group, C 1-10 Alkoxy and halogenated C 1-10 substituted by one or more substituents selected from alkoxy groups; R6 is selected from a 5- to 10-membered heteroaryl group; R7 is selected from a 3- to 12-membered heterocyclic group, a 5- to 10-membered heteroaryl group, and optionally, halogen, hydroxy, cyano, nitro, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, halogen-substituted C 1-10 Alkoxy groups and -NR 12 R 13 or any two substituents bonded to the same carbon atom on the 3- to 12-membered heterocyclic group, together with the carbon atom to which they are bonded, are substituted by one or more substituents selected from C 3-6 Forming a cycloalkyl group, 3-6 The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups and C 1-6 substituted by one or more substituents selected from alkoxy groups; R8 is hydrogen, cyano group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, halogen-substituted C 1-10 Alkoxy groups and -NR 12 R 13 is selected from Each R9 is hydrogen, deuterium, a hydroxy group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl groups, 5- to 10-membered heteroaryl groups, and -NR 12 R 13 and the groups are independently selected from the group consisting of: 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, and -NR 12 R 13 and is substituted by one or more substituents selected from Each R 10 are hydrogen, deuterium, and C 1-10 Alkyl group, C 2-10 Alkenyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 aryl groups and 5- to 10-membered heteroaryl groups, which may independently optionally further comprise deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, and -NR 12 R 13 and is substituted by one or more substituents selected from Each R 11 is hydrogen, deuterium, hydroxyl group, C 1-10 Alkyl group, C 1-10 Alkoxy group, C 2-10Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, and -NR 12 R 13 wherein the groups are independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl group, halogen-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, and -NR 12 R 13 and is substituted by one or more substituents selected from Each R 12 and R 13 are each independently hydrogen, deuterium, a hydroxyl group, or C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono-C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 alkanoyl groups, which may independently optionally further comprise deuterium, halogen, hydroxyl, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 substituted by one or more substituents selected from alkanoyl groups, Or, R 12 and R 13 together with the nitrogen atom to which they are directly bonded, form a 4- to 10-membered heterocyclic group or a 4- to 10-membered heteroaryl group, and the 4- to 10-membered heterocyclic group or the 4- to 10-membered heteroaryl group may optionally further contain deuterium, halogen, a hydroxy group, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 1-10 Alkoxy group, C 3-12 Cycloalkyl groups, C 3-12 Cycloalkoxy group, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclyloxy group, C 6-10 Aryl group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, amino group, mono C 1-10 Alkylamino group, diC 1-10 Alkylamino group and C 1-10 substituted by one or more substituents selected from alkanoyl groups, each r is independently 0, 1, or 2; n is selected from 0, 1, 2, 3 or 4.

[0007] The solution must meet one of the following conditions:

[0008] a. A is C 6-10 When selected from aryl groups and 5- to 10-membered heteroaryl groups, n is not equal to 0 and at least one R1 is selected from cyano groups, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, halogen-substituted C 3-12 Cycloalkyl groups, halogen-substituted 3- to 12-membered heterocyclic groups, halogen-substituted C 1-10 Alkoxy group, C 1-6 Alkyl-substituted C 3-12 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 12-membered heterocyclic groups; bA is C 6-10 aryl groups and 5- to 10-membered heteroaryl groups, n is not equal to 0, and R1 is selected from halogen and / or C 1-10 Alkyl and / or halogen substituted C 1-10 alkyl groups, and R3 is C 6-8 When selected from an aryl group and a 5- to 6-membered heteroaryl group, the group may be selected from a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and wherein the —NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-12 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-12 cycloalkyl groups, wherein C 3-12 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, hydroxyl, cyano, C 1-10Alkyl group, halogen-substituted C 1-10 Alkyl groups and C 1-10 substituted by one or more substituents selected from alkoxy groups; In a preferred solution, ring A is a 3- to 6-membered heterocyclic group, C 6-8 selected from an aryl group and a 5- to 8-membered heteroaryl group; R1 is a cyano group, a halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkyl group, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkylthio group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; R2 is hydrogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy and halogen substituted C 1-6 alkoxy groups, R3 is a 5- to 10-membered heteroaryl group and C 6-10 aryl groups, which may optionally further comprise halogen, cyano, nitro, hydroxy, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy groups and -S(O)rR9, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 and is substituted by one or more substituents selected from R4 and R5 together with the carbon atoms to which they are directly bonded form one C 3-6 Forming a cycloalkyl group,3-6 The cycloalkyl group may optionally further comprise hydrogen, halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6 substituted by one or more substituents selected from alkyl groups; R6 is selected from a 5- to 6-membered heteroaryl group; R7 is selected from a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group is optionally selected from a halogen, a hydroxy group, a cyano group, a nitro group, C 1-6 Alkyl and halogen substituted C 1-6 or any two substituents bonded to the same carbon atom on the 3- to 6-membered heterocyclic group are, together with the carbon atom to which they are bonded, a C 3-6 Forming a cycloalkyl group, 3-6 The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups and C 1-6 substituted by one or more substituents selected from alkoxy groups; R8 is hydrogen, cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkoxy groups and -NR 12 R 13 is selected from R 11 , R 12 and R 13 are independently hydrogen, deuterium, and C 1-6 Alkyl groups and C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0009] The solution must meet one of the following conditions:

[0010] aA is C 6-8 When selected from aryl groups and 5- to 8-membered heteroaryl groups, n is not equal to 0 and at least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; bA is C 6-8 aryl groups and 5- to 8-membered heteroaryl groups, n is not equal to 0, and R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 alkyl groups, and R3 is C 6-8 When selected from an aryl group and a 5- to 6-membered heteroaryl group, the group may be selected from a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and wherein the —NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-12 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C1-6 substituted by one or more substituents selected from alkyl groups; The above "R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 "selected only from alkyl groups" means that R is selected from halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 alkyl groups, or R1 is selected only from halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 alkyl groups are selected only from the group consisting of halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Except for alkyl groups, R1 may not be selected from other groups.

[0011] In a preferred solution, R2 is selected from the group consisting of methyl, ethyl and isopropyl, and R4 and R5 together with the carbon atom to which they are directly attached form a cyclopropyl, cyclobutyl group, which is optionally further substituted by one or more substituents selected from the group consisting of methyl, ethyl and isopropyl, R6 is [ka] is selected from.

[0012] In a preferred solution, ring A is selected from the group consisting of a phenyl group, a pyridyl group, and a pyrimidinyl group.

[0013] A preferred solution is selected from compounds of the following formula: [ka] R3 is a 5- to 10-membered heteroaryl group and C 6-10 aryl groups, which may optionally further comprise halogen, cyano, nitro, hydroxy, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -S(O)rR9, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 and is substituted by one or more substituents selected from R 11 , R 12 and R 13 are independently hydrogen, deuterium, and C 1-6 Alkyl groups and C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C 1-6 Alkyl groups and C 1-6 substituted by one or more substituents selected from alkyl groups; n is selected from 1, 2, 3 or 4; R1, R7 and R8 are as defined above; The solution must meet one of the following conditions:

[0014] a. At least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; b. R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 alkyl groups, and R3 is C 6-8 When selected from an aryl group and a 5- to 6-membered heteroaryl group, the group may be selected from a cyano group, -NR 12 R 13 , -C(O)NR 12 R13 and -N(R 12 )-C(O)R 11 and wherein the —NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0015] In a preferred solution, R3 is a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group or [ka] is selected from the group The above groups may optionally further comprise a cyano group, a nitro group, a hydroxy group, a halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 and is substituted by one or more substituents selected from R 11 , R 12 and R 13 is as defined above.

[0016] A preferred solution is selected from compounds of the following formula: [ka] n is selected from 1, 2, 3 or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6; R 14 is hydrogen, cyano group, hydroxy group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from R 11 , R 12 and R 13 are independently hydrogen, deuterium, and C 1-6 Alkyl groups and C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C 1-6 Alkyl groups and C 1-6 substituted by one or more substituents selected from alkyl groups; R1, R7 and R8 are as defined above; The solution formula (II-I) must satisfy one of the following conditions:

[0017] a. At least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; b. R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 At least one R is selected only from alkyl groups. 14 is a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 -NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0018] In a preferred solution, R7 is selected from 5- to 6-membered heterocyclic groups, which may optionally be halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl and halogen substituted C 1-6 or any two substituents bonded to the same carbon atom on the 3- to 6-membered heterocyclic group are, together with the carbon atom to which they are bonded, a C 3-6 Forming a cycloalkyl group, 3-6 The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C 1-6 Alkyl groups, halogenated C 1-6Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkoxy groups.

[0019] In a preferred solution, R7 is selected from a tetrahydropyranyl group, which is optionally substituted by one or more substituents selected from methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl and trifluoromethyl groups, or any two substituents attached to the same carbon atom on the tetrahydropyranyl group together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl and cyclopentyl group, the ring formed being optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy groups.

[0020] A preferred solution is selected from the following compounds: [ka] R 14 is hydrogen, cyano group, hydroxy group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from R 11 , R 12 and R 13 are independently hydrogen, deuterium, and C 1-6 Alkyl groups and C 3-6 cycloalkyl groups, wherein C 3-6The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C 1-6 Alkyl groups and C 1-6 substituted by one or more substituents selected from alkyl groups; R 15 is C 1-6 Alkyl and halogen substituted C 1-6 alkyl groups or any two R 15 along with the carbon atoms to which they are attached, C 3-6 forming a cycloalkyl group, p is selected from 1, 2, 3 or 4; m is selected from 1, 2, 3 or 4; n, R1 and R8 are as defined above.

[0021] The compound of the solution must satisfy one of the following conditions:

[0022] a. At least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; b. R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 At least one R is selected only from alkyl groups. 14 is a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 -NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13are each independently 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0023] A preferred solution is selected from the following compounds: [ka] R1, R8, R 14 , R 15 , p, m and n are as defined above; The compound of the solution must satisfy one of the following conditions:

[0024] a. At least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; b. R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 At least one R is selected only from alkyl groups. 14 is a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 -NR12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0025] The preferred solution is R 15 is selected from hydrogen, a methyl group, and an ethyl group, or any two R 15 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, and R 14 represents hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from R 11 , R 12 and R 13are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1,1,1]pentyl, optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, propyl, and isopropyl; The preferred solution is R 14 teeth, [ka] The group is selected from the group:

[0026] A preferred solution is selected from the following compounds: [ka] R 14 is hydrogen, cyano group, hydroxy group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from m is selected from 1, 2, 3 or 4; n is selected from 1, 2, 3 or 4; R1 and R8 are as defined above.

[0027] The compound of the solution must satisfy one of the following conditions:

[0028] a. At least one R1 is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups; b. R1 is halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 At least one R is selected only from alkyl groups. 14 is a cyano group, -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 -NR 12 R 13 and -C(O)NR 12 R 13 R in 12 or R 13 are each independently 1-6 Alkyl group, C 3-6 cycloalkyl groups, wherein the —N(R 12 )-C(O)R 11 R in 11 or R 12 is C 3-6 cycloalkyl groups, wherein C 3-6 The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C 1-6 Alkyl groups and C 1-6 It is substituted by one or more substituents selected from alkyl groups.

[0029] A more preferable solution is R 14represents hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from.

[0030] In the preferred solution, R1 is a cyano group, a halogen, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, halogen-substituted C 1-6 Alkylthio group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 alkyl-substituted 3- to 6-membered heterocyclic groups, and the condition is that at least one R1 in the compound is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 The heterocyclic group is selected from alkyl-substituted 3- to 6-membered heterocyclic groups.

[0031] In a further preferred solution, R1 is selected from the group consisting of cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or [ka] and is selected from groups such as The condition is that at least one R1 in the compound is a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, halogen-substituted C 3-6 Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C 1-6 Alkoxy group, C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups and C 1-6 The heterocyclic group is selected from alkyl-substituted 3- to 6-membered heterocyclic groups.

[0032] The preferred solution is [ka] teeth, [ka] is.

[0033] In a preferred solution, R2 is a methyl group.

[0034] The preferred solution is [ka] teeth, [ka] is.

[0035] The preferred solution is R7. [ka] is.

[0036] In a preferred solution, R8 is H.

[0037] In the preferred solution, R8 is hydrogen, a cyano group, C 3-6 Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C 1-6 Alkyl group, halogen-substituted C 1-6 Alkyl group, halogen-substituted C 1-6 Alkoxy groups and -NR 12 R 13 is selected from.

[0038] In a further preferred solution, R8 is selected from hydrogen, cyano, amino, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, azetidinyl and methylamino.

[0039] A preferred solution is selected from the following compounds: [ka] R 14 is hydrogen, cyano group, hydroxy group, nitro group, halogen, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, halogenated C 1-6 Alkoxy group, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from.

[0040] m is selected from 1, 2, 3 or 4.

[0041] A more preferable solution is R 14 represents hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR 12 R 13 , -N(R 12 )-C(O)R 11 and -NR 12 R 13 is selected from.

[0042] A more preferable solution is R 14 is hydrogen, cyano group, fluorine, chlorine, bromine, C 1-6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0043] A more preferable solution is R 14 is selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, and trifluoromethoxy groups.

[0044] A more preferable solution is [ka] teeth, [ka] and where R 14a , R 14bare each independently selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, and trifluoroethoxy; and R 14b is hydrogen, R 14a is also hydrogen.

[0045] A more preferable solution is R 14b is not hydrogen.

[0046] A more preferable solution is R 14a , R 14b At least one of R is a halogen-containing group, i.e., R 14a , R 14b At least one of the groups is fluorine, chlorine, a trifluoromethyl group, or a trifluoromethoxy group.

[0047] A more preferable solution is R 14a , R 14b are each independently selected from hydrogen, fluorine, and chlorine.

[0048] In a more preferred solution, ring A, R1, R2, R3, R4, R5, R6, R7, and R8 are each independently a group corresponding to the compound I in the examples.

[0049] A preferred solution is to choose from the following compounds: [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] A preferred solution is to choose from the following compounds: [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] Another aspect of the present invention provides a process for preparing the above compound, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the steps of: [ka] where R 16 is selected from H.

[0061] Under appropriate circumstances, conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography can be used to separate and purify the various starting materials, intermediates, and compounds described herein. Conventional methods such as melting point, mass spectrometry, nuclear magnetic resonance, and various spectroscopic analyses can be used to characterize these compounds.

[0062] Another aspect of the present invention provides a pharmaceutical composition, which comprises the compound described above, its stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0063] Another aspect of the present invention provides the use of the above compound, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing a GLP-1 receptor agonist-mediated disease.

[0064] Another aspect of the present invention provides use of the above compound, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for preventing and / or treating diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia. [Effects of the Invention]

[0065] 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 specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE INVENTION

[0066] As a result of extensive and thorough research, extensive screening and testing, the present inventors have provided a GLP-1 receptor agonist having a novel structure, and have completed the present invention based on this.

[0067] Unless otherwise defined, 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.

[0068] As used herein, "containing" or "comprising" can be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0069] The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear alkyl group or a branched alkyl group containing 1 to 10, 1 to 6, or 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, s-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-methylbutyl, and the like. Examples of alkyl groups include, but are not limited to, pentyl, 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, and various branched chain isomers thereof. 1-10 The term "alkyl group" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms.1-4 The term "alkyl group" refers to straight chain and branched chain alkyl groups containing 1 to 4 carbon atoms.

[0070] The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0071] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a completely conjugated π-electron system. The cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, and is preferably a cycloalkyl group containing 3 to 12, 3 to 8, or 3 to 6 carbon atoms, such as "C 3-12"Cycloalkyl group" refers to a cycloalkyl group containing 3 to 12 carbon atoms, 3-6 "Cycloalkyl group" refers to a cycloalkyl group containing 3 to 6 carbon atoms, wherein: Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0072] Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. "Spirocycloalkyl groups" refer to polycyclic groups that share one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bispirocycloalkyl groups, and polyspirocycloalkyl groups, and spirocycloalkyl groups are [ka] Including, but not limited to:

[0073] "Fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, where one or more rings can contain one or more (preferably one, two, or three) double bonds, but no ring has a completely conjugated pi-electron system. The number of rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, and fused cycloalkyl groups can be: [ka] Including, but not limited to:

[0074] "Bridged cycloalkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly bonded, and which may contain one or more (preferably 1, 2, or 3) double bonds, but in which no ring has a completely conjugated pi-electron system. The number of rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups are: [ka] Including, but not limited to:

[0075] The cycloalkyl ring can be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, where the ring attached to the parent structure is a cycloalkyl group, including, but not limited to, an indanyl group, a tetrahydronaphthyl group, a benzocycloheptanyl group, and the like.

[0076] Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12)-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0077] The terms "heterocyclic group" or "heterocycle" refer to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which may contain one or more (preferably 1, 2, or 3) double bonds, but in which none of the rings has a completely conjugated π-electron system; a heterocyclic group has one or more (preferably 1, 2, 3, or 4) ring atoms selected from nitrogen, oxygen, or S(O)r (where r is an integer of 0, 1, or 2) heteroatoms, but does not contain -OO-, -OS-, or -SS- ring moieties, the remaining ring atoms being carbon. Preferably, it is a heterocyclic group containing 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, a "3- to 6-membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, a "4- to 6-membered heterocyclic group" refers to a ring group containing 4 to 6 ring atoms, a "4- to 10-membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, and a "3- to 12-membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms.

[0078] Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0079] Polycyclic heterocyclic groups include spiro rings, fused rings, and bridged ring heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between monocyclic rings, where one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O)r (where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. They may contain one or more double bonds (preferably 1, 2, or 3), but none of the rings has a completely conjugated π-electron system. Depending on the number of spiro atoms shared between the rings, spiro heterocyclic groups are divided into monospiro heterocyclic groups, bispiro heterocyclic groups, and polyspiro heterocyclic groups. Spiro heterocyclic groups include: [ka] Including, but not limited to:

[0080] A "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring 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 none of the rings has a completely conjugated pi-electron system, and wherein one or more (preferably 1, 2, 3, or 4) ring atoms are 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 divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, and fused heterocyclic groups are [ka] Including, but not limited to:

[0081] A "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, which may contain one or more (preferably 1, 2, or 3) double bonds, but in which none of the rings has a completely conjugated pi-electron system, and in which one or more (preferably 1, 2, 3, or 4) ring atoms are 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 divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups are [ka] Including, but not limited to:

[0082] The heterocyclic group ring can be fused to an aryl group, heteroaryl group, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclic group; [ka] Including, but not limited to:

[0083] Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0084] The term "aryl group" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings that have adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably an all-carbon aryl group containing 5 to 10 or 5 to 8 carbons, e.g., "C 6-10 "Aryl group" refers to an all-carbon aryl group containing 6 to 10 carbons, including, but not limited to, phenyl and naphthyl groups; 6-8 "Aryl group" refers to an all-carbon aryl group containing 6 to 8 carbons, wherein the aryl ring can be fused to a heteroaryl group, a heterocyclic group, or a cycloalkyl ring, where the ring attached to the parent structure is an aryl ring; [ka] Including, but not limited to:

[0085] The "aryl group" may be substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11, -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0086] The term "heteroaryl group" refers to a heteroaromatic group 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) heteroatoms, and is preferably a heteroaromatic group containing 5 to 10, 5 to 8, or 5 to 6 ring atoms. For example, a 5- to 6-membered heteroaryl group refers to a heteroaromatic group containing 5 to 6 ring atoms, a 5- to 8-membered heteroaryl group refers to a heteroaromatic group containing 5 to 8 ring atoms, a 5- to 10-membered heteroaryl group refers to a heteroaromatic group containing 5 to 10 ring atoms, and examples thereof include furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, benzopyrazolyl, [ka] The heteroaryl ring can be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring; [ka] Including, but not limited to:

[0087] A "heteroaryl group" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0088] The term "alkenyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably a straight-chain or branched-chain alkenyl group containing 2 to 10 or 2 to 4 carbon atoms, such as C 2-10 The alkenyl group refers to a straight-chain or branched-chain alkenyl group containing 2 to 10 carbon atoms, and C 2-4 The alkenyl group refers to a straight-chain or branched-chain alkenyl group containing 2 to 4 carbon atoms, including, but not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl groups.

[0089] The "alkenyl group" may be substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0090] The term "alkynyl group" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably a straight-chain or branched-chain alkynyl group containing 2 to 10 or 2 to 4 carbon atoms, such as C 2-10 The alkynyl group refers to a straight-chain or branched-chain alkynyl group containing 2 to 10 carbon atoms, and C 2-4 The alkynyl group refers to a straight-chain or branched-chain alkynyl group containing 2 to 4 carbon atoms, including, but not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-, 2-, or 3-butynyl group, and the like.

[0091] The "alkynyl group" may be substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0092] "Alkoxy group" refers to an -O-alkyl group, where the definition of alkyl group is as described above, for example, "C 1-10 "Alkoxy group" refers to an alkyloxy group containing 1 to 10 carbon atoms, 1-4 The term "alkoxy group" refers to an alkyloxy group containing 1 to 4 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

[0093] The "alkoxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0094] "Cycloalkoxy group" refers to an -O-cycloalkyl group, where the definition of cycloalkyl group is as described above, for example, "C 3-12 "Cycloalkoxy group" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms, 3-6 The term "cycloalkoxy group" refers to a cycloalkyloxy group containing 3 to 6 carbon atoms, including, but not limited to, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.

[0095] The "cycloalkoxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13 , -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0096] "Heterocyclyloxy" refers to an -O-heterocyclic group, where heterocyclic is as defined above, including, but not limited to, azetidinyloxy, oxetanyloxy, azocyclopentyloxy, azacyclohexyloxy, oxacyclohexyloxy, and the like.

[0097] The "heterocyclyloxy group" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably deuterium, halogen, cyano, nitro, azide, C 1-10 Alkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, halogen-substituted C 1-10 Alkyl group, deuterium-substituted C 1-10 Alkyl group, C 3-12 Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, =O, -SF5, -S(O)rR9, -OR 10 , -C(O)OR 10 , -C(O)R 11 , -OC(O)R 11 , -NR 12 R 13, -C(=NR 12 )R 11 , -N(R 12 )-C(=NR 13 )R 11 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 and is substituted by one or more (preferably 1, 2, 3 or 4) substituents independently selected from:

[0098] Above R9, R 10 , R 11 , R 12 , R 13 The definition is the same as above.

[0099] "C 1-10 "Alkanoyl group" means C 1-10 It refers to the monovalent group remaining after removing the hydroxyl group from an alkyl acid, and is usually called "C 0-9 For example, "C1 alkyl-C(O)-" refers to an acetyl group, "C2 alkyl-C(O)-" refers to a propionyl group, and "C3 alkyl-C(O)-" refers to a butyryl group or an isobutyryl group.

[0100] Halogen-substituted C 1-10 The term "alkyl group" refers to an alkyl group of 1 to 10 carbon atoms in which a hydrogen atom on the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom, and includes, but is not limited to, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a tribromomethyl group, and the like.

[0101] Deuterium-substituted C 1-10 "Alkyl group" refers to an alkyl group of 1 to 10 carbon atoms in which a hydrogen atom on the alkyl group is optionally replaced with a deuterium atom. Examples include, but are not limited to, monodeuteromethyl groups, dideuteromethyl groups, trideuteromethyl groups, and the like.

[0102] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0103] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the description includes situations in which the event or circumstance occurs or does not occur, i.e., both substituted and unsubstituted situations. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0104] "Substitution" refers to the replacement of one or more "hydrogen atoms" in a group, independently of one another, with a corresponding number of substituents. Needless to say, substituents are present only at chemical positions that are possible according to the valence bond theory of chemistry, and those skilled in the art can determine (through experiment or theory) which positions are possible or impossible without undue effort. For example, an amino group or hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated bond (e.g., an olefin).

[0105] The English term for "stereoisomer" is "stereoisomer," which refers to an isomer resulting from different spatial arrangements of atoms within a molecule. These can be divided into two types: cis-trans isomers and enantiomers, or enantiomers and diastereomers. Stereoisomers resulting from the rotation of a single bond are called conformational stereoisomers, also known as rotamers. Stereoisomers resulting from bond length, bond angle, double bonds within a molecule, or the presence of a ring are called configurational isomers, which are divided into two types. Isomers resulting from the inability to freely rotate double bonds or single bonds of ring-forming carbon atoms are called geometric isomers or 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, and because there is no antiaxial symmetry in the molecule, stereoisomers with different optical properties are called optical isomers and are divided into R-configuration and S-configuration. In the present invention, the term "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers, and conformational isomers, unless otherwise specified.

[0106] "Tautomers" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers include interconversions via migration of a proton, and valence tautomers include interconversions via recombination of some of the bonding electrons. For example, [ka] and [ka] In the present invention, unless otherwise specified, the "tautomers" refer to all tautomeric forms of the compounds within the scope of the present invention.

[0107] The term "pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.

[0108] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, 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 exert its biological activity by facilitating administration to an organism and promoting absorption of the active ingredient(s).

[0109] The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 Compounds labeled with radioactive isotopes, such as CI, ...

[0110] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0111] The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0112] Liquid chromatography-mass spectrometry (LC-MS) measurements are performed using an Agilent 6120 mass spectrometer. HPLC measurements are performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

[0113] Thin-layer chromatography silica gel plates are Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates, with a 0.15mm to 0.20mm diameter used in TLC and a 0.4mm to 0.5mm diameter used in thin-layer chromatography separation and purification products. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0114] The starting materials in the examples of the present invention are known and can be purchased commercially or can be synthesized by or according to methods known in the art.

[0115] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvents are dry solvents, and reaction temperatures are in degrees Celsius (°C).

[0116] Unless specific conditions are specified in the examples, they are carried out according to conventional conditions or manufacturer's recommendations. All reagents or equipment used are conventional and commercially available unless the manufacturer's name is specified.

[0117] In the present invention, in all parts related to SFC chiral resolution, the component that appears first is a and the component that appears later is b. For example, after SFC chiral resolution of a pair of enantiomers, Compound 1, two enantiomers are obtained, which are recorded as Compound 1a and Compound 1b, respectively.

[0118] The reference compound a used in the present invention is derived from compound 67 in patent CN109790161, and compound b is derived from compound 146b in patent WO2021155841.

[0119] Preparation of intermediates Synthesis of intermediates A-1 and A-2 [ka]

[0120] Intermediates A-1 and A-2 are synthesized by the following route. [ka]

[0121] Step 1: Synthesis of intermediate 1-2 Under a nitrogen atmosphere at -78°C, LDA (117 mL, 2M / THF) was slowly added dropwise to a solution of compound 1-1 (25 g, 195.1 mmol) in tetrahydrofuran (100 mL). After stirring for 20 minutes, N,N-bis(trifluoromethylsulfonyl)aniline (44 g, 234 mmol) in tetrahydrofuran (100 mL) was added dropwise to the mixture while maintaining the temperature at -70°C. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. Saturated ammonium chloride solution was added dropwise to the mixture in an ice bath, followed by extraction with ethyl acetate, washing with saturated brine, and the organic phase was collected and dried. The crude product obtained was spin-dried under reduced pressure. The resulting product was separated and purified by column chromatography (0-15% petroleum ether / ethyl acetate) to give compound 1-2 (38.2 g, 75%).

[0122] Step 2: Synthesis of intermediates 1-4 Compound 1-3 (25 g, 0.12 mol) was dissolved in N,N-dimethylformamide (100 mL) in an ice bath, and potassium t-butoxide (13 g, 0.12 mol) was added. The mixture was stirred at room temperature for 40 minutes. Then, iodomethane (20 g, 0.14 mol) was slowly added dropwise in an ice bath, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried. The crude product was spin-dried under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to give compound 1-4 (16.6 g, 70%). LC-MS (ESI + ) m / z: 230.1 (M+H) + .

[0123] Step 3: Synthesis of intermediates 1-6 Aminoacetaldehyde dimethyl acetal (2 g, 19 mmol) was added to a solution of N,N'-carbonyldiimidazole (3.1 g, 19 mmol) in ethyl acetate (10 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. After that, the mixture was cooled to 0°C and stirred for 30 minutes. The mixture was filtered and slurried twice with methyl t-butyl ether (methanol / dichloromethane = 0-5%). The crude product was further purified to give compound 1-4 (3.6 g, 95%).

[0124] Step 4: Synthesis of intermediates 1-8 A mixture of compound 1-7 (28 g, 0.10 mol), bis(pinacolato)diboron (53 g, 0.20 mol), Pd(dppf)Cl2 (3.8 g, 5.2 mmol), and potassium acetate (20.5 g, 0.21 mol) in 1,4-dioxane / water (300 mL / 30 mL) was heated to 80 °C under a nitrogen gas atmosphere and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-15%) to obtain compound 1-8 (32.7 g, 99%). LC-MS (ESI + ) m / z: 316.2 (M+H) + .

[0125] Step 5: Synthesis of Intermediates 1-9 A mixture of compound 1-8 (20 g, 63 mmol), 1-2 (20 g, 76 mmol), Pd(dppf)Cl2 (2.32 g, 3.20 mmol), and potassium carbonate (26.30 g, 190 mol) in 1,4-dioxane / water (250 mL / 50 mL) was heated to 90 °C under a nitrogen gas atmosphere and reacted for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain compound 1-9 (9 g, 54%). LC-MS (ESI + ) m / z: 300.2 (M+H) + .

[0126] Step 6: Synthesis of Intermediates 1-10 Compound 1-9 (10.1 g, 33.67 mmol) was dissolved in 150 mL of methanol and Pd / C (500 mg, 10%) was added. The mixture was purged with nitrogen three times and stirred at room temperature for 16 hours. After the reaction was complete, the solid 1-10 (8.8 g) was filtered and spin-dried under reduced pressure. It was used directly in the next step without further purification. LC-MS (ESI + ) m / z: 302.2 (M+H) + .

[0127] Step 7: Synthesis of Intermediates 1-11 Under ice bath conditions, a solution of compound 1-10 (9.60 g, 31.8 mmol) in N,N-dimethylformamide (25 mL) was slowly added dropwise to a solution of NaH (1.70 g, 35 mmol) in N,N-dimethylformamide (100 mL) under a nitrogen atmosphere and stirred for 0.5 h. Then, chloroacetonitrile (4.8 g, 64 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 h. When the reaction was complete as determined by LCMS, it was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-15%) to give compound 1-11 (9.1 g, 84%). LC-MS (ESI + ) m / z: 341.1 (M+H) + .

[0128] Step 8: Synthesis of intermediates 1-12 Lithium hexamethyldisilazide (45 mL, 1 M) was slowly added dropwise to a solution of compound 1-11 (3.80 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) under ice bath, and the mixture was allowed to react at room temperature for 2 hours. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to give compound 1-12 (1.39 g, 33%). LC-MS (ESI + ) m / z: 381.3 (M+H) + .

[0129] Step 9: Synthesis of intermediates 1-13 A solution of compound 1-12 (1.39 g, 3.65 mmol), hydroxylamine hydrochloride (1.27 g, 18.27 mmol), and potassium carbonate (2.78 g, 20 mmol) in ethanol was heated to reflux for 2 h, filtered, and concentrated under reduced pressure to give compound 1-13 (1.83 g), which was used directly in the next step without further purification. LC-MS (ESI + ) m / z: 414.3 (M+H) + .

[0130] Step 10: Synthesis of intermediates 1-14 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) were added sequentially to a solution of compound 1-13 (1.83 g, 4.40 mmol) in dimethyl sulfoxide (8 mL) at room temperature, and the mixture was heated to 80 °C and reacted for 2 hours. After the reaction was completed, water was added, and the mixture was extracted with dichloromethane. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / dichloromethane = 0-10%) to give compound 1-14 (1.89 g, 97%). LC-MS (ESI + ) m / z: 440.3 (M+H) + .

[0131] Chiral resolution of intermediate 1-14 gives compounds 1-14a (retention time is 6.61 min) and 1-14b (retention time is 7.5 min).

[0132] Chiral Resolution Method: Chromatography conditions: Chromatography column: CHIRALPAKR IB, 10 μm, 30*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).

[0133] Step 11: Synthesis of intermediate A Compound 1-14 (1.0 g, 2.28 mmol) was dissolved in a mixture of tetrahydrofuran (12 mL) and water (3 mL) in an ice bath, and sodium hydroxide (400 mg, 10 mmol) was added. The mixture was heated to 60°C and stirred for 2 hours. After the completion of the reaction was monitored by LCMS, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (80 mL x 3). The organic phase was collected, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product Compound A, which was used directly in the next step without any purification. LC-MS (ESI + ) m / z: 412.3 (M+H) + .

[0134] Step 12: Synthesis of Intermediates A-1 and A-2 In an ice bath, compound 1-14a (294 mg, 0.67 mmol) was dissolved in a mixture of tetrahydrofuran (8 mL) and water (2 mL), and sodium hydroxide (280 mg, 7 mmol) was added. The mixture was heated to 60°C and stirred for 2 hours. After the reaction was completed, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over saturated brine and anhydrous sodium sulfate, and filtered to obtain compound A-1, which was used directly in the next step without any need for purification. LC-MS (ESI + ) m / z: 412.3 (M+H) + .

[0135] In an ice bath, compound 1-14b (305 mg, 0.70 mmol) was dissolved in a mixture of tetrahydrofuran (8 mL) and water (2 mL), and sodium hydroxide (280 mg, 7 mmol) was added. The mixture was heated to 60°C and stirred for 1 hour. After the reaction was completed, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over saturated brine and anhydrous sodium sulfate, and filtered to obtain compound A-2, which was used directly in the next step without any purification. LC-MS (ESI + ) m / z: 412.3 (M+H) + .

[0136] Synthesis of intermediate B [ka]

[0137] Intermediate B can be synthesized by the following route: [ka]

[0138] Step 1: Synthesis of intermediate 2-2 A mixture of compound 2-1 (15 g, 78.9 mmol), cyclopropylboronic acid (8.15 g, 94.7 mmol), Pd(dppf)Cl2 (5.78 g, 7.9 mmol), and potassium carbonate (32.7 g, 0.24 mol) in 1,4-dioxane (150 mL) and water (30 mL) was heated to 100 °C under a nitrogen atmosphere for 16 h. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0-5%) to give compound 2-2 (10.8 g, 85%). LC-MS (ESI + ) m / z: 152.1 (M+H) + .

[0139] Step 2: Synthesis of intermediate 2-3 A mixture of compound 2-2 (8.8 g, 58.21 mmol) in concentrated hydrochloric acid (50 mL) and water (50 mL) was stirred at room temperature for 1 hour and filtered to obtain a solid. Methyl t-butyl ether was added to the mixture, and the resulting mixture was filtered to obtain a white solid. The white solid was dissolved in concentrated hydrochloric acid (60 mL) in an ice bath, and sodium nitrite (5.10 g, 74.12 mmol) and water (20 mL) were added in batches. The mixture was stirred continuously for 0.5 hours. Finally, tin chloride (21.62 g, 114 mmol) in water (20 mL) was added, and the mixture was stirred for 2 hours. After the reaction was completed, the mixture was directly filtered and dried to obtain compound 2-3 (3.9 g, 40%). LC-MS (ESI +) m / z: 167.1 (M+H) + .

[0140] Step 3: Synthesis of intermediates 2-5 Pyridine (796 mg, 10.07 mmol) and compound 2-4 (2 g, 8.39 mmol) were added sequentially to a solution of compound 2-3 (2.03 g, 10.07 mmol) in ethanol (25 mL) at room temperature. The mixture was then heated to 80 °C under a nitrogen atmosphere and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 7-8 with sodium hydroxide solution. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-25%) to give compound 2-5 (3.09 g, 79%). LC-MS (ESI + ) m / z: 387.3 (M+H) + .

[0141] Step 4: Synthesis of intermediates 2-6 Compound 1-6 (6.36 g, 32 mmol) was added to a solution of compound 2-5 (3.09 g, 8 mmol) in N,N-dimethylformamide (40 mL) at room temperature, followed by the addition of potassium t-butoxide (4.50 g, 40 mmol) under ice-bath conditions and continued stirring for 16 hours. After the reaction was completed, the mixture was washed with water and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product compound 2-6 (4.89 g), which was used directly in the next step without the need for separation and purification by column chromatography. LC-MS (ESI + ) m / z: 518.4 (M+H) + .

[0142] Step 5: Synthesis of intermediates 2-7 In an ice bath, trifluoromethanesulfonic acid (3.50 g, 23.32 mmol) was added to a solution of crude product compound 2-6 (4.89 g) in tetrahydrofuran (20 mL), and the mixture was then heated to 60 °C and reacted for 1 hour. After cooling to room temperature, triethylamine (4.36 g, 43.08 mmol) and di-t-butyl dicarbonate (3.53 g, 16.20 mmol) were added sequentially in an ice bath and stirred for 1 hour. After the reaction was complete, the pH was adjusted to 5-6 with dilute hydrochloric acid, washed with water, and extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-50%) to give compound 2-7 (2.22 g, 61% yield for two steps). LC-MS (ESI + ) m / z: 454.3 (M+H) + .

[0143] Step 6: Synthesis of intermediates 2-8 Under a nitrogen atmosphere, compound 2-7 (400 mg, 0.90 mmol), compound 1-4 (310 mg, 1.40 mmol), copper iodide (35 mg, 0.18 mmol), trans-(1R,2R)-N,N-dimethylcyclohexanediamine (51 mg, 0.36 mmol), and potassium carbonate (375 mg, 2.70 mmol) dissolved in N-methylpyrrolidone (8 mL) were heated to 130 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, and the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (methanol / dichloromethane = 0-5%) to give compound 2-8 (102 mg, 19%). LC-MS (ESI + ) m / z: 602.4 (M+H) + .

[0144] Step 7: Synthesis of intermediate B Compound 2-8 (102 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL) and hydrochloric acid / dioxane solution (2 mL, 4N) was added under ice bath conditions and reacted for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude intermediate B (120 mg), which was used directly in the next step without further purification. LC-MS (ESI + ) m / z: 502.2 (M+H) + .

[0145] Synthesis of intermediate C: [ka]

[0146] Intermediate C can be synthesized by the following route: [ka]

[0147] Step 1: Synthesis of intermediate C-2 The compound 3,5-dimethyl-4-fluorobromobenzene (15 g, 73.89 mmol) was added to a 1000 mL three-neck bottle and purged with N2 3 times. Then, it was dissolved in tetrahydrofuran (150 mL) and cooled to -78°C. Next, 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-t-butyl azodicarboxylate (16.99 g, 73.89 mmol) dissolved in tetrahydrofuran (150 mL) was added dropwise to the reaction solution. After the addition was complete, the temperature was transferred to -40°C and stirring continued for 0.5 hours. The mixture was allowed to warm to room temperature and react for 2 hours. After the reaction was completed, 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 over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound C-2 (11.7 g, 45%). 1H NMR (400MHz, CDCl3) δ 6.98 (s, 2H), 6.65 (s, 1H), 2.16 (d, J = 2.0Hz, 6H), 1.42 (s, 18H).

[0148] Step 2: Synthesis of intermediate C-3 Compound C-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 mixture was stirred at 80°C for 12 hours, 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. (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid t-butyl ester (3 g, 8.46 mmol) and pyridine hydrochloride (98 mg, 0.85 mmol) were added to the solution in sequence, and the mixture was heated to 90°C and stirred for 1 hour. The completion of the reaction was confirmed by LCMS, water (50 mL) was added, the pH was adjusted to 9 with NaOH solution, 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. The crude product obtained was purified by silica gel column (petroleum ether:ethyl acetate = 4:1) to give compound C-3 (2.2 g, 69%). LC-MS (ESI + ) m / z: 375.2 (M+H) + .

[0149] Step 3: Synthesis of intermediate C-4 Compound CDI (38.56 g, 237.78 mmol) was added to a 2 L three-neck bottle, purged with N2, and dissolved in ethyl acetate (800 mL). The reaction mixture was then cooled to 0 °C, and aminoacetaldehyde dimethyl acetal (25 g, 237.78 mmol) was slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 3 hours. After completion of the reaction was monitored by LCMS, the mixture was washed with water (200 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound C-4 (23.5 g, 49.6%). 1H NMR(400MHz,DMSO-d6)δ 8.70(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).

[0150] Step 4: Synthesis of intermediate C-5 Compounds C-3 (1.5 g, 4.01 mmol) and C-4 (1.04 g, 5.21 mmol) were dissolved in DMA (20 mL). Potassium t-butoxide (1.35 g, 12.03 mmol) was added to the reaction mixture and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction was monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound C-5 (2 g, 99%). LC-MS (ESI + ) m / z: 506.0 (M+H) + .

[0151] Step 5: Synthesis of intermediate C-6 To a solution of compound C-5 (2 g, 3.96 mmol) in toluene (20 mL), methanesulfonic acid (300 mg, 3.17 mmol, 0.8 eq) was added and the mixture was reacted at 60° C. for 2 hours. After the reaction was completed, the reaction mixture was extracted with saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (30 mL × 3). 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 (petroleum ether: ethyl acetate = 1:1) to give compound C-6 (1.12 g, 64%). LC-MS (ESI + ) m / z: 442.0 (M+H) + ; 1H NMR(400MHz,DMSO-d6)δ 10.34(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,1H),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).

[0152] Step 6: Synthesis of intermediate C-7 To a solution of compound C-6 (1.12 g, 2.54 mmol) in NMP (10 mL), 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), copper iodide (97 mg, 0.51 mmol), and potassium carbonate (1.05 g, 7.62 mmol) were added and reacted at 130 °C for 3 hours under nitrogen gas protection. After the reaction was completed, the reaction solution 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 (petroleum ether: ethyl acetate = 2:1) to give compound C-7 (1.28 g, 86%). LC-MS (ESI + ) m / z: 590.0 (M+H) + .

[0153] Step 7: Synthesis of intermediate C To a solution of compound C-7 (1.18 g, 2.00 mmol) in ethyl acetate (10 mL), add ethyl acetate (20 mL) containing hydrogen chloride and react at room temperature for 12 hours. After the reaction is completed, the reaction mixture is concentrated, saturated aqueous sodium bicarbonate solution (20 mL) is added, the pH is adjusted to basic, and then ethyl acetate (20 mL x 3) is added for extraction. The combined organic phases are washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound C (960 mg, 98%). LC-MS (ESI + ) m / z: 490.0 (M+H)+ .

[0154] Preparation of specific compounds Example 1: Synthesis of Compounds 1a and 1b [ka]

[0155] Compounds 1a and 1b are synthesized by the following route. [ka] and [ka]

[0156] Under ice bath conditions, HATU (57 mg, 0.15 mmol) was added to a solution of intermediate A-1 (41 mg, 0.10 mmol) and DIPEA (40 mg, 0.30 mmol) in N,N-dimethylformamide and stirred for 30 minutes. Then intermediate B (50 mg, 0.1 mmol) was added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was washed with water, extracted with dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The crude product obtained was separated and purified by HPLC to obtain compound 1a (36 mg, 40%). LC-MS (ESI + ) m / z: 895.53 (M+H) + .

[0157] The synthesis of compound 1b was prepared from intermediate A-2 and intermediate B, and the synthesis procedure was the same as that of 1a to obtain compound 1b (25 mg, 28%). LC-MS (ESI + ) m / z: 895.44 (M+H) + .

[0158] Compound 1a: 1H NMR(400MHz,DMSO-d6)δ 11.77(s,1H),8.30(s,1H),7.64(d,J=8.8Hz,1H),7.53(s,1H),7.46(t,J=7.8Hz,1H),7.40(d,J=8.6Hz,1H),7.31(d, J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),7.10(d,J=3.0Hz,1H),7.03-6.82(m,3H),5.57(d,J=7.1Hz,1H),4.37(d,J=13.6H z,1H),4.11(s,3H),3.71(d,J=8.4Hz,2H),3.02(d,J=12.3Hz,1H),2.89(d,J=15.0Hz,1H),2.08(d,J=5.7Hz,1H),1.7 9(s,1H),1.64(d,J=23.9Hz,5H),1.43(d,J=6.5Hz,2H),1.27(s,6H),1.17(d,J=6.8Hz,6H),1.00(s,2H),0.65(s,2H).

[0159] Compound 1b: 1 H NMR(400MHz,DMSO-d6)δ 11.75(s,1H),8.30(s,1H),7.64(d,J=8.9Hz,1H),7.53(s,1H),7.46(t,J=7.9Hz,1H),7.40(d,J=8.6Hz,1H),7.31(d ,J=8.5Hz,2H),7.26(d,J=8.4Hz,2H),7.10(s,1H),6.95(d,J=18.1Hz,3H),5.57(d,J=7.3Hz,1H),4.38(d,J=13.8Hz, 1H),4.10(d,J=12.2Hz,3H),3.71(d,J=8.5Hz,2H),3.10-2.97(m,1H),2.89(t,J=7.5Hz,1H),2.09(s,1H),1.78(s,1H ),1.65(dd,J=14.5,8.4Hz,5H),1.43(d,J=6.5Hz,2H),1.27(s,6H),1.18(s,6H),1.01(d,J=8.9Hz,2H),0.65(s,2H).

[0160] Compounds 2 to 4 were prepared according to the preparation method of Example 1.

[0161] [Table 1]

[0162] Example 2: Synthesis of Compound 5 [ka]

[0163] Compound 5 is synthesized by the following route. [ka]

[0164] Step 1: Synthesis of compound 5-2 Compound 5-1 (10.0 g, 42.4 mmol) and N-methylcyclopropanamine (3.14 g, 44.3 mmol) were dissolved in N,N-dimethylformamide (150 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (20.7 g, 54.2 mmol) and N,N-diisopropylethylamine (16.4 g, 127.2 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was washed with saturated brine (150 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the target compound 5-2 (8.1 g, 66% yield). LC-MS (ESI + ) m / z: 290.1 ​​(M+H) + ; 1 H NMR(400MHz, CDCl3)δ 7.42-7.37(m,1H),7.10-7.04(m,1H),3.14(s,3H),2.81(s,1H),0.67-0.58(m,2H),0.54-0.43(m,2H).

[0165] Step 2: Synthesis of compound 5-3 Compound C-6 (5.0 g, 11.32 mmol) and 5-2 (3.3 g, 11.32 mmol) were dissolved in N-methylpyrrolidone (50 mL), and N,N'-dimethyl-1,2-cyclohexanediamine (0.8 g, 5.62 mmol), copper iodide (0.4 g, 2.25 mmol), and potassium carbonate (4.7 g, 34.01 mmol) were added to the reaction solution in that order. The reaction solution was stirred at 130 °C for 3 hours under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 9:1) and then by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 80% to 100%) to obtain the target compound 5-3 (5.0 g, yield 68%). LC-MS (ESI + ) m / z: 651.4 (M+H) + .

[0166] Step 3: Synthesis of compound 5-4 Compound 5-3 (5.0 g, 8.45 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (30 mL), and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated to remove most of the solvent, and the residue was adjusted to pH 9 with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 5-4 (4.4 g), which was used directly in the next step without further purification. LC-MS (ESI + ) m / z: 551.3 (M+H) + .

[0167] Step 4: Synthesis of Compound 5 Compound 5-4 (3.2 g, 5.81 mmol) and compound A-2 (2.4 g, 5.4 mmol) were dissolved in N,N-dimethylformamide (20 mL). Compound 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.7 g, 6.99 mmol) and N,N-diisopropylethylamine (2.3 g, 17.48 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid = 65% to 80%) to obtain the target compound 5 (3.15 g, 57% yield). LC-MS (ESI + ) m / z: 944.4 (M+H) + . 1 H NMR(400MHz,CDCl3)δ 11.38-11.18(m,1H),7.63-7.41(m,3H),7.30-7.27(m,1H),7.18-7.06(m,2H),6.72-6.48(m,2H),6. 38-6.09(m,1H),5.81-5.18(m,1H),4.89-4.44(m,1H),3.91-3.80(m,2H),3.65-3.34(m,1H),3.29-3. 05(m,4H),3.04-2.92(m,2H),2.88-2.75(m,1H),2.29-2.22(m,6H),1.95-1.81(m,1H),1.78-1.63(m ,8H),1.54-1.44(m,2H),1.35-1.33(m,3H),1.29-1.26(m,3H),1.21-1.04(m,3H),0.84-0.43(m,4H).

[0168] Compounds 6 to 55 can be obtained by referring to the preparation method in Example 2. [Table 2-1]

[0169] [Table 2-2]

[0170] Table 2-3

[0171] Table 2-4

[0172] Table 2-5

[0173] Table 2-6

[0174] Table 2-7

[0175] Table 2-8

[0176] Table 2-9

[0177] Table 2-10

[0178] Table 2-11

[0179] Table 2-12

[0180] [Table 2-13]

[0181] [Table 2-14]

[0182] Example 3: Synthesis of compounds 56a and 56b [ka]

[0183] Compound 56 is synthesized by the following route. [ka]

[0184] Step 1: Synthesis of compound 56-2 Compound 56-1 (1.2 g, 4.90 mmol) was dissolved in ethanol (6 mL), sodium borohydride (278 mg, 7.35 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched by adding saturated ammonium chloride (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% to 10%) to give the target compound 56-2 (580 mg, 48% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.22(s,1H),7.51(d,J=8.7Hz,1H),7.43(dd,J=8.7,6.4Hz,1H),4.07(s,4H).

[0185] Step 2: Synthesis of compound 56-3 Compound 56-2 (62 mg, 0.25 mmol) was dissolved in N-methylpyrrolidone (2 mL). INT5-4 (110 mg, 0.25 mmol), copper iodide (10 mg, 0.05 mmol), potassium carbonate (104 mg, 0.75 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (18 mg, 0.13 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 130 °C for 3 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10% to 60%) to give the target compound 56-3 (150 mg, 99% yield). LC-MS (ESI + ) m / z: 608.2 (M+H) + .

[0186] Step 3: Synthesis of compound 56-4 Compound 56-3 (100 mg, 0.16 mmol) was dissolved in a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was directly concentrated to give the crude desired product 56-4 (70 mg). LC-MS (ESI + ) m / z: 508.1 (M+H) + .

[0187] Step 4: Synthesis of compound 56 Compound 56-4 (50 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (1 mL). Compound A-1 (67 mg, 0.13 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55 mg, 0.14 mmol), and N,N-diisopropylethylamine (62 mg, 0.48 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid = 5% to 50%) to obtain compound 56a (46 mg, 42% yield). LC-MS (ESI) + m / z: 901.4(M+H) + ; 1 H NMR(400MHz, CDCl3)δ 11.26(d,J=31.5Hz,1H),7.94-7.66(m,2H),7.62-7.50(m,3H),7.39-7.27(m,1H),7.13-6.98(m, 2H),6.82-6.65(m,2H),6.43-6.15(m,1H),5.84-5.19(m,1H),4.92-4.43(m,1H),3.90-3.81(m,2 H),3.60-3.33(m,5H),3.17-2.98(m,3H),2.26-2.21(m,6H),1.95-1.86(m,1H),1.80-1.77(m,4H ),1.68-1.59(m,2H),1.54-1.51(m,2H),1.36-1.33(m,3H),1.30-1.23(m,4H),1.19-1.05(m,3H).

[0188] The synthesis method of compound 56b, the synthesis method of 56a, and the preparation method of compound A-2 and compound 56-4 are as follows.

change

[0189] Compounds 57 to 62 can be obtained by referring to the preparation method in Example 3. [Table 3-1]

[0190] [Table 3-2]

[0191] Example 4: [ka]

[0192] Compound 63 is synthesized by the following route: [ka]

[0193] Step 1: Synthesis of compound 63-2 Compound 63-1 (1.5 g, 7.89 mmol) and cyclopropanecarboxylic acid (815.52 mg, 9.47 mmol) were dissolved in N,N-dimethylformamide (10 mL). Compound 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.60 g, 9.47 mmol) and N,N-diisopropylethylamine (3.06 g, 23.68 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (60 mL x 3). The organic phase was washed with saturated brine (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1 to 4:1) to give the target compound (1 g, 49% yield). LC-MS (ESI + ) m / z: 257.9 (M+H) + ; 1 HNMR(400MHz, CDCl3)δ 8.16(t,J=8.5Hz,1H),7.46(s,1H),7.21-7.17(m,2H),1.51-1.47(m,1H),1.05-1.02(m,2H),0.85-0.81(m,2H).

[0194] Step 2: Synthesis of compound 63-3 Compound 63-2 (500 mg, 1.94 mmol) was dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was placed at 0 °C, and sodium hydride (55 mg, 2.32 mmol) was added in a batchwise manner. After stirring for 30 min, iodomethane (412 mg, 2.91 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give target compound 63-3 (300 mg, 57% yield). LC-MS (ESI + ) m / z: 272.0 (M+H) + ; 1HNMR(400MHz, CDCl3)δ 7.75(s,1H),7.66(d,J=8.4Hz,1H),7.57-7.53(m,1H),3.03(s,3H),2.77-2.72(m,1H),0.62(s,2H),0.41(s,2H).

[0195] Step 3: Synthesis of compound 63-4 Compound C-6 (180 mg, 0.41 mmol) and compound 63-3 (134 mg, 0.49 mmol) were dissolved in N-methylpyrrolidone (3 mL). Compound N,N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.17 mmol), potassium carbonate (171 mg, 1.24 mmol), and copper iodide (16 mg, 0.084 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 130 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (25 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:5) to give compound 63-4 (236 mg, 92% yield). 1HNMR(400MHz,CDCl3)δ 7.62-7.56(m,1H),7.45-7.39(m,2H),7.10-7.04(m,2H),6.75-6.68(m,1H),6.40-6.28(m,1H),3.29-3.23(m,3 H),2.86-2.74(m,2H),2.24-2.20(m,6H),1.49(s,9H),1.31-1.27(m,4H),1.10-1.00(m,3H),0.91-0.81(m,4H).

[0196] Step 4: Synthesis of compound 63-5 Add 4M hydrogen chloride in 1,4-dioxane (2 mL) to 63-4 (231 mg, 0.37 mmol) in 1,4-dioxane (4 mL) and stir at room temperature for 2 h. After the reaction is complete, concentrate directly to give the target compound (192 mg, 99% yield). LC-MS (ESI +) m / z: 533.3 (M+H) + .

[0197] Step 5: Synthesis of compound 63 Compound 63-5 (176 mg, 0.33 mmol) and compound A (90 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Compound 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid) to give the target compound 63 (102 mg, 50% yield). LC-MS (ESI + ) m / z: 926.8 (M+H) + ; 1 H NMR(400MHz,CDCl3)δ 11.34-11.20(m,1H),7.73-7.54(m,2H),7.54-7.49(m,1H),7.48-7.35(m,2H),7.30-7.26(m,1H),7.13-7.00(m,2H),6. 79-6.58(m,2H),6.39-6.14(m,1H),5.79-5.22(m,1H),4.95-4.37(m,1H),3.91-3.80(m,2H),3.69-3.46(m,1H),3.28-3. 25(m,2H),3.24-3.16(m,1H),3.16-2.92(m,3H),2.28-2.20(m,6H),1.94-1.87(m,1H),1.82-1.67(m,7H),1.66-1.59(m ,2H),1.59-1.54(m,1H),1.38-1.32(m,4H),1.29-1.25(m,3H),1.19-1.16(m,2H),1.08-1.02(m,2H),0.73-0.57(m,2H).

[0198] Compounds 63a to 77 can be obtained by referring to the preparation method in Example 4. [Table 4-1]

[0199] [Table 4-2]

[0200] [Table 4-3]

[0201] [Table 4-4]

[0202] [Table 4-5]

[0203] Example 5: [ka]

[0204] Compound 78 is synthesized by the following route: [ka] Step 1: Synthesis of compound 78-2 Compound 78-1 (72 mg, 0.27 mmol) was dissolved in N-methylpyrrolidone (2 mL). Compound C-6 (120 mg, 0.27 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (19 mg, 0.14 mmol), copper iodide (10 mg, 0.05 mmol), and potassium carbonate (110 mg, 0.81 mmol) were added to the reaction mixture. The mixture was stirred at 130 °C for 3 h under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give compound 78-2 (130 mg, 76% yield). LC-MS (ESI + ) m / z: 627.4 (M+H) + .

[0205] Step 2: Synthesis of compound 78-3 To a solution of compound 78-2 (120 mg, 0.19 mmol) in dichloromethane (5 mL), add a solution of hydrogen chloride in dioxane (4 M, 4 mL) and stir the reaction mixture at room temperature for 30 minutes. The reaction mixture was concentrated, redissolved in tetrahydrofuran (5 mL), and saturated aqueous potassium carbonate (5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The solution was diluted with water (20 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), fresh water (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to give product 78-3 (90 mg, 89%). LC-MS (ESI + ) m / z: 527.4 (M+H) + ; 1H NMR(400MHz,CDCl3)δ 7.89(s,1H),7.77(d,J=8.6Hz,1H),7.70(dd,J=8.6,2.0Hz,1H),7.03(d,J=6.2Hz,2H),6.73(d,J=3.3Hz,1H),6.34(d,J=3.2Hz) ,1H),4.11-4.05(m,1H),3.37-3.35(m,1H),3.12-3.01(m,1H),2.80-2.74(m,2H),2.20(d,J=2.1Hz,6H),1.24(d,J=7.1Hz,3H).

[0206] Step 3: Synthesis of compound 78 Compound 78-3 (63 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound A (50 mg, 0.12 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (55 mg, 0.14 mmol), and N,N-diisopropylethylamine (47 mg, 0.36 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid = 5% to 60%) to give compound 78 (59 mg, 52%). LC-MS (ESI + ) m / z: 920.4 (M+H) + ; 1 H NMR(400MHz,CDCl3)δ 11.39-11.03(m,1H),7.92-7.26(m,6H),7.13-6.96(m,2H),6.85-6.63(m,2H),6.46-6.20(m,1H),5.79-5.19(m,1H),5.03-4.32(m,1H) ,4.14-3.66(m,2H),3.65-3.36(m,1H),3.27-2.85(m,3H),2.44-2.06(m,6H),1.79-1.49(m,10H),1.38-1.25(m,6H),1.19-1.04(m,3H).

[0207] Compounds 79 to 97 can be obtained by referring to the preparation method in Example 5. [Table 5-1]

[0208] [Table 5-2]

[0209] [Table 5-3]

[0210] [Table 5-4]

[0211] [Table 5-5]

[0212] [Table 5-6]

[0213] [Table 5-7]

[0214] Biological Test Evaluation 1. Measurement of cAMP levels in HEK293T cells stably transfected with human GLP-1R 1. Experimental Equipment [Table 6]

[0215] 2. Experimental Materials [Table 7]

[0216] 3. Experimental Method Human GLP-1R HEK293T stable transfectant cells were digested with pancreatin, suspended in DMEM total (without P / S), centrifuged, washed twice with 1X stimulation buffer, resuspended and counted, and then prepared in stimulation buffer to a cell suspension of 1 million / mL. Compound powder was first prepared in DMSO to a 10 mM stock solution, then diluted to 2 mM with DMSO. 2X compound was prepared in 1X stimulation buffer (the buffer provided in the Cisbio kit, with IBMX freshly added to a final concentration of 0.5 mM). The final concentration of the highest dose was 2000 nM, and the final DMSO concentration was 0.2%. A 1:3 gradient dilution was performed, resulting in 11 gradient dilutions.

[0217] Add 5 μl of compound to each well according to the layout. The smallest well contains 100 nM GLP-1, and the largest well contains 1X stimulation buffer with 0.2% DMSO. Add 5 μl of cell suspension to each well, centrifuge at 300 rpm for 1 minute at room temperature, and then incubate at 37°C for 30 minutes. Prepare 2X cAMP standards in 1X stimulation buffer to a final concentration of 2.8 μM. Dilute 12 doses at a 1:3 gradient and add 10 μl to each well according to the layout. Finally, dilute d2 and antibodies 20-fold in 1X detection buffer (included in the Cisbio kit). Add 5 μl of each to each well according to the layout. Centrifuge at 300 rpm for 1 minute at room temperature, and then incubate at room temperature for 2 hours.

[0218] 4. Data Analysis Based on the minimum and maximum values ​​(665 nm / 615 nm ratio), the % stimulation was calculated using the formula: 100 × (maximum well ratio - test well ratio) / (maximum well ratio - minimum well ratio). The cAMP concentration of each test well was fitted according to the cAMP standard curve, and the data was analyzed using GraphPad Prism 9. A four-parameter fitting curve was plotted to determine the EC 50The formula is Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X) × HillSlope). See Table 1 for the results.

[0219] [Table 8-1]

[0220] [Table 8-2]

[0221] [Table 8-3]

[0222] [Table 8-4]

[0223] 2. Pharmacokinetic analysis of compounds in mouse plasma 1. Experimental Materials Male C57BL / 6J mice, approximately 30 g, 6-9 weeks old, administered orally by gavage and intravenously by injection: 3 mice / compound each. Animals were obtained from Shanghai MEDICILON Biopharmaceutical Co., Ltd.

[0224] 2. Experimental Method The pharmacokinetic properties of compounds are tested in mice after oral gavage (PO) or intravenous injection (IV) using standard protocols. The test compound is prepared as a clear solution in 10% (v / v) DMSO + 10% (v / v) Solutol + 80% (v / v) saline. Three mice are given a single oral gavage dose of 5 mg / kg. Blood samples are collected via the submandibular vein or other appropriate method at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Approximately 0.03 mL of each sample is anticoagulated with sodium heparin and placed on ice. Three mice were given a single intravenous injection of 1 mg / kg of the test compound. Blood samples were collected from the submandibular vein or other suitable method at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Approximately 0.03 mL of blood was collected per sample, anticoagulated with sodium heparin, and placed on ice. Plasma was centrifuged within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2-8°C), and then the concentration of the compound of the present invention was analyzed by LC-MS / MS.

[0225] Prior to analysis and detection, all samples were stored at -80°C and pharmacokinetic parameters were calculated using Phoenix WinNonlin. The results of pharmacokinetic parameters are shown in Table 2.

[0226] [Table 9]

[0227] From this, it can be seen that the compounds of the present invention have a longer half-life in the blood of mice compared to the positive compounds, and the exposure amount is significantly increased, so that superior efficacy can be expected.

[0228] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, it should 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 equivalents thereof are also included in the scope defined by the appended claims of this application.

Claims

1. A compound of formula (I), its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: Ring A is a 3- to 12-membered heterocyclic group, C ６－１０ selected from aryl groups and 5- to 10-membered heteroaryl groups; R １ represents a cyano group, a halogen, C １－１０ Alkyl group, C ３－１２ Cycloalkyl group, 3- to 12-membered heterocyclic group, halogen-substituted C １－１０ Alkyl group, halogen-substituted C ３－１２ Cycloalkyl groups, halogen-substituted 3- to 12-membered heterocyclic groups, halogen-substituted C １－１０ Alkoxy group, halogen-substituted C １－１０ Alkylthio group, C １－６ Alkyl-substituted C ３－１２ Cycloalkyl group and C １－６ alkyl-substituted 3- to 12-membered heterocyclic groups; R ２ is hydrogen, a cyano group, C １－１０ Alkyl group, halogen-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, halogen-substituted C １－１０ Alkoxy groups and -NR １２ R １３ is selected from R ３ is C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C ６－１０ aryl groups and 5- to 10-membered heteroaryl groups, which may optionally further comprise halogen, cyano, nitro, azide, C １－１０ Alkyl group, halogenated C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C ６－１０ Aryl group, 5- to 10-membered heteroaryl group, ═O, —SF ５ , -S(O)rR ９ , -O-R １０ , -C(O)OR １０ , -C(O)R １１ , —O—C(O)R １１ , -NR １２ R １３ , -C(=NR １２ ) R １１ , -N(R １２ )-C(=NR １３ ) R １１ , —C(O)NR １２ R １３ and -N(R １２ )-C(O)R １１ and is substituted by one or more substituents selected from R ４ , R ５ are each independently hydrogen, halogen, a hydroxy group, or C １－１０ Alkyl group, halogenated C １－１０ Alkyl group, C １－１０ Alkoxy groups and halogenated C １－１０ alkoxy groups, or R ４ and R ５ together with the carbon atoms to which they are directly attached form one C ３－１２ Forms a cycloalkyl group, ３－１２ The cycloalkyl group may optionally further comprise hydrogen, halogen, amino, hydroxy, C １－１０ Alkyl group, halogenated C １－１０ Alkyl group, C １－１０ Alkoxy groups and halogenated C １－１０ substituted by one or more substituents selected from alkoxy groups; R ６ is selected from 5- to 10-membered heteroaryl groups; R ７ is selected from a 3- to 12-membered heterocyclic group, a 5- to 10-membered heteroaryl group, and the groups may optionally be halogen, a hydroxy group, a cyano group, a nitro group, C １－１０ Alkyl group, halogen-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, halogen-substituted C １－１０ Alkoxy groups and -NR １２ R １３ or any two substituents attached to the same carbon atom on said 3- to 12-membered heterocyclic group, together with the carbon atom to which they are attached, are substituted by one or more substituents selected from C ３－６ Forms a cycloalkyl group, ３－６ The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C １－６ Alkyl group, halogenated C １－６ Alkyl group and C １－６ substituted by one or more substituents selected from alkoxy groups; R ８ is hydrogen, a cyano group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C １－１０ Alkyl group, halogen-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, halogen-substituted C １－１０ Alkoxy groups and -NR １２ R １３ is selected from Each R ９ is hydrogen, deuterium, hydroxyl group, C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C ６－１０ Aryl groups, 5- to 10-membered heteroaryl groups, and —NR １２ R １３ and the groups are independently selected from the group consisting of: １－１０ Alkyl group, C １－１０ Alkoxy group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ An aryloxy group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryloxy group, and —NR １２ R １３ and is substituted by one or more substituents selected from Each R １０ is hydrogen, deuterium, C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C ６－１０ aryl groups and 5- to 10-membered heteroaryl groups, which groups are independently optionally further selected from deuterium, halogen, hydroxyl group, oxo, cyano group, C １－１０ Alkyl group, C １－１０ Alkoxy group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ An aryloxy group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryloxy group, and —NR １２ R １３ and is substituted by one or more substituents selected from Each R １１ is hydrogen, deuterium, hydroxyl group, C １－１０ Alkyl group, C １－１０ Alkoxy group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ An aryloxy group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryloxy group, and —NR １２ R １３ wherein the groups are independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, C １－１０ Alkyl group, halogen-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ An aryloxy group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryloxy group, and —NR １２ R １３ and is substituted by one or more substituents selected from Each R １２ and R １３ are each independently hydrogen, deuterium, a hydroxyl group, or C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, C ３－１２ Cycloalkyl groups, 3- to 12-membered heterocyclic groups, C ６－１０ Aryl group, 5- to 10-membered heteroaryl group, sulfinyl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, aminosulfonyl group, dimethylaminosulfonyl group, amino group, mono C １－１０ Alkylamino group, diC １－１０ Alkylamino group and C １－１０ alkanoyl groups, which may independently optionally further comprise deuterium, halogen, hydroxyl, C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, halogen-substituted C １－１０ Alkyl group, deuterium-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, amino group, mono C １－１０ Alkylamino group, diC １－１０ Alkylamino group and C １－１０ substituted by one or more substituents selected from alkanoyl groups, Or, R １２ and R １３ together with the nitrogen atom to which they are directly bonded to form a 4- to 10-membered heterocyclic group or a 4- to 10-membered heteroaryl group, and the 4- to 10-membered heterocyclic group or the 4- to 10-membered heteroaryl group may optionally further contain deuterium, halogen, a hydroxy group, C １－１０ Alkyl group, C ２－１０ Alkenyl group, C ２－１０ Alkynyl group, halogen-substituted C １－１０ Alkyl group, deuterium-substituted C １－１０ Alkyl group, C １－１０ Alkoxy group, C ３－１２ Cycloalkyl group, C ３－１２ a cycloalkoxy group, a 3- to 12-membered heterocyclic group, a 3- to 12-membered heterocyclyloxy group, C ６－１０ Aryl group, C ６－１０ Aryloxy group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroaryloxy group, amino group, mono C １－１０ Alkylamino group, diC １－１０ Alkylamino group and C １－１０ substituted by one or more substituents selected from alkanoyl groups, A is C ６－１０ With the proviso that n is selected from aryl groups and 5- to 10-membered heteroaryl groups, n is not equal to 0 and at least one R １ is a cyano group, C ３－１２ Cycloalkyl group, 3- to 12-membered heterocyclic group, halogen-substituted C ３－１２ Cycloalkyl groups, halogen-substituted 3- to 12-membered heterocyclic groups, halogen-substituted C １－１０ Alkoxy group, C １－６ Alkyl-substituted C ３－１２ Cycloalkyl group and C １－６ alkyl-substituted 3- to 12-membered heterocyclic groups; Or, A is C ６－１０ aryl groups and 5- to 10-membered heteroaryl groups, n is not equal to 0, and R １ is halogen and / or C １－１０ Alkyl group and / or halogen-substituted C １－１０ alkyl groups, and R ３ is C ６－８ When selected from aryl groups and 5- to 6-membered heteroaryl groups, R ３ represents a cyano group, -NR １２ R １３ , —C(O)NR １２ R １３ and -N(R １２ )-C(O)R １１ and the —NR １２ R １３ and —C(O)NR １２ R １３ R in １２ or R １３ is C ３－１２ cycloalkyl groups, and the —N(R １２ )-C(O)R １１ R in １１ or R １２ is C ３－１２ cycloalkyl groups, wherein said C ３－１２ The cycloalkyl group may independently optionally further comprise deuterium, halogen, a hydroxy group, a cyano group, C １－１０ Alkyl group, halogen-substituted C １－１０ Alkyl group, C １－１０ substituted by one or more substituents selected from alkoxy groups; each r is independently 0, 1, or 2; A compound of formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that n is selected from 0, 1, 2, 3 or 4.

2. Ring A is a 3- to 6-membered heterocyclic group, C ６－８ selected from aryl groups and 5- to 8-membered heteroaryl groups; R １ represents a cyano group, a halogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclic group, halogen-substituted C １－６ Alkyl group, halogen-substituted C ３－６ Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C １－６ Alkoxy group, halogen-substituted C １－６ Alkylthio group, C １－６ Alkyl-substituted C ３－６ Cycloalkyl group and C １－６ alkyl-substituted 3- to 6-membered heterocyclic groups; R ２ is hydrogen, C １－６ Alkyl group, halogen-substituted C １－６ Alkyl group, C １－６ Alkoxy and halogen-substituted C １－６ alkoxy groups, R ３ represents a 5- to 10-membered heteroaryl group and C ６－１０ aryl groups, which may optionally further comprise halogen, cyano, nitro, hydroxy, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —S(O)rR ９ , —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ and is substituted by one or more substituents selected from R ４ and R ５ together with the carbon atoms to which they are directly attached form one C ３－６ Forms a cycloalkyl group, ３－６ The cycloalkyl group may optionally further comprise hydrogen, halogen, amino, hydroxy, C １－６ Alkyl groups and halogenated C １－６ substituted by one or more substituents selected from alkyl groups; R ６ is selected from 5- to 6-membered heteroaryl groups; R ７ is selected from a 3- to 6-membered heterocyclic group, and the 3- to 6-membered heterocyclic group is optionally selected from a halogen, a hydroxy group, a cyano group, a nitro group, C １－６ Alkyl and halogen-substituted C １－６ or any two substituents attached to the same carbon atom on said 3- to 6-membered heterocyclic group are, together with the carbon atom to which they are attached, a C ３－６ Forms a cycloalkyl group, ３－６ The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C １－６ Alkyl group, halogenated C １－６ Alkyl group and C １－６ substituted by one or more substituents selected from alkoxy groups; R ８ is hydrogen, a cyano group, C ３－６ Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C １－６ Alkyl group, halogen-substituted C １－６ Alkyl group, C １－６ Alkoxy group, halogen-substituted C １－６ Alkoxy groups and -NR １２ R １３ is selected from R １１ , R １２ and R １３ are each independently hydrogen, deuterium, or C １－６ Alkyl group and C ３－６ cycloalkyl groups, wherein said C ３－６ The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C １－６ Alkyl group and C １－６ substituted by one or more substituents selected from alkyl groups; A is C ６－８ With the proviso that n is selected from aryl groups and 5- to 8-membered heteroaryl groups, n is not equal to 0 and at least one R １ is a cyano group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclic group, halogen-substituted C ３－６ Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C １－６ Alkoxy group, C １－６ Alkyl-substituted C ３－６ Cycloalkyl group and C １－６ alkyl-substituted 3- to 6-membered heterocyclic groups; Or A is C ６－８ aryl groups and 5- to 8-membered heteroaryl groups, n is not equal to 0, and R １ is halogen and / or C １－６ Alkyl group and / or halogen-substituted C １－６ alkyl groups, and R ３ is C ６－８ When selected from aryl groups and 5- to 6-membered heteroaryl groups, R ３ represents a cyano group, -NR １２ R １３ , —C(O)NR １２ R １３ and -N(R １２ )-C(O)R １１ and the —NR １２ R １３ and —C(O)NR １２ R １３ R in １２ or R １３ is C ３－１２ cycloalkyl groups, and the —N(R １２ )-C(O)R １１ R in １１ or R １２ is C ３－６ cycloalkyl groups, wherein said C ３－６ The cycloalkyl groups may independently optionally further comprise deuterium, halogen, halogen-substituted C １－６ Alkyl group and C １－６ substituted with one or more substituents selected from alkyl groups; 2. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

3. Ring A is selected from a phenyl group, a pyridyl group, and a pyrimidinyl group; R ２ is selected from a methyl group, an ethyl group, and an isopropyl group; R ４ and R ５ together with the carbon atom to which they are directly attached form a cyclopropyl group, a cyclobutyl group, which is optionally further substituted by one or more substituents selected from a methyl group, an ethyl group, and an isopropyl group; R ６ teeth, 【Chemistry 2】 characterized in that it is selected from 3. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

4. is selected from compounds of the formula: 【Transformation 3】 R ３ represents a 5- to 10-membered heteroaryl group and C ６－１０ aryl groups, which may optionally further comprise halogen, cyano, nitro, hydroxy, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —S(O)rR ９ , —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ and is substituted by one or more substituents selected from R １１ , R １２ and R １３ are each independently hydrogen, deuterium, or C １－６ Alkyl group and C ３－６ cycloalkyl groups, wherein said C ３－６ The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C １－６ Alkyl group and C １－６ substituted by one or more substituents selected from alkyl groups; n is selected from 1, 2, 3 or 4; R １ , R ７ and R ８ is characterized in that it is as defined in any one of claims 1 to 3 The compound according to any one of claims 1 to 3, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

5. R ３ is a phenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, or 【Chemistry 4】 is selected from the group The above groups may optionally further include cyano groups, nitro groups, hydroxy groups, halogens, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ and is substituted by one or more substituents selected from R １１ , R １２ and R １３ is characterized in that it is as defined in any one of claims 1 to 4 5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

6. is selected from compounds of the formula: 【Transformation 5】 n is selected from 1, 2, 3 or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6; R １４ is hydrogen, cyano group, hydroxy group, nitro group, halogen, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ is selected from R １１ , R １２ and R １３ are each independently hydrogen, deuterium, or C １－６ Alkyl group and C ３－６ cycloalkyl groups, wherein said C ３－６ The cycloalkyl group may optionally further comprise a halogen, a halogen-substituted C １－６ Alkyl group and C １－６ substituted by one or more substituents selected from alkyl groups; R １ , R ７ and R ８ is characterized in that it is as defined in any one of claims 1 to 5 6. The compound according to any one of claims 1 to 5, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

7. R ７ is selected from 5- to 6-membered heterocyclic groups, and the 5- to 6-membered heterocyclic groups are optionally selected from halogen, hydroxyl, cyano, nitro, C １－６ Alkyl and halogen-substituted C １－６ or any two substituents attached to the same carbon atom on said 5- to 6-membered heterocyclic group are, together with the carbon atom to which they are attached, a C ３－６ Forms a cycloalkyl group, ３－６ The cycloalkyl group may optionally further comprise a halogen, a cyano group, a C １－６ Alkyl group, halogenated C １－６ Alkyl group and C １－６ substituted with one or more substituents selected from alkoxy groups; 7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

8. R ７ is selected from a tetrahydropyranyl group, which is optionally substituted by one or more substituents selected from a methyl group, an ethyl group, an isopropyl group, a monofluoromethyl group, a difluoromethyl group, and a trifluoromethyl group, or any two substituents attached to the same carbon atom on the tetrahydropyranyl group together with the carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group, and the ring formed is optionally further substituted by one or more substituents selected from a fluorine group, a chlorine group, a bromine group, a cyano group, a methyl group, an ethyl group, an isopropyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a methoxy group, and an ethoxy group. The compound according to any one of claims 1 to 7, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

9. R １４ represents hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ is selected from R １１ , R １２ and R １３ are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1,1,1]pentyl, optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, propyl, and isopropyl; Or R １４ teeth, 【Transformation 6】 selected from the group 7. The compound according to claim 6, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

10. selected from the following compounds: 【Transformation 7】 R １４ is hydrogen, cyano group, hydroxy group, nitro group, halogen, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ is selected from m is selected from 1, 2, 3 or 4; n is selected from 1, 2, 3 or 4; R １ and R ８ is characterized in that it is as defined in any one of claims 1 to 9 10. The compound according to any one of claims 1 to 9, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

11. R １ represents a cyano group, a halogen, C １－６ Alkyl group, halogen-substituted C １－６ Alkyl group, C ３－６ Cycloalkyl group, 3- to 6-membered heterocyclic group, halogen-substituted C ３－６ Cycloalkyl groups, halogen-substituted 3- to 6-membered heterocyclic groups, halogen-substituted C １－６ Alkoxy group, halogen-substituted C １－６ Alkylthio group, C １－６ Alkyl-substituted C ３－６ Cycloalkyl group and C １－６ alkyl-substituted 3- to 6-membered heterocyclic groups; R ８ is hydrogen, a cyano group, C ３－６ Cycloalkyl groups, 3- to 6-membered heterocyclic groups, C １－６ Alkyl group, halogen-substituted C １－６ Alkyl group, halogen-substituted C １－６ Alkoxy groups and -NR １２ R １３ characterized in that it is selected from 11. The compound according to any one of claims 1 to 10, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

12. R １ is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio; or 【Transformation 8】 and is selected from groups such as R ８ is selected from hydrogen, a cyano group, an amino group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a methyl group, an ethyl group, an isopropyl group, a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trifluoromethylthio group, an azetidinyl group, and a methylamino group.

12. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

13. selected from the following compounds: 【Chemistry 9】 R １４ is hydrogen, cyano group, hydroxy group, nitro group, halogen, C １－６ Alkyl group, halogenated C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, halogenated C １－６ Alkoxy group, —C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ is selected from m is selected from 1, 2, 3 or 4 13. The compound according to any one of claims 1 to 12, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

14. R １４ represents hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)NR １２ R １３ , -N(R １２ )-C(O)R １１ and -NR １２ R １３ and R １１ , R １２ and R １３ are each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1,1,1]pentyl, optionally substituted by one or more substituents selected from fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, propyl, and isopropyl; Preferably, R １４ is hydrogen, cyano group, fluorine, chlorine, bromine, C １－６ Alkyl group, halogenated C １－６ Alkyl group, halogenated C １－６ alkoxy groups, More preferably, R １４ is selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, and trifluoromethoxy groups. The compound according to any one of claims 10 to 13, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

15. characterized in that the compound is selected from the following compounds:

15. The compound according to any one of claims 1 to 14, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】

16. characterized in that the compound is selected from the following compounds:

16. The compound according to any one of claims 1 to 15, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】

17. It includes the following steps: 【Chemistry 21】 Here, R １６ is selected from H, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ and n are defined as defined in any one of claims 1 to 16, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

18. 1. A pharmaceutical composition comprising:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. Use of a compound according to any one of claims 1 to 16, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing a GLP-1 receptor agonist-mediated disease.

20. Use of the compound according to any one of claims 1 to 16, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, or hyperinsulinemia.

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