Pyrazole-containing fused ring compounds, pharmaceutical composition thereof and use thereof

Abstract

The present invention provides pyrazole-containing fused ring compounds, a pharmaceutical composition thereof and the use thereof. The present invention provides compounds as shown in formula I or pharmaceutically acceptable salts thereof. The compounds are small molecule compounds for non-invasive administration, have the same or similar effect as polypeptide GLP-1 agonists, and have the advantages of one or more of higher biological activity, better metabolic stability and excellent bioavailability.

Description

A pyrazolocyclic compound, its pharmaceutical composition and its use

[0001] This application claims priority to Chinese Patent Application No. 2024101831167, filed on February 19, 2024, priority to Chinese Patent Application No. 2024104586256, filed on April 17, 2024, priority to Chinese Patent Application No. 2024107933145, filed on June 19, 2024, and priority to Chinese Patent Application No. 2024114735929, filed on October 22, 2024. The entire text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a pyrazolo-containing ring compound, a pharmaceutical composition thereof and use thereof. Background Art

[0003] The GLP-1R (glucagon-like peptide 1 receptor) belongs to the glucagon receptor subfamily of the G protein-coupled receptor cluster B. This class of receptors has three distinct features: a relatively long extracellular N-terminal domain (ECD) of approximately 100-150 amino acids, connected to a seven-transmembrane domain (7TMD), and a relatively short intracellular C-terminal domain (ICD) connecting the transmembrane segments. The human GLP-1R gene is located on chromosome 6 and encodes 463 amino acids. In the pancreas, GLP-1R is primarily expressed in pancreatic β cells. Besides pancreatic islets, GLP-1R is also widely expressed in tissues and organs such as the stomach, small intestine, heart, kidney, lung, and brain. The primary function of the GLP-1R is to bind to the glucagon-like peptide-1 receptor (GLP-1), thereby regulating blood sugar.

[0004] GLP-1 is a hormone produced primarily by intestinal L cells and belongs to the incretin class. GLP-1 has a very short half-life of only 1-2 minutes, and its physiological function is primarily through binding to and activating the GLP-1R. In addition to GLP-1, the human body also contains glucose-dependent insulin-releasing peptide (GIP), but only GLP-1 can inhibit the release of glucagon, causing a feeling of satiety. As of 2021, all incretin drugs used clinically are based on GLP-1.

[0005] Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in regulating glucose homeostasis. Drugs targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety.

[0006] Diabetes mellitus refers to a group of metabolic diseases characterized by persistently high blood sugar levels. The most common type of diabetes mellitus, type 2 diabetes mellitus (T2DM), is an acquired disease, accounting for over 90% of diabetes cases. T2DM typically develops in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle changes may help control the disease, patients with T2DM may need to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas.

[0007] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) work in tandem to regulate insulin secretion in response to glucose ingestion. In patients with type 2 diabetes, although the effects of these incretins are significantly diminished (if present), and even the endocrine pancreatic response to GIP is effectively shut down, GLP-1 retains insulin properties. Therefore, incretin mimetics and other GLP-1-based therapies can help stimulate insulin production in patients with type 2 diabetes.

[0008] To date, all approved GLP-1 agonists are peptides, with no small molecule compounds. Therefore, the development of small molecule GLP-1 agonists is particularly important. The present invention is intended to address this need. Summary of the Invention

[0009] The technical problem addressed by the present invention is the limited availability of existing GLP-1 agonists. To address this issue, the present invention provides a pyrazolocyclic compound, a pharmaceutical composition thereof, and its use. The compounds of the present invention are small molecules that can be administered non-invasively and exhibit the same or similar effects as polypeptide GLP-1 agonists. They possess one or more of the following advantages: higher biological activity, improved metabolic stability, and superior bioavailability.

[0010] The present invention solves the above technical problems through the following technical solutions:

[0011] The present invention provides a compound represented by general formula (I-0) or a pharmaceutically acceptable salt thereof,

[0012] in:

[0013] Ring A is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl or 5-6 membered heteroaryl and C 5-6 Cycloalkyl;

[0014] Ring B is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0015] Ring C is selected from C 6-10 Aryl, aryl and 3-6 membered cycloalkyl, aryl and 3-6 membered heterocyclyl, aryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl;

[0016] Ring D is selected from C 6-10 Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5- to 6-membered heterocyclic aryl, 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl, or 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclic aryl;

[0017] M is R 6 and R 7 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by one or more R 6-1 Replacement; or R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 6-1 Substitution; said R 6-1 Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0018] is heteroaryl, wherein T and U are each independently N or C;

[0019] R 1 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-6 membered heteroaryl, -OR or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1 Replacement; R 1-1 Each independently selected from hydroxy, halogen, amino, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1 replace;

[0020] R 2 Selected from hydrogen, oxo, thio, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0021] R 3 and R 3’ Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; or, R 3 and R 3’ connected to form a 3-6 membered heterocyclic group;

[0022] Each R 4 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0023] Each R 5 Each independently selected from hydrogen, deuterium, hydroxyl, amino, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 、-S(=O)(=NR 5-1 )R 5-2 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted by one or more R 5-1 Replacement; R 5-1 and R 5-2 Each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0024] R 8 Selected from hydrogen, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0025] Or, two R 4 Connect to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, optionally selected from halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 substituted by one or more substituents in a cycloalkyl group or a 3-6 membered heterocyclic group;

[0026] x, y and z are each independently selected from 0, 1, 2, 3 or 4.

[0027] The present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

[0028] in:

[0029] Ring A is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl or 5-6 membered heteroaryl and C 5-6 Cycloalkyl;

[0030] Ring B is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl;

[0031] Ring C is selected from C 6-10 aryl;

[0032] Ring D is selected from C 6-10 Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5- to 6-membered heterocyclic aryl, 5- to 6-membered heteroaryl aryl, or 5- to 6-membered heteroaryl 5- to 6-membered heteroaryl;

[0033] M is R 6 and R 7 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by one or more R 6-1 Replacement; or R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 6-1 Substitution; said R 6-1 Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0034] is heteroaryl, wherein T and U are each independently N or C;

[0035] R 1 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-6 membered heteroaryl, -OR or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1Replacement; R 1-1 Each independently selected from hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1 replace;

[0036] R 2 Selected from hydrogen, oxo, thio, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0037] R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0038] Each R 4 Each independently selected from hydrogen, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1- 6-halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0039] Each R 5 Each independently selected from hydrogen, hydroxy, amino, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1- 6-haloalkoxy, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl, the amino, C 1-6Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted by one or more R 5-1 Replacement; R 5-1 and R 5-2 Each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl;

[0040] R 8 Selected from hydrogen, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0041] x and y are each independently selected from 0, 1, 2, 3 or 4.

[0042] In a preferred embodiment of the present invention, the ring A of the present invention is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5 membered heteroaryl and 5-6 membered heterocyclic group, 5 membered heteroaryl and C 5-6 Cycloalkyl or 5-membered heterocyclic group or 5-6-membered heterocyclic group;

[0043] Preferably, ring A is selected from 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heterocyclyl, 5-membered heteroaryl and cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl or 5-membered heteroaryl and 6-membered heterocyclyl.

[0044] In a certain embodiment of the present invention, the R 8 Does not exist.

[0045] In a preferred embodiment of the present invention, the ring B of the present invention is selected from a 5-membered heterocyclic group or a 5-membered heteroaryl group; preferably, the ring B is selected from

[0046] Alternatively, the ring C is selected from phenyl or benzo 5-6 membered heterocyclic group;

[0047] Alternatively, the ring D is selected from phenyl, pyridyl, benzopyrazolyl, benzimidazolyl or pyridoimidazolyl; preferably, the ring D is selected from phenyl,

[0048] In a certain embodiment of the present invention, the ring C of the present invention is selected from a 5-6 membered heteroaryl or a 5-6 membered heterocyclic group; preferably a pyridyl, pyridonyl, oxazolyl or pyrazolyl group.

[0049] In a certain embodiment of the present invention, the ring D of the present invention is selected from

[0050] In a preferred embodiment of the present invention, the ring A of the present invention is selected from wherein M1, M2, M3 and M4 are each independently selected from C, N, O, S or Se, represents a single bond or a double bond;

[0051] Preferably, ring A is selected from

[0052] In a preferred embodiment of the present invention, the Selected from

[0053] In a preferred embodiment of the present invention, the ring C of the present invention is selected from phenyl or

[0054] In a preferred embodiment of the present invention, the compound of the present invention is represented by formula (II-1), formula (II-2), formula (II-3) or formula (II-4):

[0055] Where: R 9 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy.

[0056] In a preferred embodiment of the present invention, the R 9 is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxymethyl or hydroxyethyl.

[0057] In a preferred embodiment of the present invention, the ring D is selected from phenyl, pyridyl,

[0058] In a preferred embodiment of the present invention, the ring C of the present invention is selected from phenyl or

[0059] In a preferred embodiment of the present invention, the ring C of the present invention is selected from phenyl,

[0060] In a preferred embodiment of the present invention, the ring D of the present invention is selected from phenyl,

[0061] In a preferred embodiment of the present invention, the ring D of the present invention is selected from

[0062] In a preferred embodiment of the present invention, the R 1 is selected from 4-membered heterocyclic group, 5-6-membered heterocyclic group or 5-6-membered heteroaryl, wherein the 4-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-membered heteroaryl are optionally substituted by one or more R 1-1 Substituted; preferably, the R 1 Selected from Oxetanyl, oxazolyl, pyridinyl, pyrazolyl or cyclohexyl, Oxetanyl, oxazolyl, pyridinyl, pyrazolyl and cyclohexyl, optionally further substituted by one or more R 1-1 Substitution; said R 1-1 Each independently selected from halogen, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, the R 1- 1 Each is independently selected from halogen, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, and difluoromethyl.

[0063] In a preferred embodiment of the present invention, the R 1 Selected from described Optionally further represented by one or more R 1-1 Substituted, the R 1-1 Each is independently selected from halogen, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, and difluoromethyl.

[0064] In a preferred embodiment of the present invention, the Selected from

[0065] In a preferred embodiment of the present invention, M is selected from where R 9 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy; preferably, R 9 is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxymethyl or hydroxyethyl.

[0066] In a preferred embodiment of the present invention, the R 2 Selected from hydrogen, oxo, thio, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 preferably said R 2 is selected from oxo or thio.

[0067] In a preferred embodiment of the present invention, the R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Preferably, the R 3 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl.

[0068] In a preferred embodiment of the present invention, each R 4 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1- 3-deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, each R 4 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, -CD3, vinyl, ethynyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, propoxy, cyclopropyl, oxirane, aziridine, cyclobutyl, oxetanyl or azetidinyl.

[0069] In a preferred embodiment of the present invention, each R 4 Each independently selected from hydrogen, halogen, amino, hydroxyl, C 1-3 Alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, each R 4 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, oxirane, aziridine, cyclobutyl, oxetanyl or azetidinyl. In a preferred embodiment of the present invention, each R 5 Each independently selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 、C 3-4 Cycloalkyl, 3-4 membered heterocyclic group or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted by one or more R 5-1 Substituted; preferably, each R 5 Each independently selected from hydrogen, hydroxy, amino, fluorine, chlorine, bromine, methyl, ethyl, propyl, -CD3, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, difluoromethyl, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5- 1 , -NHCH3, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl.

[0070] In a certain embodiment of the present invention, each R 5Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, -CD3, methoxy, methyl, ethyl, cyclopropyl,

[0071] The R 5-1 and R 5-2 Each independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 cycloalkyl, 3-4 membered heterocyclyl or 5-6 membered heteroaryl; preferably, R 5-1 and R 5-2 Each is independently selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl.

[0072] In a preferred embodiment of the present invention, the R 8 Selected from hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

[0073] In a preferred embodiment of the present invention, the R 8 is selected from hydrogen, oxo, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl. In a preferred embodiment of the present invention, M is R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3- 6 cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 6-1 substituted; preferably, R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl, the C 3-4 The cycloalkyl group is optionally substituted with one or more R 6-1 substituted; more preferably, R 6 and R 7 Together with the carbon atom to which they are attached, they form a cyclopropyl group, which is optionally substituted by one or more R 6-1 Substitution; said R 6-1 Each independently selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, the R 6-1 Each is independently selected from methyl, hydroxymethyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl.

[0074] In a preferred embodiment of the present invention, the for

[0075] In a preferred embodiment of the present invention, the compound of the present invention is selected from the following compounds in Table 1.1:

[0076] Table 1.1

[0077] The present invention provides a pharmaceutical composition comprising:

[0078] (1) the compound represented by formula I as described above or a pharmaceutically acceptable salt thereof, and

[0079] (2) Pharmaceutically acceptable excipients.

[0080] The present invention provides a use of a compound represented by formula I as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament, wherein the medicament can be used to prevent and / or treat metabolic diseases; preferably, the metabolic disease is diabetes.

[0081] The present invention provides a use of the compound represented by formula I as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a GLP-1 agonist.

[0082] General preparation method of the present invention:

[0083] Among them, ring A, ring B, ring C, ring D, M, R 1 、R 2 、R 3 、R 4 、R 5 、R 8 and The definition of is as described above in the present invention.

[0084] Explanation of terms

[0085] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0086] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0087] The term "thio" refers to =S, where a sulfur atom replaces two hydrogen atoms on the same carbon atom.

[0088] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include 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, and various branched isomers thereof. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred in the present invention.

[0089] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms, and more preferably 3 to 4 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

[0090] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0091] The term "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, Se, and S, but excluding the ring moieties of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, the substituent contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; and most preferably, it contains 3 to 6 ring atoms. As used herein, "membered" refers to the number of ring atoms; for example, a 3-6-membered heterocyclyl group means a substituent containing 3-6 ring atoms. Non-limiting examples of heterocyclic groups include oxetane, thietanyl, azetidinyl, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably oxetane, thietanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminoylidene-1-oxothiopyran, azepanyl, piperidinyl, piperazinyl,

[0092] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, thio, carboxyl or carboxylate.

[0093] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably, phenyl.

[0094] Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 , carboxyl or carboxylate groups.

[0095] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, Se and nitrogen. The heteroaryl group is preferably a 5-8 membered monoheteroaryl or an 8-10 membered diheteroaryl group, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl, an 8-membered diheteroaryl, a 9-membered bicyclic heteroaryl group or a 10-membered bicyclic heteroaryl group, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, thienopyrrolyl, thiazolopyrrolyl, oxazolopyrrolyl, furopyrrolyl, thienylfuryl, oxazoloimidazolyl, thiazolofuryl, thiadiazolioimidazolyl, oxazoloimidazolyl, thienothiazolyl and the like.

[0096] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0097] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0098] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0099] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0100] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -CH2OH, -C(CH3)2(OH).

[0101] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0102] In the present invention Indicates that the key may not exist;

[0103] The substituents of the present invention It indicates the position where the substituent is attached to the substituted site.

[0104] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atom in the example compounds of the present invention may also be replaced by a deuterium atom.

[0105] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0106] "One or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more, preferably 1, 2, 3 or 4.

[0107] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible 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 (e.g., olefinic) bond.

[0108] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0109] "Pharmaceutically acceptable" or "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0110] A "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0111] Unless otherwise specified, all technical and scientific terms used herein have the standard meanings in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0112] Unless otherwise indicated, the chiral compounds of the present invention can be synthesized from chiral starting materials or resolved using chiral columns conventional in the art, such as Chiracel AD-3 column (460 mm ID x 5 cm L); 2) wash solvent: CO2:Ethanol (0.05% DEA) (70:30 v / v); 3) flow rate: 2.5 ml / min, 4) detection wavelength: 254 nm; 5) column temperature: 25°C.

[0113] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0114] The reagents and raw materials used in the present invention are commercially available or prepared by methods disclosed in the prior art.

[0115] Unless otherwise specified, the chiral carbon atoms in the compounds of the present invention are in the R or S configuration.

[0116] The positive and progressive effects of the present invention are that the compounds of the present invention are small molecule compounds that are administered non-invasively and have the same or similar effects as polypeptide GLP-1 agonists, and the compounds of the present invention have one or more advantages of higher biological activity, better metabolic stability, and excellent bioavailability. DETAILED DESCRIPTION

[0117] The present invention is further illustrated by way of examples, but the invention is not limited to the scope of these examples. Experimental methods in the following examples, where specific conditions are not specified, were performed according to conventional methods and conditions, or according to the product specifications. Unless otherwise specified, the reagents used in the present invention were commercially available or prepared according to methods disclosed in the prior art.

[0118] Intermediate Preparation Example

[0119] Intermediate I01

[0120] (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0121] first step:

[0122] To a solution of compound I01-1 (2 g, 9.85 mmol) in THF (20 mL) at -78°C under nitrogen was added dropwise n-BuLi (2.5 M, 3.94 mL, 9.85 mmol, 1.0 eq). After stirring for 1 hour, compound I01-2 (2.27 g, 9.85 mmol, 1.0 eq) was added. The temperature was then raised to -40°C and stirring continued for 40 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. Saturated NH4Cl (50 mL) was added, and the mixture was extracted with EA (50 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product. Purification by column chromatography (EA:PE = 10:1) afforded I01A (2.58 g, 74%) as a light yellow solid. LCMS: 355.20 [M+H] + .

[0123] Step 2:

[0124] To a solution of (S)-3-aminobutyronitrile hydrochloride (compound I01-3, 10.1 g, 120.2 mmol, 1.0 eq) in ethanol (60 mL) were added ethyl acrylate (I01-4, 14.4 g, 144.2 mmol, 1.2 eq) and triethylamine (20 mL, 144.2 mmol, 1.2 eq) at room temperature. After stirring at 70°C for 3 hours, the mixture was cooled to room temperature. N-methylpiperazine (I01-5, 4 mL, 36.1 mmol, 0.3 eq) and (Boc)2O (33.1 mL, 144.2 mmol, 1.2 eq) were added sequentially, and the mixture was stirred overnight. Water (100 mL) was added, and the mixture was extracted with toluene (100 mL x 3), dried over Na2SO4, and concentrated to afford I01B (34.1 g, crude product). The crude product was used directly in the next step without purification. LCMS: 285.17 [M+H] + .

[0125] Step 3:

[0126] To a solution of I01B (34.1 g) in THF (500 mL) at room temperature was added t-BuOK (13.5 g, 120.2 mmol, 1.2 eq). After stirring for 2 hours, 2N HCl (90 mL) was added and stirring continued for 30 minutes. Water (100 mL) was added and the mixture was extracted with EA (500 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 20:1) to afford I01C (9.2 g, 32%) as a white solid. LCMS: 239.13 [M+H] + .

[0127] Step 4:

[0128] To a solution of I01A (2.13 g, 6.01 mmol) in NMP (7 mL) at room temperature was added methanesulfonic acid (7 mL). The mixture was stirred at 70°C for 7 hours, cooled to room temperature, and toluene (12.8 mL), KCO (0.914 g), and water (7 mL) were added. After stirring for 10 minutes, the aqueous phase was removed. A solution of I01C (1.43 g, 6.01 mmol, 1.5 eq) in toluene (6.3 mL), pyridine hydrochloride (71.0 mg, 0.60 mmol, 0.1 eq), and toluene (4.2 mL) were then added. After stirring at 90°C for 1 hour, the mixture was cooled to room temperature, and 1M aqueous NaOH (12.6 mL) was added. The organic phase was separated, dried over NaSO, and concentrated to afford I01D (1.68 g, 75%) as a white solid. LCMS: 375.21 [M+H]. + .

[0129] Step 5:

[0130] To a solution of di(1H-imidazol-1-yl)methanone (I01-6, 2 g, 5.34 mmol, 1.0 eq) in DMA (20 mL) was added dropwise 2,2-dimethoxyethylamine (I01-7, 1.8 g, 16.42 mmol, 3.0 eq) at 0°C under nitrogen. After stirring at room temperature for 2 hours, the resulting product (I01E) was used directly in the next reaction.

[0131] Step 6:

[0132] To a solution of I01D (106 mg, 0.283 mmol, 1.0 eq) in DMA (0.53 mL) at room temperature were added I01E (62.0 mg, 0.311 mol) and KOtBu (95.0 mg, 0.849 mol, 3.0 eq). After stirring for 4 hours, the reaction was quenched with water and extracted with EA, dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 3:2) to afford I01F (105 mg, 73%) as a white solid. LCMS: 506.27 [M+H] + .

[0133] Step 7:

[0134] To a solution of I01F (4.45 g, 8.79 mmol, 1.0 eq) in THF (44.5 mL) at room temperature was added methanesulfonic acid (0.676 g, 7.03 mmol, 1.0 eq). After stirring at 60°C for 2 hours, the mixture was cooled to room temperature and an aqueous solution of K3PO4 (1.87 g, 8.79 mmol, 3.0 eq) (17.8 mL) and di-tert-butyl dicarbonate (0.768 g, 3.52 mmol, 1.02 eq) were added. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with EA, dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 3:7) to afford I01G (3.43 g, 88%) as a white solid. LCMS: 442.22 [M+H] + .

[0135] Step 8:

[0136] To a solution of I01G (1.3 g, 2.9 mmol, 1.0 eq) in NMP (20 mL) were added KCO (1.2 g, 8.8 mmol, 3.0 eq), CuI (56.3 mg, 0.3 mmol, 0.1 eq), 5-bromo-4-fluoro-1-methyl-1H-indazole (I01-8, 1.0 g, 4.4 mmol, 1.5 eq), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (I01-9, 42.1 mg, 0.3 mmol, 0.1 eq) at room temperature. After stirring at 130°C for 6 hours, the mixture was cooled to room temperature, added with water, and extracted with EA, dried over NaSO, concentrated, and purified by column chromatography (EA:PE = 1:1) to afford I01H (1.1 g, 63%) as a white solid. LCMS: 590.26 [M+H]. + .

[0137] Step 9:

[0138] To a solution of I01H (430.0 mg, 0.7 mmol, 1.0 eq) in DCM (4 mL) was added dioxane / HCl (4 N, 4 mL) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated to afford I01 (500 mg, crude) as a white solid. The crude product was used directly in the next reaction without purification. LCMS: 490.21 [M+H] + .

[0139] Referring to the above method, the following intermediates were synthesized

[0140] Table 1.2

[0141] Intermediate I02

[0142] first step:

[0143] To a solution of ethyl 5-bromothiophene-3-carboxylate (I02-1, 14.7 g, 61.68 mmol, 1.0 eq) in DCM (100 mL) was added dropwise DIBAL-H (1.5 M / L, 165 mL, 246.72 mmol, 4.0 eq) at -78°C under nitrogen. After stirring for 2 hours, the reaction was quenched with saturated sodium potassium tartrate (50 mL). The mixture was extracted with EA (100 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 3:1) to afford I02A (11.88 g, 99.76%) as a colorless liquid. LCMS: 194.92 [M+H] + .

[0144] Step 2:

[0145] To a solution of I02A (11.88 g, 61.53 mmol, 1.0 eq) in DCM (100 mL) was added portionwise a Dess-Martin reagent (52.20 g, 123.07 mmol, 2.0 eq) at 0°C under nitrogen. After stirring for 2 hours, the solid was filtered off, and the filtrate was concentrated and purified by column chromatography (EA:PE = 5:1) to afford I02B (10.45 g, 88.9%) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.56(s,1H),7.53(s,1H).

[0146] Step 3:

[0147] Under nitrogen at -30°C, NaOEt (16.38 g, 240.68 mmol, 4.4 eq) and ethyl azidoacetate (35.32 g, 273.50 mmol, 5.0 eq) were added to ethanol (200 mL). After stirring for 10 minutes, I02B (10.45 g, 54.70 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 3 hours. Water (100 mL) was added, and the mixture was extracted with EA (300 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 10:1) to afford I02C (9.40 g, 56.87%) as a colorless liquid. 1 H NMR (400MHz, DMSO-d6) δ8.08(s,1H),7.69(s,1H),6.87(s,1H),4.26(q,2H),1.27(t,3H).

[0148] Step 4:

[0149] A solution of I02C (9.40 g, 31.11 mmol, 1.0 eq) in toluene (100 mL) was stirred at 120°C for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (EA:PE = 8:1) to afford I02D (7.78 g, 91.22%) as a white solid. LCMS: 275.90 [M+H] + .

[0150] Step 5:

[0151] To a solution of I02D (5 g, 18.18 mmol, 1.0 eq) in DMF (50 mL) at 0°C under nitrogen was added NaH (654 mg, 27.27 mmol, 1.5 eq) portionwise. Stirring was continued for 1 hour, followed by the dropwise addition of bromoacetonitrile (4.36 g, 36.36 mol, 2.0 eq). After stirring at room temperature for 3 hours, water (100 mL) was added, and the mixture was extracted with EA (300 mL x 3), dried over Na2SO4, and concentrated to afford the crude product. Ethanol was added to the crude product, the mixture was slurried, filtered, and further dried to afford I02E (5.23 g, 91.9%) as a white solid. 1 H NMR (399MHz, CDCl3) δ7.15(s,1H),7.08(s,1H),5.45(s,2H),4.35(q,2H),1.38(t,3H).

[0152] Step 6:

[0153] A solution of I02E (3 g, 9.58 mmol, 1.0 eq), 4-iodo-2,2-dimethyltetrahydro-2H-pyran (I02-2, 4.60 g, 19.16 mmol, 2.0 eq), compound I02-3 (150 mg, 0.96 mmol, 0.1 eq), NiBr2 / DME (296 mg, 0.96 mmol, 0.1 eq), KI (4.77 g, 28.74 mmol, 3.0 eq), and Mn (200 mesh, 1.58 g, 28.74 mmol, 3.0 eq) in DMA (50 mL) was deoxygenated and flushed with nitrogen three times. The mixture was then stirred at 80°C under nitrogen for 16 hours. Cool to room temperature, add water (70 mL), and extract with EA (100 mL * 3), dry over Na2SO4, concentrate, and purify by column chromatography (EA:PE = 5:1) to obtain colorless liquid I02F (1.6 g, 48.22%). LCMS: 347.10 [M+H] + .

[0154] Step 7:

[0155] To a solution of I02F (300 mg, 0.86 mmol, 1.0 eq) and (R)-4-methyl-1,3,2-dioxathiane 2,2-dioxide (I02-4, 298 mg, 2.16 mmol, 2.5 eq) in DMPU (3 mL) was added dropwise KHMDS (1 M / L, 3.44 mL, 3.44 mmol, 4.0 eq) at 0°C under nitrogen. After stirring for 2 hours, formic acid (0.1 mL) was added and the product was purified by column chromatography (EA:PE = 5:1) to afford a colorless liquid I02G (323 mg, 97.67%). LCMS: 387.15 [M+H] + .

[0156] Step 8:

[0157] To a solution of I02G (323 mg, 0.84 mmol, 1.0 eq) in DMSO (2 mL) at room temperature was added NH2OH (2 mL of water solution). The mixture was stirred overnight at room temperature, then water (10 mL) was added and extracted with EA (20 mL x 3). The mixture was dried over Na2SO4 and concentrated to afford a colorless liquid product. This product was dissolved in DMSO (4 mL), and CDI (272 mg, 1.68 mmol, 2.0 eq) and DBU (320 mg, 2.10 mmol, 2.5 eq) were added. After stirring at room temperature for 1 hour, 1N HCl was added to adjust the pH to 5, and the mixture was extracted with EA (20 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified on a thin-layer silica gel plate (DCM:MeOH = 20:1) to afford I02H (100 mg, 26.19%) as a white solid. LCMS: 446.35 [M+H] + .

[0158] Step 9:

[0159] To a solution of I02H (100 mg, 0.22 mmol, 1.0 eq) in methanol (4 mL) and water (2 mL) was added NaOH (26 mg, 0.66 mmol, 3.0 eq) at room temperature. After stirring at 80°C for 16 hours, 1N HCl was added to adjust the pH to 6. The mixture was extracted with EA (10 mL x 3), dried over Na2SO4, concentrated, and purified on a thin-layer silica gel plate (DCM:MeOH = 20:1) to afford I02 (50 mg, 0.11 mmol, 54.44%) as a white solid. LCMS: 418.10 [M+H] + .

[0160] Intermediates I02-P1 and I02-P2

[0161] IO2 was further purified by SFC to obtain IO2-P1 and IO2-P2. SFC purification conditions were: 1) Chiracel AD-3 column (460 mm ID x 5 cm L); 2) wash solvent: CO2:Ethanol (0.05% DEA) (70:30 v / v); 3) flow rate: 2.5 ml / min; 4) detection wavelength: 254 nm; 5) column temperature: 25°C. The retention times on the column for IO2-P1 and IO2-P2 were 2.73 and 3.39 minutes, respectively.

[0162] Referring to the above method, the following intermediates were synthesized

[0163] Table 1.3

[0164] Intermediate I06

[0165] first step:

[0166] Under nitrogen at -30°C, sodium ethoxide (29.81 g, 437.90 mmol, 4.0 eq) was added to an ethanol solution (350 mL). Ethyl azidoacetate (56.55 g, 437.90 mmol, 4.0 eq) was then added dropwise. After stirring for 10 minutes, 2-methoxynicotinaldehyde (15.00 g, 109.50 mmol, 1.0 eq) was added. The mixture was allowed to warm to room temperature and stirred for 3 hours. Water (100 mL) was added and the mixture was extracted with EA (300 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 10:1) to afford I06A (15.40 g, 56.71%) as a yellow solid. LCMS: 249.20 [M+H]. + .

[0167] Step 2:

[0168] A solution of I06A (15.40 g, 62.09 mmol, 1.0 eq) in toluene (120 mL) was stirred at 120°C under nitrogen for 16 hours. The mixture was cooled to room temperature, added with water (50 mL), and extracted with EA (100 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 8:1) to obtain I06B (12.46 g, 91.2%) as a white solid. LCMS: 221.20 [M+H] + .

[0169] Step 3:

[0170] To a solution of I06B (1 g, 4.55 mmol, 1.0 eq) in DMF (10 mL) at 0°C under nitrogen was added NaH (236 mg, 5.91 mmol, 1.3 eq). Stirring was continued for 1 hour, and then SEMCl (909 mg, 5.45 mol, 1.2 eq) was added dropwise. The mixture was warmed to room temperature and stirred for 3 hours. Water (50 mL) was then added, and the mixture was extracted with EA (100 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 8:1) to afford I06C (992.12 mg, 62.31%) as a white solid. LCMS: 351.50 [M+H] + .

[0171] Step 4:

[0172] To a solution of I06C (10.0 g, 28.57 mmol, 1.0 eq) in NMP (80 mL) at room temperature was added Py-HCl (49.52 g, 428.57 mmol, 15.0 eq), followed by stirring at 150°C for 15 minutes. The mixture was cooled to room temperature, and water (150 mL) was added. The mixture was filtered and dried to afford I06D (8.08 g, 24.04 mmol, 84.17%) as a white solid. LCMS: 337.41 [M+H] + .

[0173] Step 5:

[0174] To a solution of tetrahydro-2H-pyran-4-ol (22.0 g, 215 mmol, 1.0 eq.) in DCM (200 mL) at 0°C under nitrogen was added TEA (43.6 g, 430 mmol, 2.0 eq.) and TsCl (49.3 g, 258 mmol, 1.2 eq.) in sequence. After warming to room temperature and stirring for 4 hours, water (50 mL) was added and the product was extracted with DCM (100 mL x 3), dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 4:1) to afford I06E (26.4 g, 47.96%) as a white solid. LCMS: 257.30 [M+H]. + .

[0175] Step 6:

[0176] To a solution of I06D (7.0 g, 20.83 mmol, 1.0 eq.) and I06E (10.67 g, 41.67 mmol, 2.0 eq.) in DMF (70 ml) was added Cs2CO3 (13.57 g, 41.67 mmol, 2.0 eq.) at room temperature, followed by stirring at 100°C for 16 hours. The mixture was cooled to room temperature, added with water (100 mL), and extracted with EA (100 mL x 3). The mixture was dried over Na2SO4, concentrated, and purified by column chromatography (EA:PE = 8:1) to afford I06G (3.1 g, 7.38 mmol, 35.43%) as a yellow solid and I06F (4.36 g, 49.83%) as a yellow liquid. LCMS: 421.58 [M+H] + .

[0177] I06G: 1H NMR(400MHz,Chloroform-d)δ7.62–7.58(m,1H),7.20(d,J=7.6Hz,1H),6.54(d,J=7.6Hz,1H),5.88(s,2H),5.27(dt,J=10.7,4.4Hz,1H),4.33(q, J=7.2Hz,2H),4.17–4.07(m,2H),3.65–3.58(m,2H),3.57–3.49(m,2H),1 .90–1.83(m,4H),1.37(t,J=7.1Hz,3H),0.90–0.83(m,2H),-0.07(s,9H).

[0178] I06F: 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=6.1Hz,1H),7.44(d,J=0.9Hz,1H),7.03(d,J=6 .1Hz,1H),5.94(s,2H),5.47(tt,J=8.2,3.8Hz,1H),4.37(q,J=7.1Hz,2H),4.02(dt,J=1 0.4,4.6Hz,2H),3.66(ddd,J=11.7,8.7,3.0Hz,2H),3.57–3.46(m,2H),2.12(dt,J=12.7 ,4.1Hz,2H),1.92–1.83(m,2H),1.41(t,J=7.2Hz,3H),0.93–0.82(m,2H),-0.08(s,9H).

[0179] Step 7:

[0180] A solution of I06G (1 g, 2.38 mmol, 1.0 eq.) in DCM:TFA (20 mL:5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, followed by the addition of NH4OH (5.0 mL) and ACN (10.0 mL). The mixture was stirred for 1 hour, and water (10 mL) was added. The mixture was extracted with EA (35 mL x 3), dried over Na2SO4, and concentrated to afford I06H (690 mg, 99.6%) as a yellow solid. LCMS: 291.32 [M+H] + .

[0181] Step 8:

[0182] To a solution of I06H (600 mg, 2.07 mmol, 1.0 eq) in DMF (10 mL) at 0°C under nitrogen was added NaH (248 mg, 6.20 mmol, 3.0 eq). After stirring for 1 hour, bromoacetonitrile (1.24 g, 10.35 mol, 5.0 eq) was added. The mixture was warmed to room temperature and stirred for 3 hours. Water (10 mL) was added and the mixture was extracted with EA (50 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product. The product was purified by slurrying with ethyl acetate (150 mL) and filtered to obtain I06I (476 mg, 69.89%) as a white solid. LCMS: 330.36 [M+H] + .

[0183] Step 9:

[0184] To a solution of I06I (270 mg, 0.82 mmol, 1.0 eq) and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (226 mg, 1.64 mmol, 2.0 eq) in DMPU (4 mL) was added KHMDS (1 M / L, 2.46 mL, 2.46 mmol, 3.0 eq) at 0°C under nitrogen. After stirring for 2 h, formic acid (0.1 mL) was added and the mixture was concentrated. Purification by column chromatography (EA:PE = 1:1) afforded I06J (102 mg, 33.71%) as a yellow liquid. LCMS: 370.42 [M+H] + .

[0185] Step 10:

[0186] To a solution of I06J (102 mg, 0.27 mmol, 1.0 eq) in DMSO (2 mL) at room temperature was added NH2OH (2 mL of water). The mixture was stirred overnight, then water (10 mL) was added and extracted with EA (20 mL x 3), dried over Na2SO4, and concentrated to yield a yellow liquid. This yellow liquid was dissolved in DMSO (4 mL), and CDI (87.56 mg, 0.54 mmol, 2.0 eq) and DBU (123.31 mg, 0.81 mmol, 3.0 eq) were added. After stirring for 1 hour, the pH was adjusted to 5 with 1N HCl, and the mixture was extracted with EA (20 mL x 3), dried over Na2SO4, and concentrated to yield the crude product. Pre-TLC (DCM:MeOH = 20:1) yielded I06K (30 mg, 25.96%) as a white solid. LCMS: 429.45 [M+H] + .

[0187] Step 11:

[0188] To a solution of I06K (30 mg, 0.07 mmol, 1.0 eq) in MeOH (4 mL) and water (2 mL) at room temperature was added NaOH (14 mg, 0.35 mmol, 5.0 eq). The mixture was stirred at 60°C for 3 hours, cooled to room temperature, and the pH was adjusted to pH 6 with 1N HCl. The mixture was extracted with EA (10 mL x 3), dried over Na2SO4, and concentrated. Pre-TLC (DCM:MeOH = 20:1) yielded I06 (25 mg, 89.28%) as a white solid. LCMS: 401.30 [M+H] + .

[0189] Referring to the above method, the following intermediates were synthesized

[0190] Table 1.4

[0191] Example 1

[0192] Synthesis of compound 5

[0193] To a solution of I02 (50.0 mg, 0.11 mmol, 1.0 eq) in DMF (5 ml) at room temperature were added I01 (53.79 mg, 0.11 mmol, 1.0 eq), HATU (54.43 mg, 0.143 mmol, 1.3 eq), and DIEA (42.57 mg, 0.33 mmol, 3.0 eq). After stirring for 4 hours, water (20 mL) was added and the mixture was extracted with EA (30 mL x 2). The mixture was dried over Na2SO4, concentrated, and purified on a thin-layer silica gel plate (DCM:MeOH = 10:1) to afford compound 5 (3.59 mg, 3.6%). LCMS: 889.45 [M+H] + . 1 H NMR (400MHz, CDCl3) δ11.59(s,1H),8.12(s,1H),7.46(s,1H),7.13(d,J=5.9Hz,2H) ,6.74(s,1H),6.59(d,J=12.7Hz,2H),6.31(s,1H),5.68(s,1H),4.11(s,4H),3.86– 3.50(m,3H),3.11–2.95(m,2H),2.65(s,4H),2.27(s,6H),1.88(d,J=14.2Hz,2H),1 .63(d,J=13.2Hz,3H),1.29(d,J=9.0Hz,6H),1.24(s,2H),1.17(s,3H),0.87(s,1H).

[0194] Example 2

[0195] Synthesis of compound 26

[0196] To a solution of I03 (49 mg, 0.10 mmol, 1.0 eq) in DMF (5 ml) at room temperature were added I01 (39 mg, 0.10 mmol, 1.0 eq), HATU (58 mg, 0.14 mmol, 1.5 eq), and DIEA (39 mg, 0.28 mmol, 3.0 eq) in sequence. After stirring for 4 hours, water (20 mL) was added and the mixture was extracted with EA (30 mL x 2). The mixture was dried over Na2SO4, concentrated, and purified on a thin-layer silica gel plate (DCM:MeOH = 10:1) to afford compound 26 (3.80 mg, 4.74%). LCMS: 862.25 [M+H] +

[0197] The following compounds were synthesized by using the corresponding intermediates and referring to the general preparation method:

[0198] Table 1.5

[0199] Table 1.6

[0200] Example 3

[0201] Synthesis of compounds 185 and 186

[0202] Intermediate I13 was synthesized from methyl 3-bromo-1H-pyrazole-5-carboxylate according to the method disclosed in WO2022017338. To a solution of I02 (202 mg, 0.48 mmol, 1.0 eq) in DMF (5 mL) at room temperature were added I13 (261.6 mg, 0.53 mmol, 1.0 eq), HATU (276.1 mg, 0.72 mmol, 1.5 eq), and DIEA (187.5 mg, 1.45 mmol, 3.0 eq). After stirring for 4 hours, water (20 mL) was added and the mixture was extracted with EA (30 mL x 2). The mixture was dried over Na2SO4, concentrated, and purified on a thin-layer silica gel plate (DCM:MeOH = 10:1) to afford a yellow solid mixture (171 mg, 40.07%). Further SFC purification and separation gave compound 185 (33.57 mg, 0.03 mmol, 19.87%) and compound 186 (99.82 mg, 0.11 mmol, 59.09%).

[0203] 185: LCMS: 889.98 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.13(d,J=16.0Hz,1H),7.57(dd,J=14.4,7.1Hz,1H),7 .23(d,J=7.4Hz,2H),6.63(t,J=39.1Hz,3H),6.38–6.00(m,2H),4.71(s,1H),4.40(s ,2H),4.10(s,3H),3.80(d,J=17.9Hz,2H),3.17(s,1H),2.68(q,J=7.2Hz,1H),2.27( s,6H),1.88(s,2H),1.59(d,J=18.3Hz,6H),1.29(d,J=9.8Hz,6H),1.20–0.88(m,6H).

[0204] 186: LCMS: 889.98 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.11(s,1H),7.59(s,1H),7.23(s,2H),6.65(d,J=31.6Hz,3H),6.27(s,2H),4.90(s,1H),4.28(s,2H),4.10(s,3H), 3.79(d,J=16.5Hz,2H),3.16(s,1H),2.66(q,J=7.2Hz,1H),2.27(s,6H), 1.88(s,2H),1.77–1.38(m,6H),1.27(t,J=7.8Hz,6H),1.20–0.92(m,6H).

[0205] Example 4

[0206] Synthesis of compounds 190 and 191

[0207] first step:

[0208] 1-Bromo-2-fluoro-4-iodobenzene (4.6 g, 15.29 mmol, 1.0 eq), EtSNa (1.55 g, 18.24 mmol, 1.2 eq), Pd2(dba)3 (700 mg, 0.76 mmol, 0.05 eq), XantPhos (885 mg, 1.53 mmol, 0.1 eq), and triethylamine (4.65 g, 45.87 mmol, 3.0 eq) were dissolved in dioxane (100 mL) and stirred at 80°C overnight under nitrogen. The mixture was cooled to room temperature, added with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over Na2SO4, and concentrated to obtain the crude product. Purification by column chromatography (EA:PE = 10:1) afforded 190A (3.2 g, 13.62 mmol, 89.05%) as a white solid. LCMS: 237.10 [M+H] + .

[0209] Step 2:

[0210] To a solution of 190A (3.2 g, 13.62 mmol, 1.0 eq) in ethanol (50 mL) was added PhI(OAc)2 (13.4 g, 41.73 mmol, 3.0 eq) and H2NCO2NH4 (4.34 g, 55.64 mmol, 4.0 eq) at room temperature. After stirring at room temperature for 2 hours, the crude product was concentrated. The product was purified by reverse phase column chromatography (water (0.1% formic acid, CH3CN system)) to afford 190B (1.3 g, 4.88 mmol, 35.88%) as a white solid. LCMS: 265.90 [M+H] + .

[0211] Step 3:

[0212] To a solution of 190B (300 mg, 0.68 mmol, 1.0 eq) in NMP (10 mL) was added I01G (234 mg, 0.89 mmol, 1.3 eq), (1S, 2S)-N 1 , N 2 1,2-Dimethylcyclohexane-1,2-diamine (96 mg, 0.69 mmol, 1.0 eq), K2CO3 (192 mg, 1.38 mmol, 2.0 eq), and Cul (120 mg, 0.63 mmol, 0.9 eq). After stirring at 130°C for 4 hours, the mixture was cooled to room temperature, the solid was filtered off, and the filtrate was concentrated to obtain the crude product. Purification by preparative TLC (PE:EA = 3:1) afforded 190C (300 mg, 0.50 mmol, 74.19%) as a white solid. LCMS: 627.50 [M+H] + .

[0213] Step 4:

[0214] To a solution of 190C (300 mg, 0.50 mmol, 1.0 eq) in DMF (5 mL) at 0°C was added NaH (20 mg, 0.50 mmol, 60% in oil). After stirring at room temperature for 0.5 h, iodomethane (85 mg, 0.60 mmol, 1.2 eq) was added. Stirring was continued for 16 h, followed by addition of water (50 mL) and extraction with ethyl acetate (50 mL x 2). The mixture was dried over Na2SO4 and concentrated to afford the crude product. Purification by preparative TLC (PE:EA = 1:1) afforded 190D (150 mg, 0.25 mmol, 50.0%) as a white solid. LCMS: 641.15 [M+H] + .

[0215] Step 5:

[0216] To 190D (60 mg, 0.10 mmol, 1.0 eq) was added HCl solution (4 M / L in dioxane, 2 mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to afford the yellow oily product 190E (39 mg). LCMS: 541.20 [M+H] + .

[0217] Step 6:

[0218] To a solution of 190E (39 mg, 0.07 mmol, 1.0 eq) in DMF (2 mL) at room temperature were added DIPEA (28 mg, 0.22 mmol, 3.0 eq), I02 (30 mg, 0.07 mmol, 1.0 eq), and HATU (42 mg, 0.11 mmol, 1.5 eq). The mixture was stirred at 40°C for 48 hours and then cooled to room temperature. The solid was filtered off, and the filtrate was directly purified by prep-HPLC (Water (0.1% TFA / CH3CN)) to afford a white solid. Further SFC purification afforded Compound 190 (10 mg) and Compound 191 (12 mg).

[0219] 190: LCMS: 940.10 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.12(s,1H),7.97(s,2H),7.09(d,2H),6.76(d,2H),6.58(s, 1H),6.39(s,1H),5.71–5.62(m,1H),4.54(d,1H),3.86–3.76(m,3H),3.58(t,1H),3.19(s, 1H),3.09(d,1H),3.00(d,1H),2.75(s,2H),2.26(s,6H),1.88(d,2H),1.74–1.68(m,2H),1 .63(d,3H),1.51(t,5H),1.40(s,3H),1.30(s,3H),1.27(s,3H),1.16(d,3H),0.87(t,1H).

[0220] 191: LCMS: 939.65 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.13(s,1H),7.99(s,2H),7.09(d,2H),6.78(s,1H),6.74(s ,1H),6.58(s,1H),6.39(s,1H),5.71–5.63(m,1H),4.55(d,1H),3.85–3.76(m,3H),3.58(s ,1H),3.18(d,1H),3.12–2.97(m,2H)2.75(s,2H),2.26(s,6H),1.90(s,2H),1.71(d,2H),1 .64(d,5H),1.50(d,3H),1.41(s,3H),1.30(s,3H),1.28(s,3H),1.17(d,3H),0.88(t,1H).

[0221] Test Example 1: EC 50 Determination of

[0222] A cell line stably expressing GLP1R (GLP1R / CRE-Luc / HEK293) was cultured in complete medium (DMEM, 10% FBS, 1% PS). In this experiment, the positive compound used was liraglutide. First, a serial dilution of the test compound was prepared in DMSO to prepare a 200x working solution. The prepared 200x working solution was then diluted to a 5x working solution using a buffer solution (DPBS, 0.1% BSA, 500μM IBMX). According to the assay plate layout, 2μL of the 5x working solution was transferred to a 384-well plate. The number of cells was counted using a cell counter (Counterstar), and the cell suspension was diluted to 0.125*10^6 / mL using a buffer solution. The diluted cell suspension was mixed and 8μL was transferred to a 384-well assay plate coated with the test compound and incubated at room temperature for 30 minutes. The cAMP signal was detected using the cAMP Gs dynamic kit (Gisbio). The d2-cAMP tracer and Cry-anti-cAMP detection reagents were diluted 20-fold using the 1x detection buffer provided in the kit. After incubation of the cells with the test compound at room temperature, 5 μL / well of the diluted d2-cAMP tracer and Cry-anti-cAMP reagent were transferred to the assay plate and the plate was incubated at room temperature. After incubation, the HTRF signal values ​​at 615 nm and 665 nm were read using an Envision multi-function microplate reader (Perkin Elmer). The EC was determined by curve fitting using a four-parameter logarithmic dose-response equation. 50 value.

[0223] The biological activity results are shown in Table 2

[0224] Table 2: EC 50 data

[0225] Other compounds of the present invention were tested and the obtained EC 50 Between 0.01 and 200nM.

[0226] Test Example 2: Pharmacokinetic Analysis of Compounds in Rats Experimental Purpose: In this study, SD male rats were selected as the test compounds. The LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of rats at different time points after intravenous or oral administration of the test compounds to evaluate the pharmacokinetic characteristics of the test drugs in rats.

[0227] Experimental materials: SD rats (male, Shanghai Medicilon Biopharmaceutical Co., Ltd.).

[0228] Experimental Procedure: Test compound solutions or suspensions were injected into rats via the tail vein (without fasting) or administered orally (without fasting). Blood was collected by jugular venipuncture at 0 h (before dosing) and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous administration. Blood was placed in a sodium heparinized tube and placed on ice. Plasma was separated by centrifugation within 1 h (6800 g, 6 min, 2-8°C). For oral administration by gavage, blood was collected by jugular venipuncture at 0 h (before dosing) and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. Blood was placed in a sodium heparinized tube and placed on ice. Plasma was separated by centrifugation within 1 h (6800 g, 6 min, 2-8°C). Plasma samples were stored at -80°C until analysis. Plasma drug concentrations were determined using LC / MS / MS. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0 using plasma drug concentration data at different time points. These parameters, including AUC0-t, AUC0-∞, MRT0-∞, Cmax, Tmax, and T1 / 2, along with their means and standard deviations, were provided.

[0229] Experimental results: The test results are shown in Table 3:

[0230] Table 3: Pharmacokinetic parameters of the compounds of the present invention in rats

[0231] It can be seen that the compound of the present invention has better exposure (AUC) and bioavailability (F%).

[0232] Test Example 3: Acute food intake suppression experiment in humanized GLP-1R mice

[0233] Experimental purpose: To evaluate the effect of a single oral administration of the compound of the present invention on the food intake inhibition of GLP-1R humanized mice.

[0234] Experimental materials: hGLP-1R mice (male, Shanghai WuXi AppTec New Drug Development Co., Ltd.).

[0235] Experimental Procedure: Male hGLP-1R mice weighing approximately 30 g were acclimated to a diet for 4 days. Each mouse was housed individually in a cage, provided with toys, and labeled with a cage tag. Lights were on for 12 hours per day (7:00 AM, 7:00 PM). During the experiment, the mice were weighed daily, and the remaining and added food amounts were recorded. The mice were then divided into groups based on their weight and food intake on the final day, with five mice per group.

[0236] Mice were fasted overnight, provided only with normal drinking water, and the amount of food added was measured. The compound was administered at a concentration of 2 mg / mL in a volume of 5 μL / g, via gavage based on mouse body weight, and the time of administration was recorded. The amount of food remaining was measured at 2, 4, 6, 8, 10, and 24 hours after administration. The amount of food remaining at each time point was subtracted from the amount of food added to calculate the mouse's food intake. The appetite suppressant effect of the compound after administration was evaluated by comparing the food intake of mice in different groups.

[0237] Experimental results: In the acute food intake suppression experiment, a single oral administration of 10 mg / kg of the compound of the present invention can significantly suppress the food intake of mice.

[0238] Test Example 4: GLP-1R humanized mouse intraperitoneal glucose tolerance test (IPGTT) experiment

[0239] Experimental purpose: To evaluate the effect of a single oral administration of the compound of the present invention on the blood glucose level in GLP-1R humanized mice.

[0240] Experimental materials: hGLP-1R mice (male, Shanghai WuXi AppTec New Drug Development Co., Ltd.).

[0241] Experimental Procedure: Male hGLP-1R mice weighing approximately 30 g were acclimated to a feeding regimen for 4 days. Each cage was individually housed, provided with toys, and labeled with cage tags. Lights were on for 12 hours per day (7:00 AM, 7:00 PM). During the experiment, the mice were weighed daily and the remaining food intake and food additions were recorded. The mice were then divided into groups of 5 mice based on their body weight and food intake on the final day. Following the acute food suppression experiment, hGLP-1R mice were given a 6-day recovery period before undergoing the IPGTT.

[0242] Mice were fasted overnight and only provided with normal drinking water. 30 minutes before the start of the glucose tolerance test, the drug was administered at a concentration of 0.2 mg / mL and a dosing volume of 5 μL / g. The mice were weighed and gavage was performed based on their body weight, and the dosing time was recorded. 40% glucose injection was given to the mice intraperitoneally, and the dosing time was 0 minutes. Blood glucose levels and test times were measured by tail tip blood sampling before and 15 minutes, 30 minutes, 60 minutes, and 120 minutes after dosing. The glucose clearance ability of mice after glucose ingestion, i.e., glucose tolerance test, was evaluated by comparing the blood glucose levels of mice at different time points and the area under the blood glucose curve (AUC).

[0243] Experimental results: In the IPGTT experiment, a single oral administration of 1 mg / kg of the compound of the present invention can significantly increase the blood sugar lowering rate of mice.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, in: Ring A is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heterocyclyl and 5-6 membered heterocyclyl or 5-6 membered heteroaryl and C 5-6 Cycloalkyl; Ring B is selected from a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; Ring C is selected from C 6-10 aryl; Ring D is selected from C 6-10 Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5- to 6-membered heterocyclic aryl, 5- to 6-membered heteroaryl aryl, or 5- to 6-membered heteroaryl 5- to 6-membered heteroaryl; M is R 6 and R 7 are independently hydrogen, halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted by one or more R 6-1 Replacement; or R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 6-1 Substitution; said R 6-1 Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; is heteroaryl, wherein T and U are each independently N or C; R 1 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 5-6 membered heteroaryl, -OR or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1 Replacement; R 1-1 Each independently selected from hydroxy, halogen, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl or C 6-10 Aryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 5-6 membered heteroaryl and C 6-10 Aryl, optionally substituted with one or more R 1-1 replace; R 2 Selected from hydrogen, oxo, thio, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy; Each R 4 Each independently selected from hydrogen, halogen, amino, hydroxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1- 6-halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; Each R 5 Each independently selected from hydrogen, hydroxy, amino, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1- 6-haloalkoxy, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 、C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or 5-6 membered heteroaryl, the amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted by one or more R 5-1 Replacement; R 5-1 and R 5-2 Each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; R 8 Selected from hydrogen, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; x and y are each independently selected from 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The ring A is selected from 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5 membered heteroaryl and 5-6 membered heterocyclic group, 5 membered heteroaryl and C 5-6 Cycloalkyl or 5-membered heterocyclic group or 5-6-membered heterocyclic group; Preferably, ring A is selected from 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heterocyclyl, 5-membered heteroaryl and cyclohexyl, 5-membered heterocyclyl and 6-membered heterocyclyl or 5-membered heteroaryl and 6-membered heterocyclyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that The ring B is selected from a 5-membered heterocyclic group or a 5-membered heteroaryl group; preferably, the ring B is selected from Alternatively, the ring C is selected from phenyl or benzo 5-6 membered heterocyclic group; preferably phenyl or Alternatively, the ring C is selected from a 5-6 membered heteroaryl or a 5-6 membered heterocyclic group; preferably a pyridyl, pyridonyl, oxazolyl or pyrazolyl group; Alternatively, the ring D is selected from phenyl, pyridyl, benzopyrazolyl, benzimidazolyl or pyridoimidazolyl; preferably, the ring D is selected from phenyl, Alternatively, the ring D is selected from 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that The ring A is selected from wherein M1, M2, M3 and M4 are each independently selected from C, N, O, S or Se, represents a single bond or a double bond; preferably, ring A is selected from 5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is represented by formula (II-1), formula (II-2), formula (II-3) or formula (II-4): Where: R 9 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that: The ring D is selected from phenyl, pyridyl, 7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: The R 1 is selected from 4-membered heterocyclic group, 5-6-membered heterocyclic group or 5-6-membered heteroaryl, wherein the 4-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-membered heteroaryl are optionally substituted by one or more R 1-1 Substituted; preferably, the R 1 Selected from Oxetanyl, oxazolyl, pyridinyl, pyrazolyl or cyclohexyl, Oxetanyl, oxazolyl, pyridinyl, pyrazolyl and cyclohexyl, optionally further substituted by one or more R 1-1 Substitution; said R 1-1 Each independently selected from halogen, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3- 4-membered cycloalkyl or 3-4-membered heterocyclic group; preferably, the R 1-1 Each independently selected from halogen, amino, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl; Alternatively, the R 2 Selected from hydrogen, oxo, thio, hydroxy, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 preferably said R 2 is selected from oxo or thio; Alternatively, the R 3 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 Preferably, the R 3 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl or difluoromethyl; Or, each R 4 Each independently selected from hydrogen, halogen, amino, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, each R 4 each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, oxirane, aziridine, cyclobutyl, oxetanyl or azetidinyl; Or, each R 5 Each independently selected from hydrogen, hydroxy, amino, cyano, halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1- 3 alkoxy, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Haloalkoxy, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 、C 3-4 Cycloalkyl, 3-4 membered heterocyclic group or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, optionally substituted by one or more R 5-1 Substituted; preferably, each R 5 Each independently selected from hydrogen, hydroxy, amino, fluorine, chlorine, bromine, methyl, ethyl, propyl, -CD3, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoroethyl, difluoromethyl, -P(=O)R 5-1 R 5-2 、-NHC(O)R 5-1 、-NHS(O)2R 5-1 , -NHCH3, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl; The R 5-1 and R 5-2 Each independently selected from halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 3-4 cycloalkyl, 3-4 membered heterocyclyl or 5-6 membered heteroaryl; preferably, R 5-1 and R 5-2 each independently selected from methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl; Or, R 8 Selected from hydrogen, oxo, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, R 8 is selected from hydrogen, oxo, fluorine, chlorine, bromine, iodine, cyano, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or 6 to 7, characterized in that: The M is R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with one or more R 6-1 substituted; preferably, R 6 and R 7 Together with the carbon atom to which they are attached, they form C 3-4 Cycloalkyl, the C 3-4 The cycloalkyl group is optionally substituted with one or more R 6-1 substituted; more preferably, R 6 and R 7 Together with the carbon atom to which they are attached, they form a cyclopropyl group, which is optionally substituted by one or more R 6-1 Substitution; said R 6-1 Each independently selected from halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, the R 6-1 Each is independently selected from methyl, hydroxymethyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, oxirane, aziridine, oxetanyl or azetidinyl.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 or 6 to 8, characterized in that: described for 10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the compounds shown in Table 1.

1.

11. A pharmaceutical composition comprising: (1) The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, in the preparation of a medicament, wherein the medicament is useful for preventing and / or treating a metabolic disease; preferably, the metabolic disease is diabetes.

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