Nitrogen-containing bridged ring compound as well as preparation method and application thereof

Abstract

The invention discloses a nitrogen-containing bridged ring compound serving as a GLP-1 receptor agonist as well as a preparation method and application of the nitrogen-containing bridged ring compound. Specifically, the invention discloses a compound as shown in a formula (I), and application of the compound in preparation of drugs for treating or preventing GLP-1 mediated diseases. # imgabs0 #

Description

Technical Field

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

[0002] Obesity is a very prevalent chronic disease in modern society and is associated with many medical problems, including hypertension, hypercholesterolemia and coronary heart disease. Currently, the only treatment to eliminate obesity with high efficacy is bariatric surgery, but this treatment is expensive and has high risks. Pharmacological interventions are usually less effective and are associated with side effects. Therefore, there is a clear need for more effective pharmacological interventions with fewer side effects and convenient administration.

[0003] Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted by intestinal epithelial L cells and exerts physiological effects by binding to its receptor. 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 the blood glucose concentration in the human body increases, GLP-1 stimulates pancreatic cells, increases insulin secretion, and lowers blood sugar. GLP-1 receptor agonists are a new type of hypoglycemic drug that can effectively control blood sugar levels without causing hypoglycemia, and 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 purpose 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 II diabetes and simply obese or overweight patients, and have shown significant weight loss effects, but are often accompanied by gastrointestinal adverse reactions such as nausea and vomiting. At the same time, patients have poor compliance with peptide injection products, oral peptide drugs have low bioavailability, strict medication rules, high prices, and high gastrointestinal reaction rates. Therefore, it is very necessary to develop a new compound with good biological properties, good compliance, and safety. Summary of the invention

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

[0006] 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] Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-10 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) r R7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-8 membered heteroaryl and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkoxy substituent;

[0010] R2 is selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-8 Aryl, 5-10 membered heteroaryl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-10 membered heterocyclic group, -S(O) r R7 and -NR 10 R 11 substituted by a substituent;

[0011] R3 is selected from C 3-10 Cycloalkyl, 3-10 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 deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, deuterium substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, halogen substituted C 3-10 Cycloalkyl, halogen-substituted 3-10 membered heterocyclic group, C 1-6 Alkyl substituted C 3-10 Cycloalkyl, C 1-6 Alkyl substituted 3-10 membered heterocyclic group and -NR 10 R 11 substituted by a substituent;

[0012] R4 and R5 are each independently selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or 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 halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6 substituted by an alkyl substituent;

[0013] R6 is selected from 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally further substituted by one or more selected from C 1-4 Alkyl substituted;

[0014] R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, halogenated C 6-8 substituted by aryl and 5-8 membered heteroaryl substituents;

[0015] Z1 is selected from 3-10 membered heterocyclic group, 5-10 membered aryl group, 5-10 membered heteroaryl group, -NR 10 -CO-NR 11 -(CH2) c -and-NR 10 , or Z1 is selected from the following groups:

[0016] Ring A is selected from 5-10 membered heteroaryl;

[0017] Each r is independently 0, 1 or 2;

[0018] a, b, c, n are each independently selected from 0, 1, 2, 3 or 4.

[0019] As a preferred solution, Z1 is selected from

[0020] As a preferred embodiment, the compound is selected from the following:

[0021]

[0022] R1, R2, R3, R4, R5, R6, Ring A and n are as defined above.

[0023] As a preferred embodiment, the compound is selected from the following:

[0024]

[0025] R1, R2, R3, R4, R5, R6, Ring A and n are as defined above.

[0026] As a preferred embodiment, R4 and R5 together with the carbon atom to which they are directly connected form a C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally further substituted with one or more selected from C 1-3 The alkyl group is substituted with an alkyl substituent.

[0027] As a preferred embodiment, 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 by one or more substituents selected from methyl, ethyl and isopropyl.

[0028] As a further preferred embodiment, the compound is selected from the following:

[0029]

[0030] R1, R2, R3, R6, Ring A and n are as defined above.

[0031] As a preferred solution, Selected from

[0032] As a preferred embodiment, ring A is a 7-10 membered fused-ring heteroaryl group.

[0033] As a preferred embodiment, ring A is wherein ring A1 is a 5-6 membered heteroaryl group, and ring A2 is a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0034] As a further preferred embodiment, ring A is a nitrogen-containing fused-ring heteroaryl group.

[0035] As a further preferred embodiment, ring A1 is a 5-membered nitrogen-containing heteroaryl group, and ring A2 is a 6-membered nitrogen-containing heteroaryl group or a phenyl group. As a further preferred embodiment, ring A is wherein X1, X2, X3, X4, X5, X6, X7, and X8 are each independently selected from N or CH, represents a single bond or a double bond;

[0036] 1 indicates the position to which the carbonyl group is bonded, and 2 indicates the position to which the -CR4R5R6 group is bonded.

[0037] As a further preferred embodiment, ring A is selected from the following groups:

[0038]

[0039] 1 indicates the position to which the carbonyl group is bonded, and 2 indicates the position to which the -CR4R5R6 group is bonded.

[0040] As a preferred embodiment, the compound is selected from the following:

[0041]

[0042] R1, R2, R3, R6 and n are as defined above.

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

[0044]

[0045] R1, R2, R3, R6 and n are as defined above.

[0046] As a preferred embodiment, R6 is selected from a 5-membered heteroaryl group, preferably a 5-membered nitrogen-containing heteroaryl group.

[0047] As a preferred embodiment, R6 is selected from the following groups:

[0048]

[0049] As a preferred embodiment, the compound is selected from the following:

[0050]

[0051] R1, R2, R3 and n are as defined above.

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

[0053]

[0054] R1, R2, R3 and n are as defined above.

[0055] As a preferred embodiment, the compound is selected from the following:

[0056]

[0057] R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl and halogenated C 1-4 alkyl;

[0058] R1, R2 and R3 are as defined above.

[0059] As a preferred embodiment, the compound is selected from the following:

[0060]

[0061] R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl and halogenated C1-4 alkyl;

[0062] R1, R2 and R3 are as defined above.

[0063] As a preferred embodiment, R1 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -S(O) r R7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with a substituent, and each r is independently 0, 1 or 2.

[0064] As a preferred embodiment, R1 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-3-6 membered heterocyclic group, -(C 1-4 Alkylene)-phenyl, -(C 1-4 -(alkylene)-5-6 membered heteroaryl, -S(O) r R7, -O-R8, -C(O)R9, -NR 10 R 11 、-C(O)NR 10 R 11 and -N(R 10)C(O)R9, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with a substituent, and each r is independently 0, 1 or 2.

[0065] As a further preferred embodiment, R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, ethynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -S(O)2R7, -SR7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted by one or more selected from halogen, C 1-4 Alkyl, C 3-6 The substituents are selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with an alkoxy substituent.

[0066] As a further preferred embodiment, R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, azetidinyl, phenyl, pyrazolyl, pyridinyl, 3-8 membered heterocyclyl, -S(O)2R7, -SR7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10)C(O)R9, the above groups are optionally further substituted by one or more substituents selected from halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, phenyl, oxazolyl, imidazolyl, thienyl and pyridyl, the above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with an alkoxy substituent.

[0067] As a preferred embodiment, each R1 is independently selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered heterocyclic group, -O-R8 and -NR 10 R 11 The above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-3 Alkyl and C 1-3 The alkoxy group is substituted with an alkoxy substituent.

[0068] As a preferred embodiment, each R1 is independently selected from C 1-4 Alkyl, 3-6 membered heterocyclic group, -O-R8 and -NR 10 R 11 The above groups are optionally further substituted by one or more selected from halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group and -NR 10 R 11 The above groups are optionally further substituted by one or more halogens.

[0069] As a preferred embodiment, each R1 is independently a 5-6 membered heterocyclic group, which is optionally further substituted by one or more C 1-4 Alkyl substituted.

[0070] As a preferred solution, each R1 is independently which is optionally further represented by one or more C 1-4 As a preferred embodiment, each R1 is independently

[0071] As a preferred embodiment, the compound is selected from the following:

[0072]

[0073] R2 and R3 are as defined above.

[0074] As a preferred embodiment, R2 is selected from a 5-8 membered monocyclic heterocyclic group, an 8-12 membered condensed ring heterocyclic group, a C 6-10 Aryl and 5-8 membered monocyclic heteroaryl, 8-12 membered condensed ring heteroaryl, the above groups are optionally further substituted by one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 substituted by a substituent.

[0075] As a preferred embodiment, R2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups:

[0076]

[0077] The above groups are optionally further substituted with one or more selected from cyano, nitro, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 substituted by a substituent.

[0078] As a further preferred embodiment, R2 is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or the following groups:

[0079]

[0080] The above groups are optionally further substituted by one or more selected from cyano, nitro, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 substituted by a substituent.

[0081] As a further preferred embodiment, R2 is selected from the following groups:

[0082]

[0083] Among them, the R 2’ Selected from the group consisting of hydrogen, 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, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 ;

[0084] d is 0, 1, 2, 3, or 4.

[0085] As a further preferred embodiment, R2 is selected from the following groups:

[0086]

[0087] Among them, R 2’ Selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)NR 10 R 11 ;

[0088] R 21 Selected from the following group: cyano, -C(O)NR 10 R 11 ;

[0089] d is 0, 1, 2, 3, or 4.

[0090] As a preferred embodiment, R3 is selected from 3-6 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from cyano, halogen, hydroxyl, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-6 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 The alkyl group is substituted with a substituent of the 3-6 membered heterocyclic group.

[0091] As a further preferred embodiment, R3 is selected from phenyl, pyridyl and pyrimidyl, and the above groups are optionally further substituted with one or more selected from cyano, halogen, hydroxyl, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-4 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkyl substituted C 3-6 Cycloalkyl and C 1-4 The alkyl group is substituted with a substituent of the 3-6 membered heterocyclic group.

[0092] As a further preferred embodiment, R3 is selected from phenyl, and the above groups are optionally further substituted by one or more substituents selected from cyano, fluorine, chlorine, bromine, hydroxyl, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, pyrrolidinyl, azetidinyl, methyl-substituted azetidinyl, oxetanyl, difluorocyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy.

[0093] As a further preferred solution, R3 is

[0094] Among them, R 31 Selected from cyano, halogen, hydroxyl, nitro, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, halogen substituted C 1-3 Alkyl, halogen substituted C 3-4 Cycloalkyl, halogen-substituted 3-4 membered heterocyclic group, halogen-substituted C 1-3 Alkoxy, methyl substituted C 3-4 Cycloalkyl and methyl substituted 3-membered heterocyclic group;

[0095] R 32 Selected from halogen, halogen substituted C 1-3 Alkyl, halogen substituted C 1-3 Alkoxy;

[0096] R 33 Selected from hydrogen, C 1-3 alkyl.

[0097] As a further preferred solution, R3 is

[0098] As a preferred solution, R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group may be substituted by a substituent selected from the group consisting of a cycloalkyl group, a 3-6 membered heterocyclyl group, a phenyl group, a halogenated phenyl group, and a 5-6 membered heteroaryl group.

[0099] As a preferred solution, R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -(C 1-4 Alkylene)-C 3-6 Cycloalkyl, -(C 1-4 Alkylene)-3-6 membered heterocyclic group, -(C1-4 Alkylene)-phenyl and -(C 1-4 alkylene)-5-6 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group may be substituted by a substituent selected from the group consisting of a cycloalkyl group, a 3-6 membered heterocyclyl group, a phenyl group, a halogenated phenyl group, and a 5-6 membered heteroaryl group.

[0100] As a further preferred embodiment, R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 The cycloalkyl group may be substituted by a substituent selected from the group consisting of a cycloalkyl group, a 3-6 membered heterocyclyl group, a phenyl group, a halogenated phenyl group, and a 5-6 membered heteroaryl group.

[0101] As a further preferred embodiment, R7, R8, R9, R 10 , R 11 Each is independently selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 4-oxaspiro[2.5]octyl, phenyl, pyridyl, pyrazolyl and 3-8 membered heterocyclyl, or R 10 , R 11 Together with the nitrogen or phosphorus atom directly connected to it, The above groups are independently optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, =O, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, halophenyl and pyridyl.

[0102] As a preferred embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , Z1, ring A and n are each independently a corresponding group of the following specific compounds.

[0103] As a more preferred embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , Z1, ring A and n are each independently a corresponding group of the example compounds.

[0104] As a preferred embodiment, the compound is selected from the following:

[0105]

[0106]

[0107]

[0108] As a preferred embodiment, the compound is selected from the following:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] Another aspect of the present invention further provides a method for preparing the compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that it comprises the following steps:

[0116]

[0117] R1, R2, R3, R4, R5, R6, Z1 and n are as defined above.

[0118] 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 spectral analyses.

[0119] 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.

[0120] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomer, tautomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease mediated by a GLP-1 receptor agonist.

[0121] Another aspect of the present invention provides the use of the above-mentioned compound, its stereoisomer, tautomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia or hyperinsulinemia.

[0122] Another aspect of the present invention provides a method for treating and / or preventing diseases mediated by GLP-1 receptor agonists, the method comprising: administering the above-mentioned compound, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition to a subject in need thereof.

[0123] Another aspect of the present invention provides a method for treating and / or preventing the following diseases, the method comprising: administering the above-mentioned compound, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition to a subject in need thereof;

[0124] Wherein, the disease is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, or a combination thereof.

[0125] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0126] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided a class of GLP-1 receptor agonists with novel structures, on the basis of which the present invention was completed.

[0127] 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.

[0128] 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."

[0129] The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, preferably a straight or 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 various branched chain isomers thereof. “C 1-10 "Alkyl" refers to straight chain alkyl and branched chain alkyl groups including 1 to 10 carbon atoms. 1-4 The term "alkyl" refers to straight chain alkyl groups and branched chain alkyl groups having 1 to 4 carbon atoms.

[0130] The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0131] "Cycloalkyl" or "carbocycle" 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, and the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably a cycloalkyl group containing 3 to 12, 3 to 8 or 3 to 6 carbon atoms, for example, "C 3-12 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 12 carbon atoms. 3-6 "Cycloalkyl" refers to a cycloalkyl radical comprising 3 to 6 carbon atoms, wherein:

[0132] Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0133] Polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings and bridged rings. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called a spiro atom) is shared between the single rings. 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 divided into monospiroalkyl, dispiroalkyl or polyspiroalkyl groups according to the number of spiro atoms shared between the rings. Spiroalkyl groups include but are not limited to:

[0134]

[0135] "Fused cycloalkyl" refers to a full-carbon polycyclic group in which each ring in the system 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. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and fused cycloalkyl includes but is not limited to:

[0136]

[0137] "Bridged cycloalkyl" refers to a full-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 none of the rings has a completely conjugated π electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Bridged cycloalkyl includes but is not limited to:

[0138]

[0139] 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.

[0140] Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0141] "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, 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, the heterocyclic group includes 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclic group" refers to a ring group containing 3 to 6 ring atoms, "4-6 membered heterocyclic group" refers to a ring group containing 4 to 6 ring atoms, "4-10 membered heterocyclic group" refers to a ring group containing 4 to 10 ring atoms, and "3-12 membered heterocyclic group" refers to a ring group containing 3 to 12 ring atoms.

[0142] Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

[0143] 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 one atom (called 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 of 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 into mono-, di-, or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings. Spiro heterocyclic groups include, but are not limited to:

[0144]

[0145] "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with 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. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic alkyl groups, and fused heterocyclic groups include but are not limited to:

[0146]

[0147] "Bridged heterocyclic group" 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 none of the rings 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. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, and bridged heterocyclic groups include but are not limited to:

[0148]

[0149] The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic ring, including but not limited to:

[0150]

[0151] The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, =O, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9.

[0152] "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings 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 all-carbon aromatic groups containing 6-10 carbon atoms, including but not limited to phenyl and naphthyl. 6-8 "Aryl" refers to a full-carbon aromatic group containing 6-8 carbon atoms, wherein the aromatic ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aromatic ring, including but not limited to:

[0153]

[0154] "Aryl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0155] "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), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, a 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, a 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, 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:

[0156]

[0157] "Heteroaryl" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0158] "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 alkenyl group containing 2 to 4 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

[0159] "Alkenyl" may be substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 substituent.

[0160] "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 containing 2 to 4 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

[0161] "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, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0162] "Alkoxy" refers to an -O-alkyl group in which 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, and the like.

[0163] "Alkoxy" may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0164] "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.

[0165] "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 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0166] "Heterocyclyloxy" 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.

[0167] "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, -SF5, -C(O)OR8, -C(O)R9, -OC(O)R9, -NR 10 R 11 、-C(=NR 10 )R9、-N(R 10 )-C(=NR 11 )R9, -C(O)NR 10 R 11 and -N(R 10 )-C(O)R9 is substituted.

[0168] The above R8, R9, R 10 , R 11 The definition of is the same as above.

[0169] "Halogen-substituted C 1-10 The term "alkyl" refers to an alkyl group of 1 to 10 carbon atoms in which the hydrogen atoms on the alkyl group are optionally replaced by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0170] "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.

[0171] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0172] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes the occasions where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted situations are included. 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 the situation where the heterocyclic group is substituted with an alkyl group and the situation where the heterocyclic group is not substituted with an alkyl group.

[0173] "Substituted" means that one or more "hydrogen atoms" in a group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the valence bond theory in chemistry, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an olefin).

[0174] "Stereoisomers" are called stereoisomers in English. They refer to isomers produced by different spatial arrangements of atoms in molecules. They can be divided into two types: cis-trans isomers and enantiomers, or into two major categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational stereo-isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in molecules, rings, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely 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 properties due to the absence of anti-axial symmetry in the molecule are called optical isomers, which are divided into R and S configurations. In the present invention, the "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.

[0175] "Tautomers" refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers include interconversions via proton migration, and valence tautomers include interconversions via reorganization of some of the bonding electrons. For example and In the present invention, if the "tautomer" is not specifically indicated, all tautomeric forms of the compound are within the scope of the present invention.

[0176] "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.

[0177] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0178] The compounds of the present application 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( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. All isotopic composition changes of the compounds of the present application, whether radioactive or not, are included in the scope of the present application. The active ingredient of the present invention is a compound of formula I, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0180] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds and a pharmaceutically acceptable carrier.

[0181] Since the compounds of the present invention have excellent GLP-1 receptor agonist activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to GLP-1 receptor agonism.

[0182] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0183] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0184] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0185] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0186] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0187] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0188] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0189] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0190] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0191] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0192] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0193] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0194] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0195] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0196] 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.

[0197] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker AVANCE-400 / 500 nuclear magnetic spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0198] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6120 mass spectrometer, and 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).

[0199] 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.

[0200] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0201] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).

[0202] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0203] The abbreviations of the compounds involved in the examples are as follows:

[0204] "NMP" means N-methylpyrrolidone;

[0205] “DMA” means N,N-dimethylacetamide;

[0206] "HATU" means 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0207] "DMF" means N,N-dimethylformamide;

[0208] "DIEA" means N,N-diisopropylethylamine;

[0209] “LDA” refers to lithium dimethylamine;

[0210] "DCM" means dichloromethane;

[0211] "TMSI" means sodium trimethylsilyl iodide;

[0212] "IBMX" refers to 3-isopropyl-1-methylxanthine.

[0213] The reference compound A used in the present invention comes from compound 67 in patent CN109790161.

[0214] Preparation of intermediates

[0215] Synthesis of intermediates A, A-1 and A-2

[0216]

[0217] Intermediates A-1 and A-2 were synthesized by the following route:

[0218]

[0219] Step 1: Synthesis of intermediate 1-2

[0220] Under a nitrogen atmosphere at -78°C, slowly add LDA (117 mL, 2M / THF) to a tetrahydrofuran (100 mL) solution containing compound 1-1 (25 g, 195.1 mmol) and stir for 20 minutes. Then, add a tetrahydrofuran solution (100 mL) containing N,N-bis(trifluoromethanesulfonyl)aniline (44 g, 234 mmol) to the mixture at -70°C. After the addition is complete, react at room temperature for 16 hours. Under an ice bath, add a saturated ammonium chloride solution to the mixture, extract with ethyl acetate (200 mL×3), wash with saturated brine, collect the organic phase, dry it, and dry it under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (0-15% petroleum ether / ethyl acetate) to obtain compound 1-2 (38.2 g, yield: 75%).

[0221] Step 2: Synthesis of intermediate 1-4

[0222] Under ice bath, potassium tert-butoxide (13 g, 0.12 mol) was added to N, N-dimethylformamide solution (100 mL) containing compound 1-3 (25 g, 0.12 mol), stirred at room temperature for 40 minutes, and then 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 (120 mL × 3), washed with saturated brine, the organic phase was collected and dried, and the crude product was dried under reduced pressure and separated and purified by column chromatography (0-20% petroleum ether / ethyl acetate) to obtain compound 1-4 (16.6 g, yield: 70%).

[0223] LC-MS (ESI + )m / z:230.1(M+H) + .

[0224] Step 3: Synthesis of intermediate 1-6

[0225] Under ice bath, aminoacetaldehyde dimethyl acetal (2 g, 19 mmol) was added to an ethyl acetate solution (10 mL) containing N,N'-carbonyldiimidazole (3.1 g, 19 mmol), stirred at room temperature for 2 hours, cooled to 0 ° C, stirred for 30 minutes, filtered, and slurried twice with methyl tert-butyl ether to obtain a crude product, which was further purified (0-5% dichloromethane / methanol) to obtain compound 1-4 (3.6 g, yield: 95%).

[0226] Step 4: Synthesis of Intermediate 1-8

[0227] Under nitrogen atmosphere, a mixture of 1,4-dioxane / water (300 mL / 30 mL) containing compound 1-7 (28 g, 0.10 mol), bipyralidone (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 (0-15% petroleum ether / ethyl acetate) to obtain compound 1-8 (32.7 g, yield: 99%).

[0228] LC-MS (ESI + )m / z:316.2(M+H) + .

[0229] Step 5: Synthesis of Intermediate 1-9

[0230] Under nitrogen atmosphere, a mixture of 1,4-dioxane / water (250 mL / 50 mL) containing compound 1-8 (20 g, 63 mmol), compound 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 and reacted for 16 hours. After the reaction was complete, it was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (0-10% petroleum ether / ethyl acetate) to obtain compound 1-9 (9 g, yield: 54%).

[0231] LC-MS (ESI + )m / z:300.2(M+H) + .

[0232] Step 6: Synthesis of Intermediate 1-10

[0233] At room temperature, Pd / C (500 mg, 10%) was added to a methanol solution (150 mL) containing compound 1-9 (10.1 g, 33.67 mmol), and the mixture 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.

[0234] LC-MS (ESI + )m / z:302.2(M+H) + .

[0235] Step 7: Synthesis of Intermediate 1-11

[0236] Under ice bath conditions, a solution of compound 1-10 (9.60 g, 31.8 mmol) in N,N-dimethylformamide (25 mL) was slowly added dropwise to a solution of NaH (1.70 g, 35 mmol) in N,N-dimethylformamide (100 mL) under nitrogen atmosphere and stirred for 0.5 hours. Then chloroacetonitrile (4.8 g, 64 mmol) was added to the above mixture and stirred to room temperature for 2 hours. After LCMS showed that the reaction was complete, saturated ammonium chloride solution was added to quench, ethyl acetate was extracted (100 mL×3), 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 (0-15% petroleum ether / ethyl acetate) to obtain compound 1-11 (9.1 g, yield: 84%).

[0237] LC-MS (ESI + )m / z:341.1(M+H) + .

[0238] Step 8: Synthesis of Intermediate 1-12

[0239] Under ice bath, lithium bis(trimethylsilyl)amide (45 mL, 1 M) was slowly added dropwise to a solution of compound 1-11 (3.80 g, 11.16 mmol) and (R)-4-methyl-1,3,2-dioxathiolane-2,2-dioxide (3.86 g, 27.91 mmol) in tetrahydrofuran (40 mL), and the mixture was reacted to room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to quench, and extracted with ethyl acetate (80 mL×3). 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 (0-20% petroleum ether / ethyl acetate) to obtain compound 1-12 (1.39 g, yield: 33%).

[0240] LC-MS (ESI + )m / z:381.3(M+H) + .

[0241] Step 9: Synthesis of Intermediate 1-13

[0242] An ethanol solution containing 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) was heated to reflux for 2 hours, filtered, and concentrated under reduced pressure to obtain compound 1-13 (1.83 g) which was directly used in the next step without purification.

[0243] LC-MS (ESI + )m / z:414.3(M+H) + .

[0244] Step 10: Synthesis of Intermediate 1-14

[0245] At room temperature, N,N'-carbonyldiimidazole (1.44 g, 8.85 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 g, 11.1 mmol) were added to a solution of compound 1-13 (1.83 g, 4.40 mmol) in dimethyl sulfoxide (8 mL) in sequence, and the temperature was raised to 80°C for 2 hours. After the reaction was complete, water was added, and dichloromethane was extracted (50 mL×3). 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 (0-10% dichloromethane / methanol) to obtain compound 1-14 (1.89 g, yield: 97%).

[0246] LC-MS (ESI + )m / z:440.3(M+H) + .

[0247] Intermediate 1-14 was chirally resolved to give compounds 1-14a (retention time: 6.71 min) and 1-14b (retention time: 7.61 min).

[0248] Chiral separation method:

[0249] Chromatographic conditions Column: IB, 10μm, 30*250mm; Mobile phase A: HEX+0.2% FA; Mobile phase B: ETOH+0.2% FA; Detection wavelength: 214nm / 254nm; Flow rate: 25mL / min; Column temperature: RT; Isocratic elution program: Mobile phase A: Mobile phase B = 85:15 (V / V)

[0250] Step 11: Synthesis of Compound A

[0251] 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 the mixture was heated to 60°C and stirred for 2 hours. After LCMS monitoring, 2N dilute hydrochloric acid was added to adjust the pH to 6-7, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phase was collected, washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound A.

[0252] LC-MS (ESI+) m / z: 412.3 (M+H) + .

[0253] Step 12: Synthesis of intermediates A-1 and A-2

[0254] 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 ethyl acetate was used for extraction (20 mL×3). The organic phase was collected, saturated with brine, dried over anhydrous sodium sulfate, and filtered to obtain compound A-1, which was used directly in the next step without purification.

[0255] LC-MS (ESI + )m / z:412.3(M+H) + .

[0256] 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 ethyl acetate was extracted (20 mL×3). The organic phase was collected, saturated with brine, dried over anhydrous sodium sulfate, and filtered to obtain compound A-2, which was directly used in the next step without purification.

[0257] LC-MS (ESI + )m / z:412.3(M+H) + .

[0258] Synthesis of intermediate B

[0259]

[0260] Intermediate B was synthesized via the following route:

[0261]

[0262] Step 1: Synthesis of intermediate B-2

[0263] LDA (8.7 mL, 17.35 mmol) was added dropwise to B-1 (3.0 g, 11.57 mmol) in THF (45 mL) at -78°C, and the mixture was reacted at room temperature for 0.5 hours. TsCN (4.18 g, 23.14 mmol, 2.0 eq) was added, and the mixture was reacted at -78°C for 0.5 hours after the addition was complete. After the mixture returned to room temperature, saturated ammonium chloride (40 mL) was added for dilution, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (0-25% petroleum ether / ethyl acetate) to obtain compound B-2 (1.89 g, yield: 52%).

[0264] 1H NMR (400MHz, CDCl3) δ7.46-7.34(m,5H),5.23(s,2H),4.83(m,1H),4.67-4.64(m,1H),3.76-3.72(m, 1H),2.60-2.51(m,1H),2.28-2.16(m,2H),2.08-1.97(m,1H),1.82-1.71(m,1H),1.64-1.58(m,1H).

[0265] Step 2: Synthesis of intermediate B-3

[0266] 4-Fluoro-3,5-dimethylphenylhydrazine (1.02 g, 6.69 mmol) and pyridine hydrochloride (768 mg, 6.69 mmol) were added to a toluene (40 mL) solution of B-2 (1.89 g, 6.69 mmol) and reacted at 90°C for 1 hour. After the reaction was completed as monitored by LCMS, water (30 mL) was added for dilution, and ethyl acetate (40 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by a normal phase silica gel column (DCM / CH3OH=9 / 1) to obtain compound B-3 (1.42 g, yield: 51%).

[0267] LC-MS (ESI + )m / z:421.1(M+H) + ;

[0268] 1 H NMR(400MHz, CDCl3)δ7.42-7.36(m,6H),7.20(br s,1H),5.25-4.96(m,3H),4.78-4.59(m,1H),3.75(m,2H),3.42-3.11(m,1H),2.64-2.58(m,1H),2.35-2.31(m,6H),1.86-1.58(m,4H).

[0269] Step 3: Synthesis of intermediate B-4

[0270] Potassium tert-butoxide (1.31 g, 11.75 mmol) was added to a solution of B-3 (1.41 g, 3.36 mmol) and intermediate 1-6 (735 mg, 3.69 mmol) in DMA (20 mL) and reacted at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification.

[0271] LC-MS (ESI + )m / z:552.3(M+H)+ .

[0272] Step 4: Synthesis of intermediate B-5

[0273] Methanesulfonic acid (250 mg, 2.61 mmol) was added to a THF (20 mL) solution of B-4 (1.8 g, 3.26 mmol) and reacted at 60°C for 2 hours. After the reaction was complete as monitored by LCMS, water (30 mL) was added, pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product which was purified by a normal phase silica gel column (0-75% petroleum ether / ethyl acetate) to obtain compound B-5 (760 mg, yield: 48%).

[0274] LC-MS (ESI + )m / z:488.2(M+H) + ;

[0275] 1 H NMR (400MHz, CDCl3) δ9.44 (s, 1H), 7.43-7.29 (m, 6H), 7.02 (d, J = 5.8Hz, 2H), 5.20-4.99 (m, 3H), 4.71 (br s,1H),3.44-3.21(m,1H),2.67(d,J=16.2Hz,1H),2.23(s,6H),2.14-2.10(m,2H),2.09-2.05(m,1H),1.85-1.75(m,1H).

[0276] B-5 is chiral split to obtain:

[0277] B-5a (retention time: 3.486 min)

[0278]

[0279] LC-MS (ESI + )m / z:488.3(M+H) + ;

[0280] B-5b (retention time: 5.867 min)

[0281]

[0282] LC-MS (ESI + )m / z:488.3(M+H) + :

[0283] Split method: Column name: AD; Column size: 250*30mm 10μm; Mobile Phase A: Supercritical CO2,; Mobile Phase B: MEOH (+0.1% 7.0mol / lAmmonia in MEOH); A:B:88:12; Wavelength: 214nm; Flow:140ml / min; Column temp:RT; Back Pressure: 100bar; Injection: 4.0mL; Cycle time: 13.5min; Solvent: MeOH: redistilled grade, Supercritical CO2: Food grade.

[0284] Step 5: Synthesis of intermediate B-6

[0285] Compound 1-4 (170 mg, 0.74 mmol), CuI (20 mg, 0.12 mmol), potassium carbonate (170 mg, 1.23 mmol) and N, N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.12 mmol) were added to a solution of B-5 (300 mg, 0.62 mmol) in NMP (10 mL), and the mixture was reacted at 130 ° C for 3 hours under a nitrogen atmosphere. After the reaction was complete as monitored by LCMS, water (30 mL) was added, and ethyl acetate (30 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by a normal phase silica gel column (0-50% petroleum ether / ethyl acetate) to obtain a crude compound B-6 (400 mg).

[0286] LC-MS (ESI + )m / z:636.2(M+H) + .

[0287] Step 6: Synthesis of Intermediate B

[0288] Compound B-6 (200 mg, 0.32 mmol) was dissolved in acetonitrile (6 mL) solution, TMSI (320.1 mg, 1.6 mmol) was slowly added dropwise at 0°C, reacted at room temperature for 2 hours, Et3N (0.32 g, 3.2 mmol) was added, and the reaction was continued with stirring for 2 hours. The crude product was concentrated under reduced pressure and dissolved in ethyl acetate (30 mL), saturated sodium bicarbonate solution (30 mL) was added to wash the organic phase, the organic phase was dried over anhydrous sodium sulfate, and the crude product was filtered and purified by normal phase silica gel column (DCM / MeOH=10 / 1) to obtain compound B (50 mg, yield: 31%).

[0289] LC-MS (ESI +)m / z:502.3(M+H) + .

[0290] The synthesis of Ba and Bb was obtained by using B-5a and B-5b as starting materials according to the methods of steps 5 and 6:

[0291] Ba:

[0292]

[0293] LC-MS (ESI + )m / z:488.3(M+H) + ;

[0294] Bb:

[0295]

[0296] LC-MS (ESI + )m / z:488.3(M+H) + ;

[0297] Preparation of specific compounds

[0298] Example 1: Synthesis of Compound 1

[0299]

[0300] Compound 1 was synthesized via the following route:

[0301]

[0302] Under ice bath, HATU (55.32 mg, 0.15 mmol) and DIEA (37.61 mg, 0.29 mmol) were added to DMF (3 mL) containing intermediate A (0.1 mmol crude product) and intermediate B (48.65 mg, 0.097 mmol), and stirred for 1 hour. After the reaction was completed by LCMS monitoring, water (30 mL) was added for washing, and ethyl acetate (10 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by Prep-HPLC (C18, 0.05% HCOOH in water, MeCN) to obtain compound 1 (13 mg, yield: 15%).

[0303] LC-MS (ESI + )m / z:895.4(M+H) + ;

[0304] 1H NMR (400MHz, CDCl3) δ11.65-11.26(m,1H),8.17-7.93(m,1H),7.63-7.36(m,3H),7.36-7.26(m,1H),7.25-7.08 (m,2H),7.06-6.74(m,2H),6.70-6.52(m,1H),6.45-6.21(m,1H),5.53-5.31(m,1H),4.18-4.04(m,3H),3.96-3 .43(m,3H),3.14-2.81(m,2H),2.79-2.32(m,2H),2.30-2.23(m,6H),2.19-1.91(m,2H),1.90-1.79(m,1H),1.7 8-1.67(m,3H),1.57-1.49(m,2H),1.46-1.41(m,1H),1.38-1.24(m,6H),1.22-1.13(m,3H),1.09-0.91(m,1H).

[0305] Compounds 1-1 and 1-2 are respectively reacted with intermediates Ba and Bb as raw materials with intermediate A according to the above-mentioned synthesis method to obtain:

[0306] 1-1: LC-MS (ESI + )m / z:895.6(M+H) + ; 1-2: LC-MS (ESI + )m / z:895.5(M+H) + .

[0307] 1-1 was chiral split to obtain 1a and 1b:

[0308] 1-1 Split method: Column name: AD; Column size: 250*25mm10μm; Mobile Phase A: Supercritical CO2,; Mobile Phase B: MEOH (+0.1% 7.0mol / lAmmonia in MEOH); A:B:75:25; Wavelength: 214nm; Flow:120ml / min; Column temp:RT; Back Pressure:100bar; Injection:6.0mL; Cycle time:8min; Solvent:MeOH:redistilledgrade, Supercritical CO2:Food grade.

[0309] Compound 1a:

[0310]

[0311] Retention time: t = 3.583 min;

[0312] LC-MS (ESI + )m / z:895.6(M+H) + ;

[0313] 1 H NMR (400MHz, CDCl3) δ11.60–11.15(m,1H),8.22–8.00(m,1H),7.77–7.31(m,4H),7.22–6.98(m,3H),6.95–6.78(m, 1H),6.69–6.54(m,1H),6.41–6.20(m,1H),5.66–4.99(m,2H),4.17–4.01(m,3H),3.92–3.67(m,2H),3.47(dd,J=16. 3,4.7Hz,1H),3.22–2.66(m,2H),2.50–2.37(m,1H),2.34–2.22(m,6H),2.17–1.91(m,2H),1.89–1.74(m,2H),1.58– 1.51(m,2H),1.49–1.38(m,2H),1.31–1.23(m,5H),1.23–1.14(m,4H),0.96(t,J=7.4Hz,1H),0.81(d,J=6.2Hz,1H).

[0314] Compound 1b:

[0315]

[0316] Retention time: t = 4.261 min;

[0317] LC-MS (ESI + )m / z:895.5(M+H) + ;

[0318] 1H NMR (400MHz, CDCl3) δ11.97-11.14(m,1H),8.26-8.02(m,1H),7.61-7.29(m,4H),7.23-7.02(m,3H),6.94-6.79 (m,1H),6.71-6.47(m,1H),6.38-6.20(m,1H),5.56-4.99(m,2H),4.26-3.99(m,3H),3.96-3.66(m,2H),3.58-3. 34(m,1H),3.13-2.79(m,2H),2.47-2.37(m,1H),2.33-2.24(m,6H),2.17-1.91(m,2H),1.89-1.74(m,2H),1.74- 1.66(m,2H),1.50-1.41(m,2H),1.31-1.23(m,5H),1.22-1.16(m,4H),0.92-0.85(m,1H),0.81(d,J=6.2Hz,1H).

[0319] 1-2 was chiral split to obtain 1c and 1d:

[0320] 1-2 Split method: Column name: AD; Column size: 250*25mm10μm; Mobile Phase A: Supercritical CO2,; Mobile Phase B: MEOH (+0.1% 7.0mol / lAmmonia in MEOH); A:B:65:35; Wavelength: 214nm; Flow:120ml / min; Column temp:RT; Back Pressure:100bar; Injection:8.0mL; Cycle time: 13min; Solvent: MeOH: redistilled grade, Supercritical CO2: Food grade.

[0321] Compound 1c: retention time: t = 1.772 min;

[0322]

[0323] LC-MS (ESI + )m / z:895.3(M+H) + ;

[0324] 1H NMR (400MHz, CDCl3) δ11.51–11.25(m,1H),8.20–7.90(m,1H),7.75–7.37(m,3H),7.32–7.26(m,1H),7.26–7.19(m,1H),7.11(d,J= 6.0Hz,1H),7.07–7.00(m,1H),7.00–6.91(m,1H),6.80–6.63(m,1H),6.59–6.33(m,1H),6.28–5.86(m,1H),5.86–5.26(m,1H),5.16 –4.66(m,1H),4.24–4.01(m,3H),3.94–3.76(m,2H),3.72–3.41(m,1H),3.17–2.76(m,2H),2.68–2.35(m,2H),2.33–2.20(m,6H),2. 15–1.93(m,2H),1.73–1.59(m,3H),1.55–1.40(m,2H),1.37–1.32(m,3H),1.31–1.27(m,3H),1.21–1.15(m,2H),1.03–0.93(m,2H).

[0325] Compound 1d: retention time: t = 2.401 min;

[0326]

[0327] LC-MS (ESI + )m / z:895.6(M+H) + ;

[0328] 1H NMR (400MHz, CDCl3) δ11.52–11.25(m,1H),8.22–7.91(m,1H),7.79–7.28(m,3H),7.24–7.20(m,1H),7.11(d,J=6.0Hz,1H),7.0 6–7.01(m,1H),6.96(d,J=6.0Hz,1H),6.80–6.62(m,1H),6.65–6.31(m,1H),6.30–5.86(m,1H),5.86–5.29(m,1H),5.11–4.69(m ,1H),4.19–4.00(m,3H),3.95–3.75(m,2H),3.73–3.41(m,1H),3.11–2.82(m,2H),2.69–2.32(m,2H),2.31–2.19(m,6H),2.13– 1.92(m,3H),1.77–1.59(m,3H),1.56–1.37(m,2H),1.40–1.32(m,3H),1.31–1.23(m,3H),1.23–1.13(m,2H),1.11–0.93(m,2H).

[0329] Compounds 2 to 5 can be obtained by referring to the preparation method of Example 1:

[0330]

[0331]

[0332]

[0333] Example 2: Synthesis of Compound 6

[0334]

[0335] Compound 6 was synthesized via the following route:

[0336]

[0337] Step 1: Synthesis of intermediate 6-2

[0338] Compound 6-1 (61 mg, 0.32 mmol) was dissolved in N-methylpyrrolidone (2 mL), and B-5 (150 mg, 0.32 mmol), cuprous iodide (12 mg, 0.06 mmol), potassium carbonate (131 mg, 0.95 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (45 mg, 0.32 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at 130°C for 3 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% to 40%) to obtain the target compound 6-2 (145 mg, yield 69%).

[0339] LC-MS (ESI + )m / z:679.2(M+H) + .

[0340] Step 2: Synthesis of intermediate 6-3

[0341] Compound 6-2 (145 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), and boron trichloride (25 mg, 0.21 mmol) was added dropwise to the reaction solution under ice bath, and the reaction solution was stirred at room temperature for 1 hour. Methanol (0.5 mL) was added to the reaction solution, and stirred at room temperature for 5 minutes, and then saturated sodium bicarbonate (30 mL) was added to the reaction solution for dilution, and extracted with dichloromethane (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound crude product 6-3 (124 mg), which was used directly in the next step without further purification.

[0342] LC-MS (ESI + )m / z:545.4(M+H) + .

[0343] Step 3: Synthesis of compound 6

[0344] Compound 6-3 (124 mg, 0.23 mmol) and intermediate A (114 mg, 0.28 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol) and N,N-diisopropylethylamine (74 mg, 0.58 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution for dilution, and then extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 5%-60%) to obtain the target compound 6 (32 mg, yield 15%).

[0345] LC-MS (ESI + )m / z:938.6(M+H) + ;

[0346] 1 H NMR (400MHz, CDCl3) δ11.57-11.16(m,1H),7.72-7.39(m,4H),7.24-7.13(m,1H),7.11-6.92 (m,2H),6.83-6.47(m,2H),6.36-5.91(m,1H),5.84-5.40(m,1H),5.34-4.76(m,1H),3.94-3 .76(m,2H),3.68-3.04(m,4H),2.97-2.81(m,2H),2.76-2.33(m,2H),2.28-2.21(m,6H),2.1 9-1.83(m,3H),1.75-1.54(m,8H),1.35-1.24(m,6H),1.21-1.10(m,2H),1.02-0.51(m,5H).

[0347] Compounds 7 to 11b can be prepared by referring to the preparation method of Example 1:

[0348]

[0349]

[0350]

[0351]

[0352] Example 3: Synthesis of Compound 12

[0353]

[0354] Compound 12 was synthesized via the following route:

[0355]

[0356] Step 1: Synthesis of intermediate 12-2

[0357] Compound 12-1 (72 mg, 0.36 mmol) was dissolved in N-methylpyrrolidone (2 mL), and B-5 (150 mg, 0.30 mmol), cuprous iodide (11 mg, 0.06 mmol), potassium carbonate (124 mg, 0.90 mmol), and N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.15 mmol) were added to the reaction solution in sequence, and the reaction solution was stirred at 130°C for 3 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction solution for dilution, and then extracted with ethyl acetate (30 mL×3), and 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, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0% to 50%) to obtain the target compound 12-2 (117 mg, yield 63%).

[0358] LC-MS (ESI + )m / z:607.6(M+H) + .

[0359] Step 2: Synthesis of intermediate 12-3

[0360] Compound 12-2 (115 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and boron trichloride (22 mg, 0.19 mmol) was added dropwise to the reaction solution under ice bath, and the reaction solution was stirred at room temperature for 1 hour. Methanol (0.5 mL) was added to the reaction solution, and stirred at room temperature for 5 minutes, and then saturated sodium bicarbonate (30 mL) was added to the reaction solution for dilution, and then extracted with dichloromethane (30 mL × 3), and the organic phases were combined and washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target compound (81 mg), which was used directly in the next step without further purification.

[0361] LC-MS (ESI + )m / z:473.3(M+H) + .

[0362] Step 3: Synthesis of intermediate 12

[0363] Compound 12-3 (81 mg, 0.17 mmol) and intermediate A (84 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78 mg, 0.20 mmol) and N,N-diisopropylethylamine (55 mg, 0.43 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution for dilution, and then extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by reverse phase chromatography (acetonitrile / water containing 0.05% formic acid = 5%-60%) to obtain the target compound 12 (18 mg, yield 12%).

[0364] LC-MS (ESI + )m / z:866.5(M+H) + .

[0365] 1 H NMR (400MHz, CDCl3) δ11.51-11.17(m,1H),8.03-7.62(m,1H),7.58-7.43(m,3H),7.22-7.04(m,2H) ,7.03-6.86(m,1H),6.85-6.69(m,1H),6.68-6.48(m,1H),6.39-5.99(m,1H),5.47-5.31(m,1H),5. 13-4.23(m,1H),3.88-3.67(m,2H),3.47-2.88(m,2H),2.76-2.32(m,2H),2.31-2.18(m,7H),2.12- 1.83(m,4H),1.53-1.40(m,2H),1.38-1.21(m,9H),1.14(m,J=24.2,19.6Hz,2H),0.97-0.78(m,2H).

[0366] Compounds 13 to 15 can be obtained by referring to the preparation method of Example 3:

[0367]

[0368]

[0369] Example 4: Synthesis of Compound 16

[0370]

[0371] Compound 16 was synthesized via the following route:

[0372]

[0373] Step 1: Synthesis of intermediate 16-2

[0374] To a solution of compound 16-1 (130 mg, 0.53 mmol) in N-methylpyrrolidone (5 mL), B-5 ​​(233 mg, 0.48 mmol), cuprous iodide (46 mg, 0.24 mmol), potassium carbonate (199 mg, 1.44 mmol) and N,N'-dimethyl-1,2-cyclohexanediamine (34 mg, 0.24 mmol) were added in sequence, and the reaction solution was stirred at 130 ° C for 16 hours under a nitrogen atmosphere. Water (30 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60% to 70%) to obtain the target compound 16-2 (282 mg, yield 89%).

[0375] LC-MS (ESI + )m / z:654.4(M+H) + .

[0376] Step 2: Synthesis of intermediate 16-3

[0377] Compound 16-2 (100 mg, 0.15 mmol) was dissolved in dichloromethane (4 mL) solution, and boron trichloride (3 mL, 1 M) was added dropwise to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 2 hours. Methanol (1.5 mL) was added to the reaction solution to quench, and then saturated sodium bicarbonate (30 mL) was added to the reaction solution to dilute, and then extracted with dichloromethane (30 mL × 3), and 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 reverse phase chromatography (acetonitrile / water containing 0.05% trifluoroacetic acid = 25%-40%) to obtain the target compound 16-3 (76 mg, yield 95%).

[0378] LC-MS (ESI + )m / z:520.3(M+H) + .

[0379] Step 3: Synthesis of compound 16

[0380] Compound A (79 mg, 0.19 mmol), N,N-diisopropylethylamine (52 mg, 0.40 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (73 mg, 0.19 mmol) were added to a solution of compound 16-3 (85 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) in sequence, and the reaction solution was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by reverse phase chromatography (acetonitrile / water containing 0.1% formic acid = 80%-85%) to obtain compound 16 (20 mg, yield 14%).

[0381] LC-MS (ESI + )m / z:913.5(M+H) + ;

[0382] 1 H NMR (400MHz, CDCl3) δ11.96-10.79(m,1H),7.86-7.80(m,1H),7.80-7.43(m,3H),7.39-7.27(m,1H),7.26-7.04 (m,2H),7.02-6.74(m,2H),6.71-6.34(m,1H),6.33-5.42(m,1H),5.39-4.78(m,1H),3.94-3.74(m,2H),3.72-3 .06(m,5H),3.05-2.72(m,2H),2.70-2.30(m,2H),2.28-2.19(m,6H),2.15-1.92(m,2H),1.91-1.75(m,3H),1.7 3-1.59(m,4H),1.53-1.39(m,2H),1.36-1.31(m,3H),1.29-1.23(m,3H),1.19-1.16(m,1H),0.97-0.79(m,1H).

[0383] Compound 17 can be obtained by referring to the preparation method of Example 4:

[0384]

[0385] Biological test evaluation

[0386] 1. Determination of cAMP levels in HEK293T cells stably transfected with human GLP-1R

[0387] 1. Experimental instruments

[0388] Instrument Name Manufacturer / Source model ELISA reader Molecula Devices Spectramax i3 Benchtop centrifuge BECKMAN Avanti J15R Mini Vortex Mixer Titan VM-M1 Type A2 Class II Biological Safety Cabinet - Double ESCO AC2-658-CN Incubator Thermo thermofisher 371 Water bath Yiheng DK-8AX microscope Leica Dmi1 Cell Counter BIO-RAD /

[0389] 2. Experimental Materials

[0390]

[0391] 3. Experimental Methods

[0392] Human GLP-1R HEK293T stable cells were digested with trypsin, terminated with DMEM total (without p / s), washed twice with 1X Stimulation buffer after centrifugation, resuspended with 1X stimulation buffer (buffer provided with Cisbio kit) and counted, and then the cells were prepared into 1Million / mL cell suspension with stimulation buffer. Compound powder was first prepared into 10mM stock solution with DMSO, then the 10mM compound stock solution was diluted to 2mM with DMSO, and then 2X compound was prepared with 1X stimulation buffer (buffer provided with Cisbio kit, IBMX was freshly added with a final concentration of 0.5mM), the top dose final concentration was 2000nM, the final DMSO concentration was 0.2%, 1:3 gradient dilution, 11 gradients.

[0393] According to the layout, add 5ul of compound to each well; Min well is GLP-1 100nM, Max well is 1Xstimulation buffer with 0.2% DMSO. Add 5ul of cell suspension to each well, centrifuge at 300rpm for 1min at room temperature, and incubate at 37 degrees for 30min. Prepare 2X cAMP standard with 1X Stimulation buffer, with a final concentration of 2.8uM at top, 1:3 gradient dilution for 12 doses, and add 10ul to each well according to the layout. Finally, dilute d2 and antibody 20 times with 1X Detection buffer (buffer provided by Cisbio kit), add 5ul to each well according to the layout, centrifuge at 300rpm for 1min at room temperature, and incubate at room temperature for 2hr.

[0394] 4. Data Analysis

[0395] Stimulation% was calculated based on the Min and Max readings (665nm / 615nm ratio), using the formula: 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 standard curve, and the data was analyzed using GraphPad Prism 9 to draw a four-parameter fitting curve to calculate EC 50 , the formula is: Y = Bottom + (Top-Bottom) / (1 + 10^((LogEC 50 -X)*HillSlope)). The results are shown in Table 1.

[0396] Table 1: Determination of cAMP levels in HEK293T cells stably transfected with human GLP-1R

[0397] Compound No. <![CDATA[EC 50 (nM)]]> 1 65.84 1a 965.50 1b 791.30 1c 830.50 1d 28.53 2 270.20 3 97.87 4 250.90 5 68.27 6 436.90 7 358.70 8 205.00 9 200.60 10 141.90 10b 152.60 11 99.20 11b 145.20 12 159.70 13 698.70 14 313.50 15 204.50 16 180.70 17 479.70

[0398] 2. Pharmacokinetic analysis of compounds in rat plasma

[0399] 1. Experimental Materials

[0400] Male SD rats, oral administration by gavage and intravenous injection: 3 rats / compound respectively, animals were transferred from Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0401] 2. Experimental Methods

[0402] The pharmacokinetic characteristics of the compounds were tested by oral gavage (PO) or intravenous injection (IV) in rats according to the standard protocol. The test compound was prepared into a clear solution, the solvent: 10% DMSO + 10% Solutol + 80% Saline. Three rats were given a single oral gavage of 5 mg / kg, and blood was collected from the submandibular vein or other appropriate methods at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. About 0.03 mL of each sample was collected, and sodium heparin was used for anticoagulation. After collection, it was placed on ice. And 3 rats were injected intravenously with 1 mg / kg of the test compound once, and blood was collected from the submandibular vein or other appropriate methods at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. About 0.03 mL of each sample was collected, and sodium heparin was used for anticoagulation. After collection, it was 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 method.

[0403] All samples were stored at -80°C before analysis and testing, and pharmacokinetic parameters were calculated using Phoenix WinNonlin. The pharmacokinetic parameter results are shown in Table 2.

[0404] Table 2: Pharmacokinetic parameters

[0405]

[0406] It can be seen that the compounds of the present invention have higher exposure in rats and higher bioavailability than the positive compounds, and are expected to have better efficacy.

[0407] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, in, Each R1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-10 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) r R7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, 5-8 membered heteroaryl and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-6 Alkyl and C 1-6 substituted by an alkoxy substituent; R2 is selected from C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-12 membered heteroaryl, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-10 membered heterocyclic group, -S(O) r R7 and -NR 10 R 11 substituted by a substituent; R3 is selected from C 3-10 Cycloalkyl, 3-10 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 deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen substituted C 1-6 Alkyl, deuterium substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, halogen substituted C 3-10 Cycloalkyl, halogen-substituted 3-10 membered heterocyclic group, C 1-6 Alkyl substituted C 3-10 Cycloalkyl, C 1-6 Alkyl substituted 3-10 membered heterocyclic group and -NR 10 R 11 substituted by a substituent; R4 and R5 are each independently selected from hydrogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or 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 halogen, amino, hydroxy, C 1-6 Alkyl and halogenated C 1-6 substituted by an alkyl substituent; R6 is selected from 5-6 membered heteroaryl, the 5-6 membered heteroaryl is optionally further substituted by one or more selected from C 1-4 Alkyl substituted; R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-8 Aryl, halogenated C 6-8 substituted by aryl and 5-8 membered heteroaryl substituents; Z1 is selected from 3-10 membered heterocyclic group, 5-10 membered aryl group, 5-10 membered heteroaryl group, -NR 10 -CO-NR 11 -(CH2) c -and-NR 10 , or Z1 is selected from the following groups: Ring A is selected from 5-10 membered heteroaryl; Each r is independently 0, 1 or 2; a, b, c, n are each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Z1 is selected from 3. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R 1 , R2, R3, R4, R5, R 6 , Ring A and n are as defined in claim 1.

4. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, R2, R3, R4, R5, R6, Ring A and n are as defined in claim 1.

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 and R5 together with the carbon atom to which they are directly attached form a cyclopropyl or cyclobutyl group, wherein the cyclopropyl or cyclobutyl group is optionally further substituted with one or more substituents selected from methyl, ethyl and isopropyl; And / or, Ring A is selected from the following groups: 1 indicates the position to which the carbonyl group is bonded, and 2 indicates the position to which the -CR4R5R6 group is bonded.

6. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, R2, R3, R6 and n are as defined in claim 1.

7. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, R2, R3, R6 and n are as defined in claim 1.

8. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R6 is selected from the following groups:

9. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, R2, R3 and n are as defined in claim 1.

10. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R1, R2, R3 and n are as defined in claim 1.

11. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl and halogenated C 1-4 alkyl; R1, R2 and R3 are as defined in claim 1.

12. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl and halogenated C 1-4 alkyl; R1, R2 and R3 are as defined in claim 1.

13. The compound according to any one of claims 1 to 10, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -S(O) r R7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted with one or more selected from halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and -NR 10 R 11 The above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 substituted by an alkoxy substituent, each r is independently 0, 1 or 2; Preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, ethynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl, 5-6 membered heteroaryl, -S(O)2R7, -SR7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted by one or more selected from halogen, C 1-4 Alkyl, C 3-6 The substituents are selected from cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 substituted by an alkoxy substituent; More preferably, R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, azetidinyl, phenyl, pyrazolyl, 3-8 membered heterocyclyl, -S(O)2R7, -SR7, -O-R8, -C(O)R9, -NR 10 R 11 、-P(O)R 10 R 11 、-C(O)NR 10 R 11 and -N(R 10 )C(O)R9, the above groups are optionally further substituted by one or more substituents selected from halogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl, phenyl, oxazolyl, imidazolyl, thienyl and pyridyl, the above groups are optionally further substituted by one or more substituents selected from =O, halogen, C 1-4 Alkyl and C 1-4 The alkoxy group is substituted with an alkoxy substituent.

14. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds: R2 and R3 are as defined in claim 1.

15. The compound according to any one of claims 1 to 14, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups: The above groups are optionally further substituted with one or more selected from cyano, nitro, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 substituted by a substituent; Preferably, R2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or the following groups: The above groups are optionally further substituted by one or more selected from cyano, nitro, hydroxyl, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -P(O)R 10 R 11 、-S(O) r R7, -C(O)NR 10 R 11 、-N(R 10 )-C(O)R9 and -NR 10 R 11 substituted by a substituent.

16. The compound according to any one of claims 1 to 15, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from 3-6 membered heterocyclic group, C 6-8 Aryl and 5-8 membered heteroaryl, the above groups are optionally further substituted with one or more selected from cyano, halogen, hydroxyl, nitro, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-6 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-6 Alkoxy, C 1-6 Alkyl substituted C 3-6 Cycloalkyl and C 1-6 Alkyl substituted 3-6 membered heterocyclic group substituent; Preferably, R3 is selected from phenyl, pyridyl and pyrimidinyl, and the above groups are optionally further substituted with one or more selected from cyano, halogen, hydroxyl, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, halogen substituted C 1-4 Alkyl, halogen substituted C 3-6 Cycloalkyl, halogen-substituted 3-6 membered heterocyclic group, halogen-substituted C 1-4 Alkoxy, C 1-4 Alkyl substituted C 3-6 Cycloalkyl and C 1-4 Alkyl substituted 3-6 membered heterocyclic group substituent; More preferably, R3 is selected from phenyl, which is optionally further substituted by one or more substituents selected from cyano, fluorine, chlorine, bromine, hydroxyl, nitro, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, pyrrolidinyl, azetidinyl, methyl-substituted azetidinyl, oxetanyl, difluorocyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy and trifluoromethoxy.

17. The compound according to any one of claims 1 to 16, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, characterized in that: R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a substituent selected from the group consisting of cycloalkyl, 3-6 membered heterocyclic, phenyl, halogenated phenyl and 5-6 membered heteroaryl; Preferably, R7, R8, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, or, R 10 and R 11 Together with the nitrogen atom or phosphorus atom directly connected thereto, a 3-6 membered heterocyclic group is formed, wherein the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 substituted by a substituent selected from the group consisting of cycloalkyl, 3-6 membered heterocyclic, phenyl, halogenated phenyl and 5-6 membered heteroaryl; More preferably, R7, R8, R9, R 10 , R 11 Each is independently selected from hydrogen, deuterium, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, 4-oxaspiro[2.5]octyl, phenyl, pyridyl, pyrazolyl and 3-8 membered heterocyclyl, or R 10 , R 11 Together with the nitrogen or phosphorus atom directly connected to it, The above groups are independently optionally further substituted by one or more substituents selected from fluorine, chlorine, bromine, hydroxyl, =O, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, halophenyl and pyridyl.

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

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

20. A method for preparing the compound according to any one of claims 1 to 19, its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, characterized in that: The steps include: R1, R2, R3, R4, R5, R6, Z1 and n are as defined in claim 1.

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. Use of the compound according to any one of claims 1 to 19, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating and / or preventing a disease mediated by a GLP-1 receptor agonist.

23. Use of a compound according to any one of claims 1 to 19, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 21 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 and / or hyperinsulinemia.

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