A glp-1 receptor agonist and methods of making and using the same

Abstract

Disclosed are a GLP-1 receptor agonist and a preparation method and use thereof. Specifically, a compound shown in formula (I) is disclosed, and the compound can be used for preparing a GLP-1 receptor-mediated disease.

Description

Technical Field

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

[0002] Obesity is a prevalent chronic disease in modern society and is associated with numerous medical problems, including hypertension, hypercholesterolemia, and coronary heart disease. Currently, the only treatment that effectively eliminates obesity is bariatric surgery, but this treatment is expensive and carries high risks. Pharmacological interventions are often less effective and are 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. When GLP-1 binds to the GLP-1 receptor, it triggers a series of biological effects. Studies have shown that GLP-1 promotes insulin secretion in a glucose-dependent manner. That is, when blood glucose concentrations in the human body rise, GLP-1 stimulates pancreatic cells, increases insulin secretion, and lowers blood glucose. GLP-1 receptor agonists are a new type of hypoglycemic drug that can effectively control blood glucose levels without causing hypoglycemia. They can also effectively reduce weight by increasing satiety, delaying gastric emptying, suppressing appetite, slowing small intestinal motility, delaying food absorption, and reducing fat accumulation, thereby achieving the goal of weight loss.

[0004] GLP-1 receptor agonist-based peptide drugs such as liraglutide, exenatide, and semaglutide have been used in obese patients with type 2 diabetes, as well as those who are simply obese or overweight. They have demonstrated significant weight loss, but are often associated with gastrointestinal adverse reactions such as nausea and vomiting. Furthermore, patient compliance with injectable peptide products is poor, while oral peptide drugs have low bioavailability, strict dosing protocols, high costs, and a high rate of gastrointestinal side effects. Therefore, the development of new compounds with excellent biological properties, good compliance, and safety is crucial. Summary of the Invention

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

[0006] In one aspect, the present invention provides a compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in,

[0009] Ring A is selected from 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl;

[0010] R1 is selected from cyano, halogen, C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, halogen substituted C 1-10 Alkyl, halogen substituted C 3-12 Cycloalkyl, halogen-substituted 3-12 membered heterocyclic group, halogen-substituted C 1-10 Alkoxy, halogen substituted C 1-10 Alkylthio, C 1-6 Alkyl substituted C 3-12 Cycloalkyl and C 1-6 Alkyl-substituted 3-12 membered heterocyclic group;

[0011] R2 is selected from hydrogen, cyano, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy and -NR 12 R 13 ;

[0012] R3 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, azido, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent;

[0013] R4 and R5 are each independently selected from hydrogen, halogen, hydroxyl, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy and halogenated C 1-10 Alkoxy, or R4 and R5 together with the carbon atom to which they are directly attached form a C 3-12 Cycloalkyl, the C 3-12 The cycloalkyl group is optionally further substituted with one or more radicals selected from hydrogen, halogen, amino, hydroxy, C 1-10 Alkyl, halogenated C 1-10 Alkyl, C 1-10 Alkoxy and halogenated C 1-10 substituted by an alkoxy substituent;

[0014] R6 is selected from 5-10 membered heteroaryl;

[0015] R7 is selected from 3-12 membered heterocyclic group, 5-10 membered heteroaryl, and the above groups are optionally substituted by one or more selected from halogen, hydroxyl, cyano, nitro, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy and -NR 12 R 13 or any two substituents on the 3-12 membered heterocyclic group connected to the same carbon atom form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 substituted by an alkoxy substituent;

[0016] R8 is selected from hydrogen, cyano, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C 1-10 Alkoxy, halogen substituted C 1-10 Alkoxy and -NR 12 R 13 ;

[0017] Each R9 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 12 R 13 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 12 R 13 substituted by a substituent;

[0018] Each R 10 independently selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 12 R 13 substituted by a substituent;

[0019] Each R 11 Selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 12 R 13 The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl, C1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR 12 R 13 substituted by a substituent;

[0020] Each R 12 and R 13 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0021] Or, R 12 and R 13 Together with the nitrogen atom directly connected thereto, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group is formed, wherein the 4-10 membered heterocyclic group or the 4-10 membered heteroaryl group is optionally further substituted by one or more radicals selected from deuterium, halogen, hydroxyl, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C1-10 Alkoxy, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 substituted with an alkanoyl substituent;

[0022] Each r is independently 0, 1 or 2;

[0023] n is selected from 0, 1, 2, 3 or 4.

[0024] This plan must meet any of the following conditions:

[0025] a. When A is selected from C 6-10 When aryl and 5-10 membered heteroaryl, n is not equal to 0, at least one R1 is selected from cyano, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, halogen substituted C 3-12 Cycloalkyl, halogen-substituted 3-12 membered heterocyclic group, halogen-substituted C 1-10 Alkoxy, C 1-6 Alkyl substituted C 3-12 Cycloalkyl and C 1-6 an alkyl-substituted 3-12-membered heterocyclic group,

[0026] b. When A is selected from C 6-10 Aryl and 5-10 membered heteroaryl, n is not equal to 0, and R1 is selected only from halogen and / or C 1-10 Alkyl and / or halogen substituted C 1-10 Alkyl, and R3 is selected from C 6-8 Aryl and 5-6 membered heteroaryl, the above groups are at least one selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 Substituted by a substituent, the -NR 12 R 13 and -C(O)NR 12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R12 Selected from C 3-12 Cycloalkyl, the C 3-12 The cycloalkyl groups are independently optionally further substituted with one or more radicals selected from deuterium, halogen, hydroxyl, cyano, C 1-10 Alkyl, halogen substituted C 1-10 Alkyl and C 1-10 substituted by an alkoxy substituent;

[0027] As a preferred embodiment, ring A is selected from 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl;

[0028] R1 is selected from cyano, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-6 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, halogen substituted C 1-6 Alkylthio, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0029] R2 is selected from hydrogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy and halogen substituted C 1-6 alkoxy;

[0030] R3 is selected from 5-10 membered heteroaryl and C 6-10 Aryl, the above groups are optionally further substituted by one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy and -S(O) r R9, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 substituted by a substituent;

[0031] R4 and R5 together with the carbon atom to which they are directly attached form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from hydrogen, halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6substituted by an alkyl substituent;

[0032] R6 is selected from 5-6 membered heteroaryl;

[0033] R7 is selected from 3-6 membered heterocyclic groups, wherein the 3-6 membered heterocyclic groups are optionally substituted by one or more selected from halogen, hydroxy, cyano, nitro, C 1-6 Alkyl and halogen substituted C 1-6 or any two substituents on the same carbon atom of the 3-6 membered heterocyclic group and the carbon atom to which they are connected form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 substituted by an alkoxy substituent;

[0034] R8 is selected from hydrogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy and -NR 12 R 13 ;

[0035] R 11 、R 12 and R 13 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogens, 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0036] This plan must meet any of the following conditions:

[0037] a. When A is selected from C 6-8 Aryl and 5-8 membered heteroaryl, n is not equal to 0, at least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0038] b. When A is selected from C 6-8Aryl and 5-8 membered heteroaryl, n is not equal to 0, and R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, and R3 is selected from C 6-8 When aryl and 5-6 membered heteroaryl, the above groups are at least one selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 Substituted by a substituent, the -NR 12 R 13 and -C(O)NR 12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-12 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent;

[0039] Said "R1 is only selected from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 "Alkyl" means that R1 is selected only from halogen, C 1-6 Alkyl, halogen substituted C 1-6 Any one of alkyl, or R1 is selected only from halogen, C 1-6 Alkyl, halogen substituted C 1-6 Multiple alkyl groups, except halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, R1 is no longer selected from other groups.

[0040] As a preferred embodiment, R2 is selected from methyl, ethyl and isopropyl; R4 and R5 together with the carbon atom to which they are directly connected form a cyclopropyl or cyclobutyl group, and the cyclopropyl or cyclobutyl group is optionally further substituted with one or more substituents selected from methyl, ethyl and isopropyl;

[0041] R6 is selected from

[0042] As a preferred embodiment, ring A is selected from phenyl, pyridyl and pyrimidinyl.

[0043] As a preferred embodiment, the compound is selected from the following formula:

[0044]

[0045] R3 is selected from 5-10 membered heteroaryl and C 6-10 Aryl, the above groups are optionally further substituted by one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -S(O) r R9, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 substituted by a substituent;

[0046] R 11 、R 12 and R 13 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogens, 1-6 Alkyl and C 1-6 substituted by an alkyl substituent;

[0047] n is selected from 1, 2, 3 or 4;

[0048] R1, R7 and R8 are as defined above;

[0049] This plan must meet any of the following conditions:

[0050] a. At least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0051] b. R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, and R3 is selected from C 6-8 When aryl and 5-6 membered heteroaryl, the above groups are at least one selected from cyano, -NR12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 Substituted by a substituent, the -NR 12 R 13 and -C(O)NR 12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0052] As a preferred embodiment, R3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups:

[0053]

[0054] The above groups are optionally further substituted by one or more selected from cyano, nitro, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 substituted by a substituent;

[0055] R 11 、R 12 and R 13 As defined above.

[0056] As a preferred embodiment, the compound is selected from the following formula:

[0057]

[0058] n is selected from 1, 2, 3 or 4;

[0059] m is 0, 1, 2, 3, 4, 5 or 6;

[0060] R 14 Selected from hydrogen, cyano, hydroxy, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 ;

[0061] R 11 、R 12 and R 13 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogens, 1-6 Alkyl and C 1-6 substituted by an alkyl substituent;

[0062] R1, R7 and R8 are as defined above;

[0063] This scheme (II-I) must meet any of the following conditions:

[0064] a. At least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0065] b. R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, at least one R 14 Selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the -NR 12 R 13 and -C(O)NR 12 R 13Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0066] As a preferred embodiment, R7 is selected from 5-6 membered heterocyclic groups, which are optionally substituted by one or more halogen, hydroxy, cyano, nitro, C 1-6 Alkyl and halogen substituted C 1-6 or any two substituents on the same carbon atom of the 3-6 membered heterocyclic group and the carbon atom to which they are connected form a C 3-6 Cycloalkyl, the C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more radicals selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and C 1-6 substituted by an alkoxy substituent.

[0067] As a preferred embodiment, R7 is selected from tetrahydropyranyl, and the tetrahydropyranyl is optionally substituted by one or more substituents selected from methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl and trifluoromethyl, or any two substituents on the tetrahydropyranyl attached to the same carbon atom form a cyclopropyl, cyclobutyl and cyclopentyl group with the carbon atom to which they are attached, and the ring formed is optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy and ethoxy.

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

[0069]

[0070] R 14 Selected from hydrogen, cyano, hydroxy, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 12 R13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 ;

[0071] R 11 、R 12 and R 13 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl and C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted by one or more halogens, 1-6 Alkyl and C 1-6 substituted by an alkyl substituent;

[0072] R 15 Selected from C 1-6 Alkyl and halogen substituted C 1-6 Alkyl, or any two R attached to the same carbon atom 15 The carbon atom to which it is connected forms a C 3-6 Cycloalkyl;

[0073] p is selected from 1, 2, 3 or 4;

[0074] m is selected from 1, 2, 3 or 4;

[0075] n, R1 and R8 are as defined above.

[0076] The compounds in this scheme must meet any of the following conditions:

[0077] a. At least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0078] b. R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, at least one R 14 Selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the -NR 12 R 13 and -C(O)NR12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0079] As a preferred embodiment, the compound is selected from the following:

[0080]

[0081] R1, R8, R 14 、R 15 , p, m and n are as defined above;

[0082] The compounds in this scheme must meet any of the following conditions:

[0083] a. At least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0084] b. R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, at least one R 14 Selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the -NR 12 R 13 and -C(O)NR 12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the -N(R12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0085] As a preferred solution, R 15 Selected from hydrogen, methyl and ethyl, or any two R attached to the same carbon atom 15 The carbon atom to which it is attached forms a cyclopropyl, cyclobutyl or cyclopentyl group; R 14 selected from hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, 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 ;

[0086] 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]pentanyl, which are optionally substituted with one or more substituents selected from fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, propyl and isopropyl;

[0087] As a preferred solution, R 14 Selected from the following groups:

[0088]

[0089] As a preferred embodiment, the compound is selected from the following:

[0090]

[0091] R 14 Selected from hydrogen, cyano, hydroxy, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 ;

[0092] m is selected from 1, 2, 3 or 4;

[0093] n is selected from 1, 2, 3 or 4;

[0094] R1 and R8 are as defined above.

[0095] The compounds in this scheme must meet any of the following conditions:

[0096] a. At least one R1 is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl-substituted 3-6 membered heterocyclic group;

[0097] b. R1 is selected only from halogen and / or C 1-6 Alkyl and / or halogen substituted C 1-6 Alkyl, at least one R 14 Selected from cyano, -NR 12 R 13 、-C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the -NR 12 R 13 and -C(O)NR 12 R 13 Middle R 12 or R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, the -N(R 12 )-C(O)R 11 Middle R 11 or R 12 Selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl groups are optionally further substituted with one or more radicals selected from deuterium, halogen, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkyl substituent.

[0098] As a further preferred solution, R14 selected from hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, 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 .

[0099] As a preferred embodiment, R1 is selected from cyano, halogen, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, halogen substituted C 1-6 Alkylthio, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl substituted 3-6 membered heterocyclic group; provided that at least one R1 in the compound is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 The 3- to 6-membered heterocyclic group is substituted by an alkyl group.

[0100] As a further preferred embodiment, R1 is selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and trifluoromethylthio, or is selected from the following groups:

[0101]

[0102] Provided that at least one R1 in the compound is selected from cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl substituted 3-6 membered heterocyclic group

[0103] As a preferred solution, for

[0104] As a preferred embodiment, R2 is methyl.

[0105] As a preferred solution, for

[0106] As a preferred solution, R7 is

[0107] As a preferred embodiment, R8 is H.

[0108] As a preferred embodiment, R8 is selected from hydrogen, cyano, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkoxy and -NR 12 R 13 .

[0109] As a further preferred embodiment, R8 is selected from hydrogen, cyano, amino, cyclopropyl, cyclobutyl, cyclopentyl, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, azetidinyl and methylamino.

[0110] As a preferred embodiment, the compound is selected from the following:

[0111]

[0112] R 14 Selected from hydrogen, cyano, hydroxy, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 12 R 13 、-N(R 12 )-C(O)R 11 and -NR 12 R 13 .

[0113] m is selected from 1, 2, 3 or 4.

[0114] As a further preferred solution, R 14selected from hydrogen, cyano, nitro, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropyloxy, 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 .

[0115] As a further preferred solution, R 14 Selected from hydrogen, cyano, fluorine, chlorine, bromine, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy.

[0116] As a further preferred solution, R 14 Selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, trifluoromethoxy.

[0117] As a further preferred solution, for

[0118] Among them, R 14a 、R 14b are each independently selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, and R 14b When it is hydrogen, R 14a Also hydrogen.

[0119] As a further preferred solution, R 14b Not hydrogen.

[0120] As a further preferred solution, R 14a 、R 14b At least one of them is a halogen-containing group, that is, R 14a 、R 14b At least one of them is fluorine, chlorine, trifluoromethyl, or trifluoromethoxy.

[0121] As a further preferred solution, R 14a 、R 14b Each is independently selected from hydrogen, fluorine and chlorine.

[0122] As a further preferred embodiment, Ring A, R1, R2, R3, R4, R5, R6, R7, and R8 are each independently a group corresponding to the compounds in the examples.

[0123] As a preferred embodiment, the compound is selected from the following:

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] As a preferred embodiment, the compound is selected from the following:

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] Another aspect of the present invention provides a method for preparing the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

[0137]

[0138] where R 16 Selected from H.

[0139] Where appropriate, the various starting materials, intermediates and compounds described herein can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. These compounds can be characterized using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance and various spectroscopic analyses.

[0140] Another aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

[0141] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing diseases mediated by GLP-1 receptor agonists.

[0142] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical composition in the preparation of a method for preventing and / or treating diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia and hyperinsulinemia.

[0143] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0144] The present inventors have conducted extensive and in-depth research, and through extensive screening and testing, have provided a class of GLP-1 receptor agonists with novel structures, on the basis of which the present invention was completed.

[0145] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0146] As used herein, "comprising" or "including" may be open, semi-closed or closed. In other words, the term also includes "consisting essentially of" or "consisting of."

[0147] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched alkyl group having 1 to 10, 1 to 6, or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl , 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or its various branched chain isomers, etc. “C1-10 "Alkyl" refers to a straight chain alkyl group or a branched chain alkyl group containing 1 to 10 carbon atoms. 1-4 The term "alkyl" refers to straight-chain and branched-chain alkyl groups having 1 to 4 carbon atoms.

[0148] Alkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0149] "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system. Cycloalkyl is divided into monocyclic cycloalkyl and polycyclic cycloalkyl, preferably a cycloalkyl containing 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 12 carbon atoms, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:

[0150] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0151] Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spiroalkyl" refers to a polycyclic group in which the rings share a carbon atom (called a spiro atom). These may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl groups are classified as monospiroalkyl, bispiroalkyl, or polyspiroalkyl groups based on the number of spiro atoms shared between the rings. Spiroalkyl groups include, but are not limited to:

[0152]

[0153] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused cycloalkyl groups include, but are not limited to:

[0154]

[0155] "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged cycloalkyl groups include, but are not limited to:

[0156]

[0157] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl and the like.

[0158] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0159] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, or 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, the heterocyclic group comprises 3 to 12, 3 to 8, or 3 to 6 ring atoms. For example, a "3-6 membered heterocyclic group" refers to a ring group comprising 3 to 6 ring atoms, a "4-6 membered heterocyclic group" refers to a ring group comprising 4 to 6 ring atoms, a "4-10 membered heterocyclic group" refers to a ring group comprising 4 to 10 ring atoms, and a "3-12 membered heterocyclic group" refers to a ring group comprising 3 to 12 ring atoms.

[0160] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0161] Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the single rings share an atom (called a spiro atom), wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (where r is an integer 0, 1, or 2) with the remaining ring atoms being carbon. These may contain one or more double bonds (preferably 1, 2, or 3), but no ring has a completely conjugated π electron system. Spiro heterocyclic groups are classified as monospiro heterocyclic groups, dispiro heterocyclic groups, or polyspiro heterocyclic groups based on the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0162]

[0163] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, fused heterocyclic alkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Fused heterocyclic groups include, but are not limited to:

[0164]

[0165] "Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a completely conjugated π electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, or 2) and the remaining ring atoms are carbon. Depending on the number of rings, bridged heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. Bridged heterocyclic groups include, but are not limited to:

[0166]

[0167] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:

[0168]

[0169] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 replaced.

[0170] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings with adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably an all-carbon aromatic group containing 5-10 or 5-8 carbon atoms, for example, "C 6-10 "Aryl" refers to an all-carbon aromatic group containing 6-10 carbon atoms, including but not limited to phenyl and naphthyl. 6-8 "Aryl" refers to an all-carbon aromatic group containing 6-8 carbon atoms, wherein the aromatic ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, including but not limited to:

[0171]

[0172] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0173] "Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, benzopyrazolyl, The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:

[0174]

[0175] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0176] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2-10 or 2-4 carbon atoms, for example, C 2-10 Alkenyl refers to a straight or branched chain alkenyl containing 2 to 10 carbon atoms. 2-4 Alkenyl refers to a straight or branched chain alkenyl group containing 2 to 4 carbon atoms, including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.

[0177] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0178] "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbon atoms, for example, C 2-10 Alkynyl refers to a straight or branched chain alkynyl containing 2 to 10 carbon atoms. 2-4 Alkynyl refers to a straight or branched chain alkynyl group containing 2 to 4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

[0179] "Alkynyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0180] "Alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above, for example, "C 1-10 "Alkoxy" refers to an alkyloxy group containing 1 to 10 carbon atoms, C 1-4 The term "alkoxy" refers to an alkyloxy group containing 1 to 4 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0181] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0182] "Cycloalkoxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above, for example, "C 3-12 "Cycloalkyloxy" refers to a cycloalkyloxy group containing 3 to 12 carbon atoms. 3-6 The term "cycloalkyloxy" refers to cycloalkyloxy groups containing 3 to 6 carbon atoms, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0183] "Cycloalkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0184] "Heterocyclyl" refers to an -O-heterocyclyl group, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy, azopentyloxy, nitrogen, oxhexyloxy, and the like.

[0185] "Heterocyclyloxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -S(O) r R9, -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 substituted by a substituent.

[0186] The above R9, R 10 、R 11 、R 12 、R 13 The definition of is the same as above.

[0187] “C 1-10 "Alkanoyl" refers to C 1-10 The monovalent atomic group remaining after removing the hydroxyl group from the alkyl acid is usually expressed as "C 0-9 "C1 alkyl-C(O)-" refers to acetyl; "C2 alkyl-C(O)-" refers to propionyl; "C3 alkyl-C(O)-" refers to butyryl or isobutyryl.

[0188] "Halogen-substituted C 1-10The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl and tribromomethyl.

[0189] "Deuterium replaces C 1-10 "Alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by deuterium atoms, including but not limited to monodeuteriomethyl, dideuteriomethyl, trideuteriomethyl, etc.

[0190] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0191] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, i.e., includes both substituted and unsubstituted instances. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group.

[0192] "Substituted" means that one or more "hydrogen atoms" in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, consistent with chemical valence theory, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated bonds (such as olefins).

[0193] "Stereoisomers," whose English name is stereoisomer, refer to isomers resulting from the different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by rotation about single bonds are called conformational stereoisomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, the presence of double bonds or rings in the molecule are called configuration stereoisomers, which are further divided into two categories. Among them, isomers caused by the inability to rotate freely around double bonds or single bonds of ring carbon atoms are called geometric isomers, also called cis-trans isomers, and are divided into two configurations: Z and E. For example, cis-2-butene and trans-2-butene are a pair of geometric isomers. Stereoisomers with different optical rotation properties due to the lack of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations. In this invention, "stereoisomers," unless otherwise specified, are understood to include one or more of the aforementioned enantiomers, configurational isomers, and conformational isomers.

[0194] "Tautomers" refer to structural isomers of different energies that can be interconverted with a low energy barrier. For example, proton tautomers include interconversions by proton migration, and valence tautomers include interconversions by reorganization of some bonding electrons. For example and In the present invention, if the “tautomer” is not otherwise specified, all tautomeric forms of the compound are within the scope of the present invention.

[0195] "Pharmaceutically acceptable salt" in the present invention refers to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which can be prepared by methods known in the art.

[0196] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0197] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0198] The present invention will be further described below in conjunction with specific implementations. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0199] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 / 500 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0200] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer. HPLC was performed using an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0201] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0202] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0203] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures expressed in degrees Celsius (°C).

[0204] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or those recommended by the manufacturer. All reagents or instruments used, if the manufacturer is not specified, are commercially available conventional products.

[0205] In the present invention, whenever SFC chiral resolution is involved, 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 of Compound 1, two enantiomers are obtained, which are designated as Compound 1a and Compound 1b, respectively.

[0206] The reference compound a used in the present invention comes from compound 67 in patent CN109790161, and compound b comes from compound 146b in patent WO2021155841.

[0207] Preparation of intermediates

[0208] Synthesis of intermediates A-1 and A-2

[0209]

[0210] Intermediates A-1 and A-2 were synthesized by the following routes:

[0211]

[0212] Step 1: Synthesis of intermediate 1-2

[0213] To a solution of compound 1-1 (25 g, 195.1 mmol) in tetrahydrofuran (100 mL) was slowly added dropwise LDA (117 mL, 2M / THF) at -78°C under a nitrogen atmosphere. The mixture was stirred for 20 minutes. Then, a solution of N,N-bis(trifluoromethanesulfonyl)aniline (44 g, 234 mmol) in tetrahydrofuran (100 mL) was added dropwise at -70°C. After the addition was complete, the mixture was allowed to react at room temperature for 16 hours. Under an ice bath, saturated ammonium chloride solution was added dropwise, the mixture was extracted with ethyl acetate, and the mixture was washed with saturated brine. The organic phase was collected, dried, and then dried under reduced pressure to obtain the crude product, which was then purified by column chromatography (0-15% petroleum ether / ethyl acetate) to afford compound 1-2 (38.2 g, 75%).

[0214] Step 2: Synthesis of Intermediates 1-4

[0215] To a solution of compound 1-3 (25 g, 0.12 mol) in N,N-dimethylformamide (100 mL) was added potassium tert-butoxide (13 g, 0.12 mol) under ice-bath. After stirring at room temperature for 40 minutes, iodomethane (20 g, 0.14 mol) was slowly added dropwise under ice-bath and stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride solution was added, extracted with ethyl acetate, and washed with saturated brine. The organic phase was collected and dried, and the crude product was dried under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to obtain compound 1-4 (16.6 g, 70%).

[0216] LC-MS (ESI+ )m / z:230.1(M+H) + .

[0217] Step 3: Synthesis of Intermediates 1-6

[0218] Under ice bath, 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). After stirring at room temperature for 2 hours, the mixture was cooled to 0 ° C and stirred for 30 minutes. The mixture was filtered and beaten with methyl tert-butyl ether twice to obtain a crude product which was further purified (methanol / dichloromethane = 0-5%) to give compound 1-4 (3.6 g, 95%).

[0219] Step 4: Synthesis of Intermediates 1-8

[0220] Under a nitrogen atmosphere, a mixture of 1,4-dioxane / water (300 mL / 30 mL) containing compound 1-7 (28 g, 0.10 mol), diboronic acid pinacol ester (53 g, 0.20 mol), Pd(dppf)Cl2 (3.8 g, 5.2 mmol) and potassium acetate (20.5 g, 0.21 mol) was heated to 80 ° C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-15%) to give compound 1-8 (32.7 g, 99%).

[0221] LC-MS (ESI + )m / z:316.2(M+H) + .

[0222] Step 5: Synthesis of Intermediate 1-9

[0223] Under a nitrogen atmosphere, a mixture of 1,4-dioxane / water (250 mL / 50 mL) containing 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) was heated to 90 ° C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain compound 1-9 (9 g, 54%).

[0224] LC-MS (ESI + )m / z:300.2(M+H) + .

[0225] Step 6: Synthesis of Intermediate 1-10

[0226] To a solution of compound 1-9 (10.1 g, 33.67 mmol) in methanol (150 mL) was added Pd / C (500 mg, 10%) at room temperature. The atmosphere was replaced with nitrogen three times and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and dried under reduced pressure to obtain solid 1-10 (8.8 g), which was used directly in the next step without purification.

[0227] LC-MS (ESI + )m / z:302.2(M+H) + .

[0228] Step 7: Synthesis of Intermediate 1-11

[0229] Under an ice bath, 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 hours. Chloroacetonitrile (4.8 g, 64 mmol) was then added to the mixture, and the mixture was stirred at room temperature for 2 hours. After LCMS indicated the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate = 0-15%) to afford compound 1-11 (9.1 g, 84%).

[0230] LC-MS (ESI + )m / z:341.1(M+H) + .

[0231] Step 8: Synthesis of Intermediates 1-12

[0232] Under ice bath, 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) was slowly added dropwise lithium bis(trimethylsilyl)amide (45 mL, 1 M), and the reaction was allowed to reach room temperature for 2 hours. Saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was 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 obtain a crude product which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-20%) to obtain compound 1-12 (1.39 g, 33%).

[0233] LC-MS (ESI + )m / z:381.3(M+H) + .

[0234] Step 9: Synthesis of Intermediate 1-13

[0235] 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 hours, filtered, and concentrated under reduced pressure to obtain compound 1-13 (1.83 g), which was used directly in the next step without purification.

[0236] LC-MS (ESI + )m / z:414.3(M+H) + .

[0237] Step 10: Synthesis of Intermediate 1-14

[0238] To a solution of compound 1-13 (1.83 g, 4.40 mmol) in dimethyl sulfoxide (8 mL) were added N,N'-carbonyldiimidazole (1.44 g, 8.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 g, 11.1 mmol) in sequence at room temperature. The mixture was heated to 80°C for 2 hours. After the reaction was complete, 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 to afford the crude product, which was then separated and purified by column chromatography (methanol / dichloromethane = 0-10%) to afford compound 1-14 (1.89 g, 97%).

[0239] LC-MS (ESI + )m / z:440.3(M+H) + .

[0240] Intermediate 1-14 was chirally resolved to give compounds 1-14a (retention time: 6.61 min) and 1-14b (retention time: 7.5 min).

[0241] Chiral separation method:

[0242] Chromatographic conditions Column: 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).

[0243] Step 11: Synthesis of Intermediate A

[0244] Under ice bath, sodium hydroxide (400 mg, 10 mmol) was added to a mixed solution of tetrahydrofuran (12 mL) and water (3 mL) containing compound 1-14 (1.0 g, 2.28 mmol) and heated to 60 ° C with stirring for 2 hours. After LCMS monitoring, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was collected, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound A, which was used directly in the next step without purification.

[0245] LC-MS (ESI+) m / z: 412.3 (M+H) + .

[0246] Step 12: Synthesis of Intermediates A-1 and A-2

[0247] Under ice bath, sodium hydroxide (280 mg, 7 mmol) was added to a mixed solution of tetrahydrofuran (8 mL) and water (2 mL) containing compound 1-14a (294 mg, 0.67 mmol) and heated to 60 ° C with stirring for 2 hours. After the reaction was complete, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate. The organic phase was collected, added with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound A-1, which was used directly in the next step without purification.

[0248] LC-MS (ESI + )m / z:412.3(M+H) + .

[0249] Under ice bath, sodium hydroxide (280 mg, 7 mmol) was added to a mixed solution of tetrahydrofuran (8 mL) and water (2 mL) containing compound 1-14b (305 mg, 0.70 mmol) and heated to 60 ° C with stirring for 1 hour. After the reaction was complete, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain compound A-2, which was used directly in the next step without purification.

[0250] LC-MS (ESI + )m / z:412.3(M+H) + .

[0251] Synthesis of intermediate B

[0252]

[0253] Intermediate B was synthesized via the following route:

[0254]

[0255] Step 1: Synthesis of intermediate 2-2

[0256] Under a nitrogen atmosphere, 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 for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate = 0-5%) to afford compound 2-2 (10.8 g, 85%).

[0257] LC-MS (ESI + )m / z:152.1(M+H) + .

[0258] Step 2: Synthesis of intermediate 2-3

[0259] 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. The mixture was then slurried with methyl tert-butyl ether and filtered to obtain a white solid. Under ice, the white solid was dissolved in concentrated hydrochloric acid (60 mL) and sodium nitrite (5.10 g, 74.12 mmol) and water (20 mL) were added portionwise and stirred for 0.5 hour. Finally, a 20 mL aqueous solution of stannous chloride (21.62 g, 114 mmol) was added and stirred for 2 hours. After the reaction was complete, the mixture was filtered and dried to obtain compound 2-3 (3.9 g, 40%).

[0260] LC-MS (ESI + )m / z:167.1(M+H) + .

[0261] Step 3: Synthesis of Intermediate 2-5

[0262] At room temperature, 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). The mixture was then heated to 80°C and stirred for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and adjusted to pH 7 to 8 by adding sodium hydroxide solution. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 0-25%) to obtain compound 2-5 (3.09 g, 79%).

[0263] LC-MS (ESI +)m / z:387.3(M+H) + .

[0264] Step 4: Synthesis of Intermediate 2-6

[0265] To a solution of compound 2-5 (3.09 g, 8 mmol) in N,N-dimethylformamide (40 mL) at room temperature was added compound 1-6 (6.36 g, 32 mmol), followed by the addition of potassium tert-butoxide (4.50 g, 40 mmol) in an ice bath, and stirring continued for 16 hours. After the reaction was complete, 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 afford crude compound 2-6 (4.89 g), which was used directly in the next step without further column chromatography.

[0266] LC-MS (ESI + )m / z:518.4(M+H) + .

[0267] Step 5: Synthesis of Intermediate 2-7

[0268] To a solution of crude compound 2-6 (4.89 g) in tetrahydrofuran (20 mL) was added trifluoromethanesulfonic acid (3.50 g, 23.32 mmol) under ice, followed by heating to 60°C for 1 hour. After cooling to room temperature, triethylamine (4.36 g, 43.08 mmol) and di-tert-butyl dicarbonate (3.53 g, 16.20 mmol) were added sequentially under ice, and stirred for 1 hour. After completion of the reaction, 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 to afford the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate = 0-50%) to afford compound 2-7 (2.22 g, 61% yield over two steps).

[0269] LC-MS (ESI + )m / z:454.3(M+H) + .

[0270] Step 6: Synthesis of Intermediate 2-8

[0271] Under a nitrogen atmosphere, compound 2-7 (400 mg, 0.90 mmol), compound 1-4 (310 mg, 1.40 mmol), cuprous 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) in N-methylpyrrolidone (8 mL) were heated to 130°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, 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 obtain the crude product, which was separated and purified by column chromatography (methanol / dichloromethane = 0-5%) to obtain compound 2-8 (102 mg, 19%).

[0272] LC-MS (ESI + )m / z:602.4(M+H) + .

[0273] Step 7: Synthesis of Intermediate B

[0274] Under ice bath conditions, hydrochloric acid / dioxane solution (2 mL, 4 N) was added to a dichloromethane solution (6 mL) containing compound 2-8 (102 mg, 0.17 mmol) and the mixture was reacted for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude intermediate B (120 mg), which was used directly in the next step without further purification.

[0275] LC-MS (ESI + )m / z:502.2(M+H) + .

[0276] Synthesis of intermediate C:

[0277]

[0278] Intermediate C was synthesized via the following route:

[0279]

[0280] Step 1: Synthesis of intermediate C-2

[0281] 3,5-Dimethyl-4-fluorobromobenzene (15 g, 73.89 mmol) was added to a 1000 mL three-necked flask. After nitrogen was displaced three times, tetrahydrofuran (150 mL) was added to dissolve the mixture and the temperature was lowered to -78°C. Then, n-butyllithium (2.5 M, 29.5 mL, 73.89 mmol) was added to the reaction system and stirred for 1 hour. Finally, a solution of di-tert-butyl azodicarboxylate (16.99 g, 73.89 mmol) dissolved in tetrahydrofuran (150 mL) was added dropwise to the reaction mixture. After addition, the mixture was cooled to -40°C and stirred for 0.5 hour. The temperature was slowly raised to room temperature and the reaction was continued for 2 h. 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 with Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound C-2 (11.7 g, 45%).

[0282] 1 H NMR (400MHz, CDCl3) δ6.98 (s, 2H), 6.65 (s, 1H), 2.16 (d, J = 2.0Hz, 6H), 1.42 (s, 18H).

[0283] Step 2: Synthesis of intermediate C-3

[0284] 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 was stirred at 80 °C for 12 h, then cooled to room temperature, toluene (10 mL) was added, and the pH was adjusted to 9 with potassium carbonate solution to obtain an organic phase. Tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (3 g, 8.46 mmol) and pyridine hydrochloride (98 mg, 0.85 mmol) were added to the above solution in sequence, and the temperature was raised to 90 °C and stirred for 1 h. After the reaction was completed by LCMS, water (50 mL) was added, and the pH was adjusted to 9 with NaOH solution. The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 4:1) to obtain compound C-3 (2.2 g, 69%).

[0285] LC-MS (ESI + )m / z:375.2(M+H) + .

[0286] Step 3: Synthesis of intermediate C-4

[0287] Compound CDI (38.56 g, 237.78 mmol) was added to a 2L three-necked flask. After N2 replacement, ethyl acetate (800 mL) was added to dissolve the mixture. The reaction solution was then cooled to 0°C and aminoacetaldehyde dimethyl acetal (25 g, 237.78 mmol) was slowly added dropwise. After the addition, the mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was washed with water (200 mL) and then with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound C-4 (23.5 g, 49.6%).

[0288] 1 H NMR(400MHz,DMSO-d6)δ8.70(t,J=5.5Hz,1H),8.28(s,1H),7.74-7.70(m,1H) ,7.06-7.04(m,1H),4.52(t,J=5.4Hz,1H),3.36(t,J=5.6Hz,2H),3.32(s,6H).

[0289] Step 4: Synthesis of intermediate C-5

[0290] 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 tert-butoxide (1.35 g, 12.03 mmol) was then added to the reaction mixture and allowed to react at room temperature for 2 h. After completion of the reaction, as monitored by LCMS, the mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford compound C-5 (2 g, 99%).

[0291] LC-MS (ESI + )m / z:506.0(M+H) + .

[0292] Step 5: Synthesis of intermediate C-6

[0293] Methanesulfonic acid (300 mg, 3.17 mmol, 0.8 eq) was added to a toluene (20 mL) solution of compound C-5 (2 g, 3.96 mmol), and the mixture was allowed to react at 60°C for 2 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL × 3) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase purification (petroleum ether:ethyl acetate = 1:1) to obtain compound C-6 (1.12 g, 64%).

[0294] LC-MS (ESI + )m / z:442.0(M+H)+ ;

[0295] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.07(d,J=6.3Hz,2H),6.58(dd,J=11.1,8.6Hz,2H),5.05(br.s,1H),4.20(br.s,1 H), 3.30 (d, J = 2.6Hz, 1H), 3.10 (br.s, 2H), 2.70-2.60 (m, 2H), 2.19 (d, J = 1.6Hz, 6H), 1.43 (s, 9H), 1.13 (d, J = 6.3Hz, 3H).

[0296] Step 6: Synthesis of intermediate C-7

[0297] To a solution of compound C-6 (1.12 g, 2.54 mmol) in NMP (10 mL) were added 5-bromo-4-fluoro-1-methyl-1H-indazole (1.16 g, 5.08 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (180 mg, 1.27 mmol), cuprous iodide (97 mg, 0.51 mmol), and potassium carbonate (1.05 g, 7.62 mmol). The mixture was reacted at 130°C under nitrogen for 3 h. After completion of the reaction, the reaction mixture was washed with water (50 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase purification (petroleum ether:ethyl acetate = 2:1) to obtain compound C-7 (1.28 g, 86%).

[0298] LC-MS (ESI + )m / z:590.0(M+H) + .

[0299] Step 7: Synthesis of Intermediate C

[0300] To a solution of compound C-7 (1.18 g, 2.00 mmol) in ethyl acetate (10 mL) was added ethyl acetate (20 mL) and the mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was concentrated, and saturated aqueous sodium bicarbonate (20 mL) was added. The pH was adjusted to alkaline, and then ethyl acetate (20 mL × 3) was added for extraction. The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound C (960 mg, 98%).

[0301] LC-MS (ESI + )m / z:490.0(M+H) + .

[0302] Preparation of specific compounds

[0303] Example 1: Synthesis of Compounds 1a and 1b

[0304]

[0305] Compounds 1a and 1b were synthesized via the following route:

[0306]

[0307] To a solution of Intermediate A-1 (41 mg, 0.10 mmol) and DIPEA (40 mg, 0.30 mmol) in N,N-dimethylformamide was added HATU (57 mg, 0.15 mmol) under ice-cooling conditions and stirred for 30 minutes. Intermediate B (50 mg, 0.1 mmol) was then added and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was washed with water and extracted with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered to obtain the crude product, which was then purified by preparative HPLC to afford Compound 1a (36 mg, 40%).

[0308] LC-MS (ESI + )m / z:895.53(M+H) + .

[0309] Compound 1b was prepared from intermediate A-2 and intermediate B. The synthetic procedure was similar to that of 1a to obtain compound 1b (25 mg, 28%).

[0310] LC-MS (ESI + )m / z:895.44(M+H) + .

[0311] Compound 1a:

[0312] 1H NMR (400MHz, DMSO-d6) δ11.77(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=13.6Hz,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 ), 1.79 (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).

[0313] Compound 1b:

[0314] 1 H NMR (400MHz, DMSO-d6) δ11.75(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).

[0315] Compounds 2 to 4 can be obtained by referring to the preparation method of Example 1:

[0316]

[0317] Example 2: Synthesis of Compound 5

[0318]

[0319] Compound 5 was synthesized via the following route:

[0320]

[0321] Step 1: Synthesis of compound 5-2

[0322] Compound 5-1 (10.0 g, 42.4 mmol) and N-methylcyclopropaneamine (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. The reaction mixture was stirred at room temperature for 1 hour. The 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 obtain the target compound 5-2 (8.1 g, 66% yield).

[0323] LC-MS (ESI + )m / z:290.1(M+H) + ;

[0324] 1 H NMR (400MHz, CDCl3) δ7.42-7.37(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).

[0325] Step 2: Synthesis of compound 5-3

[0326] Compounds C-6 (5.0 g, 11.32 mmol) and 5-2 (3.3 g, 11.32 mmol) were dissolved in N-methylpyrrolidone (50 mL) solution, and then compound N,N'-dimethyl-1,2-cyclohexanediamine (0.8 g, 5.62 mmol), cuprous iodide (0.4 g, 2.25 mmol) and potassium carbonate (4.7 g, 34.01 mmol) were added to the reaction solution in sequence. The reaction solution was stirred at 130 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution to dilute it. The mixture was 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 give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 9:1) and then purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 80%-100%) to give the target compound 5-3 (5.0 g, yield 68%).

[0327] LC-MS (ESI + )m / z:651.4(M+H) + .

[0328] Step 3: Synthesis of compound 5-4

[0329] 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). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to remove most of the solvent, and saturated aqueous sodium bicarbonate (50 mL) was added to the residue to adjust the pH to 9. The mixture was 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 obtain the crude target product 5-4 (4.4 g), which was used directly in the next step without purification.

[0330] LC-MS (ESI + )m / z:551.3(M+H) + .

[0331] Step 4: Synthesis of compound 5

[0332] 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). 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 hours. The reaction mixture was purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 65%-80%) to obtain the target compound 5 (3.15 g, 57% yield).

[0333] LC-MS (ESI + )m / z:944.4(M+H) + .

[0334] 1 H NMR (400MHz, CDCl3) δ11.38-11.18(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).

[0335] Compounds 6 to 55 can be obtained by referring to the preparation method of Example 2:

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350] Example 3: Synthesis of Compounds 56a and 56b

[0351]

[0352] Compound 56 was synthesized via the following route:

[0353]

[0354] Step 1: Synthesis of compound 56-2

[0355] Compound 56-1 (1.2 g, 4.90 mmol) was dissolved in ethanol (6 mL), and sodium borohydride (278 mg, 7.35 mmol) was added. The mixture was stirred at room temperature overnight. Saturated ammonium chloride (100 mL) was added to the reaction mixture to quench the reaction. The mixture was 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 obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% to 10%) to obtain the target compound 56-2 (580 mg, 48% yield).

[0356] 1 H NMR (400MHz, DMSO-d6) δ8.22 (s, 1H), 7.51 (d, J = 8.7Hz, 1H), 7.43 (dd, J = 8.7, 6.4Hz, 1H), 4.07 (s, 4H).

[0357] Step 2: Synthesis of compound 56-3

[0358] Compound 56-2 (62 mg, 0.25 mmol) was dissolved in N-methylpyrrolidone (2 mL), and INT5-4 (110 mg, 0.25 mmol), cuprous 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. The reaction mixture was stirred at 130°C under a nitrogen atmosphere for 3 hours. Water (30 mL) was added to the reaction mixture for dilution, followed by extraction 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 obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10% to 60%) to obtain the target compound 56-3 (150 mg, yield 99%).

[0359] LC-MS (ESI + )m / z:608.2(M+H) + .

[0360] Step 3: Synthesis of compound 56-4

[0361] Compound 56-3 (100 mg, 0.16 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (4 M, 2 mL), and the reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was directly concentrated to obtain the crude target product 56-4 (70 mg).

[0362] LC-MS (ESI + )m / z:508.1(M+H) + .

[0363] Step 4: Synthesis of compound 56

[0364] 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 hour. The reaction mixture was directly purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 5%-50%) to obtain the target compound 56a (46 mg, 42% yield).

[0365] LC-MS (ESI + )m / z:901.4(M+H) + ;

[0366] 1 H NMR (400MHz, CDCl3) δ11.26 (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,2H),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).

[0367] Compound 56b was prepared by using compound A-2 and compound 56-4 according to the synthetic method of 56a.

[0368]

[0369] LC-MS (ESI + )m / z:901.3(M+H) + ;

[0370] 1 H NMR (400MHz, CDCl3) δ11.27 (d, J = 32.1Hz, 1H), 7.99-7.65 (m, 2H), 7.63-7.44 (m, 3H), 7.40-7.27 (m, 1H) ,7.14-6.97(m,2H),6.83-6.63(m,2H),6.41-6.16(m,1H),5.81-5.19(m,1H),4.91-4.40(m,1H),3.91-3 .78(m,2H),3.63-3.28(m,5H),3.22-2.94(m,3H),2.23(dd,J=15.6,1.8Hz,6H),1.94-1.83(m,1H),1.76 -1.68(m,4H),1.65-1.57(m,2H),1.53-1.50(m,2H),1.34(s,3H),1.31-1.21(m,4H),1.19-1.03(m,3H).

[0371] Compounds 57 to 62 can be obtained by referring to the preparation method of Example 3:

[0372]

[0373]

[0374] Example 4:

[0375]

[0376] Compound 63 was synthesized via the following route:

[0377]

[0378] Step 1: Synthesis of compound 63-2

[0379] 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). 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. The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The organic phase was washed with saturated brine (80 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 = 9:1 to 4:1) to obtain the title compound (1 g, 49% yield).

[0380] LC-MS (ESI + )m / z:257.9(M+H) + ;

[0381] 1 HNMR (400MHz, CDCl3) δ8.16(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).

[0382] Step 2: Synthesis of compound 63-3

[0383] 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 portionwise. The mixture was stirred for 30 minutes, followed by the slow dropwise addition of iodomethane (412 mg, 2.91 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Ice water (50 mL) was added to the reaction mixture to quench the reaction mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound 63-3 (300 mg, 57% yield).

[0384] LC-MS (ESI + )m / z:272.0(M+H) + ;

[0385] 1 HNMR (400MHz, CDCl3) δ7.75 (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).

[0386] Step 3: Synthesis of compound 63-4

[0387] Compound C-6 (180 mg, 0.41 mmol) and compound 63-3 (134 mg, 0.49 mmol) were dissolved in N-methylpyrrolidone (3 mL). N,N'-dimethyl-1,2-cyclohexanediamine (24 mg, 0.17 mmol), potassium carbonate (171 mg, 1.24 mmol), and cuprous iodide (16 mg, 0.084 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 130°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The mixture was 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 obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:5) to obtain the target compound 63-4 (236 mg, 92% yield).

[0388] 1HNMR(400MHz, CDCl3)δ7.62-7.56(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,3H),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).

[0389] Step 4: Synthesis of compound 63-5

[0390] A 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added to a solution of 63-4 (231 mg, 0.37 mmol) in 1,4-dioxane (4 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to afford the title compound (192 mg, 99% yield).

[0391] LC-MS (ESI + )m / z:533.3(M+H) + .

[0392] Step 5: Synthesis of compound 63

[0393] Compound 63-5 (176 mg, 0.33 mmol) and compound A (90 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). 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. The reaction mixture was stirred at room temperature for 16 hours. Water (30 mL) was added to dilute the reaction mixture and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by reverse-phase chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound 63 (102 mg, 50% yield).

[0394] LC-MS (ESI + )m / z:926.8(M+H) + ;

[0395] 1H NMR (400MHz, CDCl3) δ11.34-11.20(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).

[0396] Compounds 63a to 77 can be obtained by referring to the preparation method of Example 4:

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403] Example 5:

[0404]

[0405] Compound 78 was synthesized via the following route:

[0406]

[0407] Step 1: Synthesis of compound 78-2

[0408] 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), cuprous iodide (10 mg, 0.05 mmol), and potassium carbonate (110 mg, 0.81 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130°C under a nitrogen atmosphere for 3 hours. 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 obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the target compound 78-2 (130 mg, yield 76%).

[0409] LC-MS (ESI + )m / z:627.4(M+H) + .

[0410] Step 2: Synthesis of compound 78-3

[0411] Compound 78-2 (120 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and a 4M solution of hydrogen chloride in dioxane (4 mL) was added. The reaction mixture was stirred 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) and water (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to yield product 78-3 (90 mg, 89%).

[0412] LC-MS (ESI + )m / z:527.4(M+H) + ;

[0413] 1H NMR (400MHz, CDCl3) δ7.89(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).

[0414] Step 3: Synthesis of Compound 78

[0415] 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. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 5%-60%) to obtain the target compound 78 (59 mg, 52%).

[0416] LC-MS (ESI + )m / z:920.4(M+H) + ;

[0417] 1 H NMR (400MHz, CDCl3) δ11.39-11.03(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),2.4 4-2.06(m,6H),1.79-1.49(m,10H),1.38-1.25(m,6H),1.19-1.04(m,3H).

[0418] Compounds 79 to 97 can be obtained by referring to the preparation method of Example 5:

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426] Biological test evaluation

[0427] 1. Determination of cAMP levels in HEK293T cells stably transfected with human GLP-1R

[0428] Experimental instruments

[0429]

[0430] 2. Experimental Materials

[0431]

[0432]

[0433] 3. Experimental Methods

[0434] Human GLP-1R HEK293T stably transfected cells were trypsinized and terminated with DMEM total (without p / s). After centrifugation, cells were washed twice with 1X stimulation buffer, resuspended in 1X stimulation buffer, counted, and then resuspended in stimulation buffer to a 1 million / mL cell suspension. Compound powder was first prepared with DMSO to a 10mM stock solution. The 10mM compound stock solution was then diluted to 2mM with DMSO. A 2X compound was then prepared in 1X stimulation buffer (the buffer provided with the Cisbio kit, with IBMX freshly added to a final concentration of 0.5mM). The top dose final concentration was 2000nM, the final DMSO concentration was 0.2%, and a 1:3 serial dilution was performed over 11 steps.

[0435] According to the layout, add 5 μl of compound to each well; the Min well contains 100 nM GLP-1, and the Max 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 incubate at 37°C for 30 minutes. Prepare a 2X cAMP standard in 1X stimulation buffer to a final concentration of 2.8 μM. Make a 1:3 serial dilution across 12 doses, and according to the layout, add 10 μl to each well. Finally, dilute d2 and the antibody 20-fold in 1X detection buffer (included with the Cisbio kit). According to the layout, add 5 μl of each to each well. Centrifuge at 300 rpm for 1 minute at room temperature, and incubate at room temperature for 2 hours.

[0436] 4. Data Analysis

[0437] Stimulation% was calculated based on the Min and Max readings (665nm / 615nm ratio): 100*(Ratio Max well - Ratio Test well) / (Ratio Max well - Ratio Min well). The cAMP concentration of each test well was fitted based on the cAMP curve. The data were then analyzed using GraphPad Prism 9, and a four-parameter fitting curve was drawn to calculate the EC. 50 , the formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope)). The results are shown in Table 1.

[0438] Table 1: cAMP level determination in HEK293T cells stably transfected with human GLP-1R

[0439]

[0440]

[0441]

[0442]

[0443] 2. Pharmacokinetic Analysis of Compounds in Mouse Plasma

[0444] 1. Experimental Materials

[0445] Male C57BL / 6J mice, about 30 g, 6-9 weeks old, were administered orally by gavage and intravenously: 3 mice / compound, respectively. Animals were obtained from Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0446] 2. Experimental Methods

[0447] The pharmacokinetic characteristics of the compounds were tested in mice following oral (PO) or intravenous (IV) administration using standard protocols. The test compound was prepared as a clear solution in a vehicle consisting of 10% (v / v) DMSO, 10% (v / v) Solutol, and 80% (v / v) Saline. Three mice were given a single oral dose of 5 mg / kg. Blood samples were collected via the submandibular vein or other appropriate means at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Approximately 0.03 mL of blood was collected via the submandibular vein or other appropriate means, anticoagulated with heparin, and placed on ice. Three mice were also given a single intravenous dose of 1 mg / kg of the test compound. Blood samples were collected via the submandibular vein or other appropriate means at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Approximately 0.03 mL of blood was collected via the submandibular vein or other appropriate means, anticoagulated with heparin, and placed on ice. The plasma was separated by centrifugation 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.

[0448] All samples were stored at -80°C prior to analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin. The results are shown in Table 2.

[0449] Table 2: Pharmacokinetic parameters

[0450]

[0451] It can be seen that the compound of the present invention has a longer half-life in mouse blood than the positive compound, the exposure amount is significantly increased, and it is expected to have better efficacy.

[0452] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, in, The compound of formula (I) is a compound of formula (V) or formula (VA): in, for Among them, R 14a 、R 14b are each independently selected from hydrogen, cyano, fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, and R 14b When it is hydrogen, R 14a Also hydrogen.

2. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 14b Not hydrogen.

3. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 14a 、R 14b At least one of them is fluorine, chlorine, trifluoromethyl, or trifluoromethoxy.

4. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: R 14a 、R 14b Each is independently selected from hydrogen, fluorine and chlorine.

5. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

6. A method for preparing the compound according to claim 1, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that: The steps include: where R 16 Selected from H; R1, R2, R3, R4, R5, R6, R7, R8 and n are defined as the same as for the compound of formula (V) or (VA) in claim 1.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 5, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing diseases mediated by GLP-1 receptor agonists.

9. Use of the compound according to any one of claims 1 to 5, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing and / or treating diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia or hyperinsulinemia.

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