A class of polycyclic compounds and their uses

Abstract

The present invention provides a class of compounds as shown in Formula (I), pharmaceutically acceptable stereoisomers, tautomers, or salts thereof. The compounds of the present invention are used as GLP-1R agonists, and the compounds and pharmaceutical compositions thereof may be used in the preparation of drugs to treat and / or prevent GLP-1R-mediated disorders. (I)

Description

A class of polycyclic compounds and uses thereof

[0001] This application requires the applicant to:

[0002] The priority benefit of the prior application, patent application number 202311782864.9, entitled “A class of polycyclic compounds and their uses,” filed with the State Intellectual Property Office of China on December 22, 2023;

[0003] The priority benefit of the prior application, patent application number 202410173188.3, ​​entitled “A class of polycyclic compounds and their uses,” filed with the State Intellectual Property Office of China on February 7, 2024;

[0004] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0005] The present application relates to the field of medical technology, and in particular, to a class of polycyclic compounds, pharmaceutical compositions containing the same, and uses thereof as GLP-1R agonists, wherein the polycyclic compounds can prevent and / or treat diseases, disorders, and conditions mediated by GLP-1R. Background Art

[0006] Overweight and obesity have become a global health concern, contributing significantly to several chronic diseases, including diabetes, cardiovascular disease, liver disease, and cancer. Approximately 50% of type 2 diabetes, 30% of ischemic cardiovascular and cerebrovascular diseases, and 10%-40% of cancers are attributable to obesity or overweight. China already leads the world in the number of overweight and obese people, creating a significant unmet clinical need for obesity treatment.

[0007] Diabetes mellitus is a common metabolic endocrine disease characterized by impaired glucose and fat metabolism and elevated plasma glucose levels. Type 2 diabetes is the most common, accounting for over 90% of all diabetic patients. The pathogenesis of type 2 diabetes remains unclear, but is currently believed to be related to unhealthy lifestyles, genetic factors, environmental factors, and the toxic effects of lipotoxicity and glucotoxicity on pancreatic beta cells. Furthermore, long-term poor blood sugar control in patients may lead to a variety of pathological changes, such as the following diabetic complications: vascular complications (macrovascular disease (atherosclerosis) and microvascular disease (retinopathy and neuritis, etc.)), renal complications (renal insufficiency and proteinuria), cardiac complications (myocarditis, heart failure), and urinary tract infections.

[0008] GLP-1 (glucagon-like peptide-1) is primarily synthesized and secreted by L cells located in the ileum and colon. Its receptor, GLP-1R (glucagon-like peptide-1 receptor), is primarily distributed in pancreatic β and α cells, the gastrointestinal tract, the central nervous system, and the cardiovascular system. The GLP-1R belongs to the glucagon receptor subfamily within the G protein-coupled receptor B cluster and is characterized by a seven-transmembrane core domain and a relatively large extracellular domain.

[0009] In the pancreas, GLP-1 induces glucose-dependent insulin secretion. It increases insulin secretion and reduces glucagon. In the central nervous system, GLP-1R stimulation has the effects of increasing satiety, reducing food intake, nausea, and promoting nerve cell survival. In other tissue systems, GLP-1R stimulation also has the effects of lowering blood pressure, improving microvascular function, reducing inflammation; reducing gastric emptying, lowering blood sugar, increasing insulin sensitivity, and reducing gluconeogenesis. Therefore, stimulating GLP-1R can have the effect of lowering blood sugar and / or reducing weight, thereby preventing and / or treating diabetes and / or obesity. Moreover, stimulating GLP-1R can have the effect of reducing weight through various biological mechanisms.

[0010] In addition, there is evidence that agonizing GLP-1R is also a promising strategy for preventing and / or treating Alzheimer's disease (AD), non-alcoholic fatty liver disease (NAFLD), etc.

[0011] Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by incurable cognitive impairment. The underlying mechanisms of AD development and progression remain incompletely elucidated. Recent experimental and clinical studies suggest that AD can be considered a metabolic disorder comparable to type 2 diabetes mellitus (T2DM), or in some cases, type 3 diabetes. Insulin resistance is also present in the brains of deceased AD patients, and insulin receptor expression decreases significantly with disease progression, suggesting that defects in insulin signaling are involved in the pathogenesis of AD. Furthermore, studies have shown that in AD, when glucose metabolism is impaired and mitochondrial function is impaired, the shuttling of lactate during glial glycolysis becomes increasingly important for neuronal survival, serving as an energy substitute. GLP-1 can partially restore astrocyte glycolytic function and increase lactate flux, which helps alleviate neuronal energy crisis. The neuroprotective mechanisms of GLP-1 are closely related to its promotion of aerobic glycolysis, alleviation of oxidative phosphorylation activation, and activation of the PI3K / Akt pathway. Therefore, GLP-1 agonists are promising strategies for the prevention and treatment of AD.

[0012] Nonalcoholic fatty liver disease (NAFL) is divided into two main categories: nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH). With an oversupply of metabolic substrates, excess fat accumulates in hepatocytes, accompanied by the gradual production of potentially toxic lipid species and a progressive increase in de novo lipogenesis (DNL) in NAFLD. Characterized by cellular damage and inflammatory cell infiltration, NASH is considered a more aggressive form of NAFLD, potentially progressing to cirrhosis and hepatocellular carcinoma, with limited treatment options. Obesity and type 2 diabetes are two major risk factors for NASH, and individuals with a history of NASH are significantly more likely to develop liver and cardiovascular disease. Furthermore, insulin resistance in the liver and adipose tissue is considered a key driver of morbidity and mortality in NASH. GLP-1 analogs can improve glycemic control, reduce weight, and activate liver enzymes in patients with T2DM. Several studies have shown that liraglutide, acting directly on human hepatocytes in vitro, reduces steatosis by reducing DNL levels and increasing fatty acid oxidation. Notably, most patients experience improvement in steatosis and hepatocyte swelling after liraglutide treatment. Exciting experimental evidence is available in patients with NASH that suggests liraglutide has the potential to reduce lipotoxicity by improving insulin sensitivity in adipose tissue. Only a small percentage of NASH patients experience progression after liraglutide treatment. Semaglutide, a similar drug to liraglutide, has also been reported to reduce levels of alanine aminotransferase and inflammatory markers, with significant reductions in inflammatory biomarkers following treatment. Given the lack of hepatic GLP-1R expression, the potential mechanism of action of GLP-1R agonists in NASH may involve indirect benefits on body weight and reductions in metabolic dysfunction, lipotoxic effects, and inflammation. Summary of the Invention

[0013] In a first aspect, the present invention provides a compound represented by formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, which has the following structure:

[0014] in,

[0015] Ring A is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0016] Ring B is selected from 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0017] Ring C is selected from 9-membered bicyclic heteroaryl;

[0018] Ring D is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0019] Ring E is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0020] R a Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR a1 、-S(O)R a1 、-SO2(R a1 ),-C(O)R a1 、-C(O)OR a1 、-OC(O)R a1 、-N(R a1 )(R a2 )、-C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)R a2 、-S(O)N(R a1 )(R a2 )、-SO2N(R a1 )(R a2 )、-N(R a1 )S(O)R a2 、-N(R a1 )S(O)2R a2 , and optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0021] or two R a Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups;

[0022] R a1 、R a2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0023] R a3 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R a4 、-OR a4 、-SR a4 、-S(O)R a4 、-S(O)2R a4 、-C(O)R a4 、-C(O)OR a4 、-OC(O)R a4 、-N(R a4 )(R a5 )、-C(O)N(R a4 )(R a5 )、-N(R a4 )C(O)R a5 、-S(O)N(R a4 )(R a5 )、-S(O)2N(R a4 )(R a5 )、-N(R a4 )S(O)R a5 、-N(R a4 )S(O)2R a5 ;

[0024] R a4 、R a5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl group, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0025] R b Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R b1 replaced by;

[0026] or two R b Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups;

[0027] R b1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R b2 、-OR b2 、-SR b2 、-S(O)R b2 、-S(O)2R b2、-C(O)R b2 、-C(O)OR b2 、-OC(O)R b2 、-N(R b2 )(R b3 )、-C(O)N(R b2 )(R b3 )、-N(R b2 )C(O)R b3 、-S(O)N(R b2 )(R b3 )、-S(O)2N(R b2 )(R b3 )、-N(R b2 )S(O)R b3 、-N(R b2 )S(O)2R b3 ;

[0028] R b2 、R b3 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted by aryl or 5-12 membered heteroaryl groups;

[0029] R c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14Aryl, 5-12 membered heteroaryl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R c1 replaced by;

[0030] or two R c Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups;

[0031] R c1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R c2 、-OR c2 、-SR c2 、-S(O)R c2 、-S(O)2R c2 、-C(O)R c2 、-C(O)OR c2 、-OC(O)R c2 、-N(R c2 )(R c3 )、-C(O)N(R c2 )(R c3 )、-N(R c2 )C(O)R c3 、-S(O)N(R c2 )(R c3 )、-S(O)2N(R c2 )(R c3 )、-N(R c2 )S(O)R c3 、-N(R c2 )S(O)2R c3 ;

[0032] R c2 、R c3 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted by aryl or 5-12 membered heteroaryl groups;

[0033] R d Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR d1 、-S(O)R d1 、-S(O)2R d1 、-C(O)R d1 、-C(O)OR d1 、-OC(O)R d1 、-N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)R d2 、-S(O)N(R d1 )(R d2 )、-S(O)2N(R d1 )(R d2 )、-N(R d1 )S(O)R d2 、-N(R d1 )S(O)2R d2 , and optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0034] or two R dTogether with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 3-7 membered cycloalkyl, or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted alkyl group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted with aryl and 5-12 membered heteroaryl groups;

[0035] R d1 、R d2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0036] R d3 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R d4 、-OR d4 、-SR d4 、-S(O)R d4 、-S(O)2R d4 、-C(O)R d4 、-C(O)OR d4 、-OC(O)R d4 、-N(R d4 )(R d5 )、-C(O)N(R d4 )(R d5 )、-N(R d4 )C(O)R d5 、-S(O)N(R d4 )(R d5 )、-S(O)2N(R d4)(R d5 )、-N(R d4 )S(O)R d5 、-N(R d4 )S(O)2R d5 ;

[0037] R d4 、R d5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl group, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0038] R e Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR e1 、-SR e1 、-S(O)R e1 、-S(O)2R e1 、-C(O)R e1 、-C(O)OR e1 、-OC(O)R e1 、-N(R e1 )(R e2 )、-C(O)N(R e1 )(R e2 )、-N(R e1 )C(O)R e2 、-S(O)N(R e1 )(R e2 )、-S(O)2N(R e1 )(R e2 )、-N(R e1 )S(O)R e2 、-N(R e1 )S(O)2R e2 、-C(O)N(R e1 )S(O)2N(R e1 )(Re2 )、-C(O)N(R e1 )S(O)2R e2 、-P(O)(R e1 )R e2 , and optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R e3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0039] or two R e Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups;

[0040] R e1 、R e2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from hydrogen, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0041] R e3Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R e4 、-OR e4 、-SR e4 、-S(O)R e4 、-S(O)2R e4 、-C(O)R e4 、-C(O)OR e4 、-OC(O)R e4 、-N(R e4 )(R e5 )、-C(O)N(R e4 )(R e5 )、-N(R e4 )C(O)R e5 、-S(O)N(R e4 )(R e5 )、-S(O)2N(R e4 )(R e5 )、-N(R e4 )S(O)R e5 、-N(R e4 )S(O)2R e5 、-C(O)N(R e4 )S(O)2N(R e4 )(R e5 )、-C(O)N(R e4 )S(O)2R e5 、-P(O)(R e4 )R e5 ;

[0042] R e4 、R e5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl group, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0043] R f Selected from -C(O)OR f1 、-C(O)N(R f1 )(R f2 ),

[0044] R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0045] R 1 and R 2 Together with the atoms to which they are attached, they form C 3-15 Carbocyclic group; the C 3-15 The carbocyclyl group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R 3 Replaced by; R 3 are independently selected from hydrogen, deuterium, halogen, hydroxyl or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0046] L1 is selected from a bond, -C(R L1 )2-、-O-、-C(R L1)2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L1 )C(O)-、-C(O)N(R L1 )-or-N(R L1 )-;R L1 are independently selected from hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0047] L2 is independently selected from a bond, -C(R L2 )2-、-O-、-C(R L2 )2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )C(O)-、-C(O)N(R L2 )-or-N(R L2 )-;R L2 are independently selected from hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0048] L3 is independently selected from a bond, -C(R L3 )2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(RL3 )C(O)-、-C(O)N(R L3 )-or-N(R L3 )-;R L3 are independently selected from hydrogen, deuterium, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0049] L4 is independently selected from a bond, -L 4x -C(R L4a )(R L4b )-L 4y -、-L 4x -OL 4y -、-L 4x -SL 4y -、-L 4x -C(O)-L 4y -、-L 4x -C(O)OL 4y -、-L 4x -OC(O)-L 4y -、-L 4x -N(R L4a )C(O)-L 4y -、-L 4x -C(O)N(R L4a )-L 4y -、-L 4x -N(R L4a )-L 4y -、-L 4x -N(R L4a )C(O)N(R L4b )-L 4y -、-L 4x -N(R L4a )C(S)N(R L4b )-L 4y -or

[0050] L4x , L 4y are independently selected from a bond, or an optionally substituted C 1-10 Alkylene; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0051] R L4a 、R L4b are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0052] Ring L 4Z Selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0053] R L4z are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; the optional substitution means that one or more substitutable sites of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0054] L 5x , L 5y are independently selected from a bond, or an optionally substituted C 1-10 Alkylene; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group;

[0055] m, n, o, p, q, and r are each independently 0, 1, 2, or 3;

[0056] Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0057] The prerequisite is that the definitions of the above variables are combined to form a stable chemical structure.

[0058] In some embodiments, R d Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR d1 、-S(O)R d1 、-S(O)2R d1 、-C(O)R d1 、-C(O)OR d1 、-OC(O)R d1 、-N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)R d2 、-S(O)N(R d1 )(R d2 )、-S(O)2N(R d1 )(R d2 )、-N(R d1 )S(O)Rd2 、-N(R d1 )S(O)2R d2 , and optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl;

[0059] or two R d Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl and 5-12 membered heteroaryl groups.

[0060] In some embodiments, wherein Ring A is selected from C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0061] Alternatively, Ring A is selected from C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl;

[0062] Alternatively, Ring A is selected from C 3-6 Carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl;

[0063] The heteroatoms in the heterocyclic group and heteroaryl group are selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0064] In some embodiments, wherein Ring A is C 3-10 Carbocyclic group; or, Ring A is C 3-6 Carbocyclic group;

[0065] Alternatively, ring A is C 3-6 Carbocyclic, provided that Ring A is not or cyclohexyl.

[0066] In some embodiments, ring A is a 3-10 membered heterocyclic group; or, ring A is a 3-6 membered heterocyclic group; preferably, the heteroatom in the heterocyclic group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0067] In some embodiments, ring A is a 5-10 membered heteroaryl group; or, ring A is a 5-8 membered heteroaryl group, the heteroatom in the heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3; or, ring A is selected from a 5-membered heteroaryl group, a 6-membered heteroaryl group, the heteroatom in the heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2; or, ring A is selected from pyridyl, pyrrolyl, furanyl, thienyl; or, ring A is pyrrolyl, furanyl, thienyl.

[0068] In some embodiments, Ring A is pyridinyl.

[0069] In some embodiments, wherein Ring A is selected from C 6-10 Aryl; or, Ring A is selected from C 6-8 aryl; or, ring A is selected from phenyl.

[0070] In some embodiments, wherein R a independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)R a1 、-C(O)OR a1 、-OC(O)R a1 、-N(R a1 )(R a2 )、-C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), and optionally one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2- 4-alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; or, R a independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), and optionally one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) Ra3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2;

[0071] Or, R a independently selected from halogen, hydroxy, amino, cyano, and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclic group; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2;

[0072] Or, R a independently selected from halogen, hydroxy, amino, cyano, and optionally substituted with one or more (eg, 2, 3) substituents: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclic group; the substituent is selected from halogen, hydroxyl and amino; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0073] In some embodiments, wherein R a independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more R a3 replaced by;

[0074] Or, R a Independently selected from halogen, hydroxy, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy; the C 1-4 Alkyl, C 1-4 The alkoxy group is optionally substituted with one or more R a3 replaced.

[0075] In some embodiments, wherein R aIndependently selected from halogen, hydroxy, amino, cyano, optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy or ethoxy; the optionally substituted group means unsubstituted or substituted with one or more (e.g., 2, 3, 4) substituents selected from deuterium, halogen, hydroxy, amino.

[0076] In some embodiments, wherein R a are independently selected from halogen, methyl, cyclopropyl; or, R a Independently selected from fluoro, methyl, cyclopropyl.

[0077] In some embodiments, wherein R a Independently selected from fluorine, methyl, deuterated methyl (-CD3), -CF3, methoxy, cyclopropyl, -OCF3.

[0078] In some embodiments, wherein two R a Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 substituted by an aryl or 5-6 membered heteroaryl group;

[0079] Or, two R a Together with the atoms to which they are attached, they form an optionally substituted 3-6 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, and ethoxy.

[0080] In some embodiments, wherein R a1 、R a2 are independently selected from hydrogen, deuterium, and optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1- 6 alkyl, C 1-6 Alkoxy, C 3-6substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0081] Or, R a1 、R a2 are independently selected from hydrogen, C 1-6 Alkyl (e.g., C 1-3 Alkyl; preferably methyl or ethyl); the C 1-6 The alkyl group is optionally substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, and amino; or, R a1 、R a2 are each independently selected from hydrogen.

[0082] In some embodiments, wherein R a3 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R a4 、-OR a4 、-C(O)R a4 、-C(O)OR a4 、-OC(O)R a4 、-N(R a4 )(R a5 )、-C(O)N(R a4 )(R a5 )、-N(R a4 )C(O)R a5 .

[0083] In some embodiments, wherein R a3 are independently selected from hydrogen, halogen, hydroxy, amino, -R a4 ; Among them, R a4 Independently selected from C 1-6 Alkyl (e.g., C 1-3 Alkyl; preferably methyl or ethyl), C 1-6 Alkoxy (e.g., C 1-3 Alkoxy; preferably methoxy or ethoxy); the C 1-6 The alkyl group is optionally substituted with one or more substituents selected from hydrogen and halogen.

[0084] In some embodiments, wherein R a3 are independently selected from hydrogen, halogen; or, R a3 Independently selected from hydrogen, fluorine, and chlorine.

[0085] In some embodiments, wherein R a4 、R a5 are independently selected from hydrogen, optionally substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy;

[0086] Or, R a4 、R a5 are independently selected from hydrogen, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more (eg, 2, 3, 4) substituents selected from hydrogen and halogen.

[0087] In some embodiments, wherein R a4 、R a5 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

[0088] In some embodiments, m is selected from 0, 1, 2, and 3; or, m is selected from 2 and 3.

[0089] In some embodiments, wherein L1 is selected from a bond, -C(R L1 )2-、-C(R L1 )2O-、-O-、-C(O)-、-N(R L1 )C(O)-、-C(O)N(R L1 )-;R L1 is selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0090] Alternatively, L1 is selected from a bond, -C(R L1 )2-、-C(R L1 )2O-;R L1 is selected from hydrogen, or optionally substituted C 1-4 Alkyl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3) groups selected from halogen, hydroxy, amino, and cyano;

[0091] Alternatively, L1 is selected from a bond, -C(R L1 )2-、-C(RL1 )2O-;R L1 is selected from hydrogen, optionally substituted methyl or optionally substituted ethyl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3) groups selected from fluorine, chlorine, bromine, hydroxyl, amino, and cyano;

[0092] Alternatively, L1 is selected from a bond, -CH(CH3)-, -CH2-, -CH2O-; alternatively, L1 is selected from a bond, -CH2-; alternatively, L1 is selected from a bond.

[0093] In some embodiments, L1 is not -CH(CH3)-.

[0094] In some embodiments, wherein Ring B is selected from 3-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl;

[0095] Alternatively, Ring B is selected from 4-6 membered monocyclic heterocyclyl, 8-10 membered bicyclic heterocyclyl, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, 8-10 membered bicyclic heteroaryl;

[0096] Alternatively, Ring B is selected from 8-10 membered bicyclic heterocyclyl, 8-10 membered bicyclic heteroaryl;

[0097] Alternatively, Ring B is selected from an 8-9 membered bicyclic heterocyclic group or an 8-9 membered bicyclic heteroaryl group; the heteroatoms in the 8-9 membered bicyclic heterocyclic group or the 8-9 membered bicyclic heteroaryl group are selected from N or S, and the number of heteroatoms is 1, 2 or 3;

[0098] In some embodiments, ring B is selected from a 9-membered cyclic heterocyclyl and a 9-membered bicyclic heteroaryl; wherein the cyclic heterocyclyl is a heterocyclyl-cyclic heteroaryl, and the bicyclic heteroaryl is a heteroaryl-fused heteroaryl or a heteroaryl-fused aryl; the heteroatom in the 9-membered cyclic heterocyclyl is N, and the number of heteroatoms is 3; the heteroatom in the 9-membered bicyclic heteroaryl is N, and the number of heteroatoms is 1 or 2.

[0099] In some embodiments, wherein Ring B is selected from 4-6 membered heterocyclyl, 4-6 membered monocyclic heterocycloalkenyl, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, 3-membered / 5-membered heterocyclyl, 5-membered / 3-membered heterocyclyl, 4-membered / 4-membered heterocyclyl, 4-membered / 5-membered heterocyclyl, 5-membered / 4-membered heterocyclyl, 5-membered / 5-membered heterocyclyl, 4-membered / 6-membered heterocyclyl, 6-membered / 4-membered heterocyclyl, 5-membered / 6-membered heterocyclyl, 6-membered / 5-membered heterocyclyl, 6-membered / 6-membered heterocyclyl, 6-membered / 7-membered heterocyclyl, 7-membered / 6-membered heterocyclyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl;

[0100] Alternatively, Ring B is selected from 5-membered / 5-membered fused heterocyclyl, 5-membered / 6-membered fused heterocyclyl, 6-membered / 5-membered fused heterocyclyl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, and 6-membered / 5-membered fused heteroaryl;

[0101] Alternatively, Ring B is selected from a 5-membered / 5-membered heterocyclyl, a 5-membered / 6-membered heterocyclyl, or a 6-membered / 5-membered heterocyclyl, wherein the heteroatoms in the 5-membered / 5-membered heterocyclyl, the 5-membered / 6-membered heterocyclyl, or the 6-membered / 5-membered heterocyclyl are selected from N, and the number of heteroatoms is 1, 2, or 3;

[0102] Alternatively, Ring B is selected from a 5-membered / 6-membered heterocyclic group and a 6-membered / 5-membered heterocyclic group, and the heteroatoms in the 5-membered / 6-membered heterocyclic group and the 6-membered / 5-membered heterocyclic group are selected from N, and the number of heteroatoms is 3.

[0103] In some embodiments, wherein Ring B is selected from the following groups:

[0104] In some embodiments, wherein Ring B is selected from the following groups:

[0105] The "*" end is connected to L1, the "**" end is connected to L2, and the "***" end is connected to L4;

[0106] Alternatively, Ring B is selected from the following groups: The "*" end is connected to L1, the "**" end is connected to L2, and the "***" end is connected to L4;

[0107] Alternatively, Ring B is selected from The “*” end is connected to L1, the “**” end is connected to L2, and the “***” end is connected to L4.

[0108] In some embodiments, wherein R b are independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently replaced by R b1 replaced by;

[0109] Or, Rb are independently selected from halogen, hydroxy, amino, mercapto, cyano, oxo, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently replaced by R b1 replaced by;

[0110] Or, R b are independently selected from halogen, hydroxy, amino, cyano, or optionally substituted groups: C 1-4 Alkyl, C 1-4 Alkoxy; the optional substitution refers to being unsubstituted or one or more (eg, 2, 3, 4 or 5) substitutable positions of the substituted group are independently replaced by R b1 replaced by;

[0111] Or, R b Independently selected from C 1-4 Alkyl (preferably C 1-3 alkyl);

[0112] Or, R b are independently selected from methyl.

[0113] In some embodiments, wherein two R b Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 substituted by an aryl or 5-6 membered heteroaryl group;

[0114] Or, two R b Together with the atoms to which they are attached, they form an optionally substituted 3-7 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, methoxy, and ethoxy.

[0115] In some embodiments, wherein R b1 are independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R b2 、-OR b2、-C(O)R b2 、-C(O)OR b2 、-OC(O)R b2 、-N(R b2 )(R b3 )、-C(O)N(R b2 )(R b3 )、-N(R b2 )C(O)(R b3 );

[0116] Or, R b1 are independently selected from halogen, hydroxy, amino, -R b2 ;

[0117] Or, R b1 are independently selected from halogen (eg, fluorine, chlorine, bromine).

[0118] In some embodiments, wherein R b2 、R b3 are independently selected from hydrogen, optionally substituted by: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy;

[0119] Or, R b2 、R b3 are independently selected from hydrogen, optionally substituted by: C 1-4 Alkyl, C 1-4 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) selected from halogen, hydroxy, amino, cyano;

[0120] Or, R b2 、R b3 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

[0121] In some embodiments, n is independently selected from 0, 1, and 2; preferably, n is independently selected from 0 and 1; further preferably, n is 1.

[0122] In some embodiments, wherein L2 is independently selected from a bond, -C(R L2 )2-、-O-、-C(RL2 )2O-、-C(O)-、-N(R L2 )C(O)-、-C(O)N(R L2 )-;R L2 is selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution refers to optionally substituted means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0123] Alternatively, L2 is independently selected from a bond, -C(R L2 )2-、-C(R L2 )2O-、-C(O)-;R L2 is selected from hydrogen, or C optionally substituted by one or more (e.g., 2, 3, 4) of halogen, hydroxy, amino, and cyano 1-4 alkyl;

[0124] Alternatively, L2 is independently selected from a bond, -C(R L2 )2-、-C(O)-;R L2 Selected from hydrogen, or methyl or ethyl optionally substituted by one or more (e.g., 2 or 3) of fluorine, chlorine, bromine, hydroxyl, amino, and cyano.

[0125] In some embodiments, wherein L2 is independently selected from a bond, -CH2-, -CH2O-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-;

[0126] Alternatively, L2 is independently selected from a bond, -CH2-, -C(O)-;

[0127] Alternatively, L2 is -C(O)-.

[0128] In some embodiments, wherein ring C is independently selected from a 9-membered bicyclic heteroaryl group (e.g., a bicyclic ring composed of a heteroaryl group and a heteroaryl group, or a bicyclic ring composed of an aryl group and a heteroaryl group); the heteroatom in the 9-membered bicyclic heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3;

[0129] Alternatively, Ring C is independently selected from a 5-membered / 6-membered fused heteroaryl group (e.g., a bicyclic ring formed by condensing a heteroaryl group and a heteroaryl group, or a bicyclic ring formed by condensing an aryl group and a heteroaryl group), wherein the heteroatom in the 5-membered / 6-membered fused heteroaryl group is selected from N, and the number of heteroatoms is 1 or 2;

[0130] Alternatively, Ring C is independently selected from the following groups:

[0131] Alternatively, ring C is selected from the following groups:

[0132] The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end;

[0133] Alternatively, Ring C is independently selected from the following groups: The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end.

[0134] Alternatively, ring C is selected from the following groups:

[0135] The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end;

[0136] In some embodiments, Ring C is independently selected from The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end.

[0137] In some embodiments, Ring C is The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end.

[0138] In some embodiments, wherein R c are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means that one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R c1 replaced by;

[0139] Or, R care independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, or optionally substituted groups: C 1-6 Alkyl, C 1- 6 alkoxy (preferably C 1-3 Alkoxy, such as methoxy, ethoxy); the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6) substitutable positions of the unsubstituted or substituted group are independently replaced by R c1 replaced by;

[0140] Or, R c are independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, or optionally substituted C 1-4 Alkyl; the optional substitution refers to unsubstituted or one or more (eg, 2, 3) substitutable sites of the substituted group are independently replaced by R c1 replaced by;

[0141] Or, R c independently selected from hydrogen, halogen, hydroxy, amino, cyano, oxo, C 1-4 Alkyl (preferably C 1-3 alkyl);

[0142] Or, R c independently selected from hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0143] Or, R c independently selected from hydrogen, fluorine, and chlorine;

[0144] Or, R c are independently selected from hydrogen.

[0145] In some embodiments, wherein two R c Together with the atoms to which they are attached, they form an optionally substituted 3-6 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0146] Or, two R cTogether with the atoms to which they are attached, they form an optionally substituted 3-6 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, cyano, oxo, methyl, ethyl, methoxy, and ethoxy.

[0147] In some embodiments, wherein R c1 are independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R c2 、-OR c2 、-C(O)R c2 、-C(O)OR c2 、-OC(O)R c2 、-N(R c2 )(R c3 )、-C(O)N(R c2 )(R c3 )、-N(R c2 )C(O)R c3 ;

[0148] Or, R c1 are independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R c2 、-OR c2 ;

[0149] Or, R c1 are independently selected from halogen (eg, fluorine, chlorine, bromine).

[0150] In some embodiments, wherein R c2 、R c3 are independently selected from hydrogen, optionally substituted by: C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 substituted with an alkoxy group;

[0151] Or, R c2 、R c3 are independently selected from hydrogen, optionally substituted by: C 1-4 Alkyl (preferably C 1-3 Alkyl), C1-4 Alkoxy (preferably C 1-3 Alkoxy); the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from halogen, hydroxy, amino, cyano;

[0152] Or, R c2 、R c3 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

[0153] In some embodiments, o is independently selected from 0, 1, and 2; preferably, o is independently selected from 0 and 1; preferably, o is 0.

[0154] In some embodiments, wherein L3 is independently selected from a bond, -C(R L3 )2-、-O-、-C(O)-、-N(R L3 )C(O)-、-C(O)N(R L3 )-;R L3 is selected from hydrogen, or an optionally substituted group: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0155] Alternatively, L3 is independently selected from a bond, -C(R L3 )2-、-C(O)-;R L3 is selected from hydrogen, or optionally substituted C 1-4 The alkyl group, wherein the optional substitution is unsubstituted or substituted by one or more (eg, 2, 3, 4) groups selected from halogen, hydroxy, amino, and cyano.

[0156] Alternatively, L3 is independently selected from a bond, -C(R L3 )2-、-C(O)-;R L3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0157] In some embodiments, wherein L3 is independently selected from a bond, -CH2-, -CH(CH3)-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-;

[0158] Alternatively, L3 is independently selected from a bond, -CH2-, -C(O)-;

[0159] Alternatively, L3 is independently selected from a bond.

[0160] In some embodiments, wherein ring D is selected from C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0161] Alternatively, ring D is selected from C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, C 6-8 Aryl, 5-8 membered heteroaryl;

[0162] Alternatively, ring D is selected from C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group; the heteroatom in the heterocyclic group and heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0163] In some embodiments, wherein Ring D is independently selected from C 3-10 Carbocyclic group;

[0164] Alternatively, ring D is independently selected from C 3-6 Carbocyclic group.

[0165] In some embodiments, wherein ring D is independently selected from 3-10 membered heterocyclyl;

[0166] Alternatively, ring D is independently selected from a 3-6 membered heterocyclyl.

[0167] In some embodiments, wherein ring D is independently selected from a 4-6 membered heterocyclic group; the heteroatom in the heterocyclic group is selected from N or O, and the number of heteroatoms is 1 or 2.

[0168] In some embodiments, wherein ring D is selected from tetrahydropyranyl, morpholinyl, piperidinyl, pyrazinyl, tetrahydrofuranyl;

[0169] Alternatively, ring D is selected from tetrahydropyranyl.

[0170] In some embodiments, wherein Ring D is independently selected from

[0171] Alternatively, ring D is independently selected from

[0172] In some embodiments, wherein Ring D is independently selected from

[0173] Alternatively, ring D is independently selected from

[0174] In some embodiments, wherein Ring D is independently selected from C 6-10Aryl, 5-10 membered heteroaryl;

[0175] Alternatively, ring D is independently selected from C 6-8 Aryl, 5-8 membered heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, O or S, and the number of heteroatoms is 1 or 2;

[0176] Alternatively, ring D is independently selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, the heteroatom in the heteroaryl is selected from N, O or S, and the number of heteroatoms is 1 or 2;

[0177] Alternatively, ring D is independently selected from phenyl, pyridyl, pyrrolyl, furyl, thienyl;

[0178] Alternatively, ring D is independently selected from pyridyl.

[0179] In some embodiments, wherein R d independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)R d1 、-C(O)OR d1 、-OC(O)R d1 、-N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)(R d2 ), optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl;

[0180] Or, R d are independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)(R d2 ), optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2;

[0181] Or, R d independently selected from halogen, hydroxy, amino, cyano, optionally substituted by one or more (e.g., 2, 3) R d3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclic group; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2;

[0182] Or, R d independently selected from halogen, hydroxy, amino, cyano, optionally substituted: C 1-4 Alkyl (preferably C 1-3 Alkyl), C 1-4 Alkoxy (preferably C 1-3 Alkoxy), C 3-4 Cycloalkyl, 4-5 membered heterocyclic group; the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3) substituents selected from halogen, hydroxyl, amino; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0183] In some embodiments, wherein R d are independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)(R d2 ), optionally replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 alkoxy;

[0184] Or, R d independently selected from halogen, hydroxy, amino, cyano, optionally substituted with one or more (e.g., 2, 3, 4) R d3 Substituted with the following groups: C 1-4 Alkyl, C 1-4 alkoxy;

[0185] Or, R d independently selected from halogen, hydroxy, amino, cyano, optionally substituted: C 1-4 Alkyl (preferably C1-3 Alkyl), C 1-4 Alkoxy (preferably C 1-3 alkoxy); the optional substitution means being unsubstituted or substituted by one or more (eg, 2, 3) substituents selected from halogen, hydroxyl, and amino.

[0186] In some embodiments, wherein R d Independently selected from halogen, hydroxy, amino, cyano, optionally substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy; the optionally substituted group means unsubstituted or substituted by one or more (e.g., 2, 3) substituents selected from halogen, hydroxy, amino;

[0187] Preferably, R d Independently selected from methyl, methoxy, ethoxy.

[0188] In some embodiments, wherein two R d Together with the atoms to which they are attached, they form an optionally substituted: 3-10 membered heterocyclyl, 3-7 membered cycloalkyl or 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-8 substituted by an aryl or 5-6 membered heteroaryl group;

[0189] Or, two R d Together with the atoms to which they are attached, they form an optionally substituted: 3-6 membered heterocyclyl (e.g., 3, 4, 5, 6 membered heterocyclyl), 3-6 membered cycloalkyl (e.g., 3, 4, 5, 6 membered cycloalkyl) or 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy.

[0190] In some embodiments, wherein R d1 、R d2 are independently selected from hydrogen, deuterium, and optionally substituted groups: C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy), C 3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0191] Or, R d1 、R d2 are independently selected from hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl); the C 1-6 Alkyl (preferably C 1-3 alkyl) is optionally substituted with one or more (e.g., 2, 3, 4) substituents selected from hydrogen, halogen, hydroxy, and amino;

[0192] Or, R d1 、R d2 are each independently selected from hydrogen.

[0193] In some embodiments, wherein R d3 are independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R d4 、-OR d4 、-C(O)R d4 、-C(O)OR d4 、-OC(O)R d4 、-N(R d4 )(R d5 )、-C(O)N(R d4 )(R d5 )、-N(R d4 )C(O)R d5 .

[0194] In some embodiments, wherein R d3 are independently selected from hydrogen, halogen, hydroxy, amino, -R d4 ; R d4 Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substituents selected from hydrogen, halogen;

[0195] Or, R d3 are independently selected from hydrogen, halogen, hydroxy, amino, -R d4 ; Rd4 Independently selected from C 1-4 Alkyl, C 1-4 Alkoxy; the C 1- 4 alkyl, C 1-4 The alkoxy group is optionally substituted with one or more (e.g., 2, 3, 4, or 5) substituents selected from hydrogen, halogen;

[0196] Or, R d3 are independently selected from hydrogen, halogen, hydroxy, amino, -R d4 ; R d4 Independently selected from C 1-3 Alkyl, C 1-3 Alkoxy; the C 1- 3 alkyl, C 1-3 The alkoxy group is optionally substituted with one or more (eg, 2 or 3) substituents selected from hydrogen, halogen, and atom.

[0197] In some embodiments, wherein R d3 independently selected from hydrogen, halogen;

[0198] Or, R d3 Independently selected from hydrogen, fluorine, and chlorine.

[0199] In some embodiments, wherein R d4 、R d5 are independently selected from hydrogen, optionally substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from halogen, hydroxy, amino, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy;

[0200] Or, R d4 、R d5 are independently selected from hydrogen, C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more (e.g., 2, 3, 4) substituents selected from hydrogen and halogen;

[0201] Preferably, R d4 、R d5 are independently selected from hydrogen, C 1-3 Alkyl; the C 1-3 The alkyl group is optionally substituted with one or more (eg, 2, 3) substituents selected from hydrogen and halogen.

[0202] In some embodiments, wherein Rd4 、R d5 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

[0203] In some embodiments, wherein p is independently selected from 0, 1, 2;

[0204] Alternatively, p is independently selected from 1, 2;

[0205] Alternatively, p is 2.

[0206] In some embodiments, wherein L4 is selected from a bond, -L 4x -OL 4y -、-L 4x -SL 4y -、-L 4x -C(O)-L 4y -、、-L 4x -N(R L4a )C(O)-L 4y -、-L 4x -C(O)N(R L4a )-L 4y -、-L 4x -N(R L4a )-L 4y -、-L 4x -N(R L4a )C(O)N(R L4b )-L 4y -、-L 4x -N(R L4a )C(S)N(R L4b )-L 4y -;L 4x , L 4y are independently selected from a bond, or an optionally substituted C 1-6 Alkylene (preferably C 1-3 Alkylene), wherein the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-16 Substituted by a cycloalkyl group or a 3-6 membered heterocyclic group; R L4a 、R L4b are independently selected from hydrogen or the following optionally substituted groups: C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy (preferably C1-3 Alkoxy), C 3-6 Cycloalkyl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The alkyl group is substituted by a cycloalkyl group or a 3- to 6-membered heterocyclic group.

[0207] In some embodiments, wherein L4 is selected from -L 4x -N(R L4a )-L 4y -、-L 4x -N(R L4a )C(O)N(R L4b )-L 4y -、-L 4x -N(R L4a )C(S)N(R L4b )-L 4y -;L 4x , L 4y R is independently selected from a bond, or an optionally substituted methylene or ethylene group, wherein the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently substituted by a substituent selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano or oxo; L4a 、R L4b Each of the following is independently selected from hydrogen, or optionally substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropane, cyclobutane, wherein the optional substitution means that the group is unsubstituted or one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substitutable sites of the substituted group are independently substituted by a substituent selected from fluorine, chlorine, bromine, hydroxyl, amino, and cyano.

[0208] In some embodiments, wherein L4 is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH-;

[0209] Alternatively, L4 is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-;

[0210] Alternatively, L4 is selected from -NHC(O)NH-.

[0211] In some embodiments, wherein L4 is selected from Ring L 4Z Independently selected from C 3-10 Carbocyclic group, 5-10 membered heterocyclic group, C 6-8 Aryl, 5-10 membered heteroaryl; L 4x , L 4y are independently selected from a bond, or an optionally substituted C 1-6 Alkylene (preferably C 1-3 Alkylene, more preferably C 1-2 alkylene); the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-4 Alkyl, C 1- 4 alkoxy, C 3-6 is substituted by a cycloalkyl group or a 3-6 membered heterocyclic group; R L4z are independently selected from hydrogen, halogen, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution refers to unsubstituted or substituted groups, one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions are independently selected from deuterium, halogen, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group; r is independently selected from 0, 1, or 2.

[0212] In some embodiments, wherein L4 is selected from Ring L 4Z is selected from 5-10 membered heterocyclic group, phenyl group, 6-8 membered monocyclic heteroaryl group, 8-10 membered bicyclic heteroaryl group; L 4x , L 4y are independently selected from a bond, or the following optionally substituted groups: methylene, ethylene, wherein the optional substitution means that one or more (e.g., 2, 3) substitutable sites of the unsubstituted or substituted group are independently substituted by a group selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, and oxo; R L4z are independently selected from hydrogen, halogen, oxo, or optionally substituted: C 1-4 Alkyl, C 1-4 Alkoxy, the optional substitution means unsubstituted or one or more (e.g., 2, 3) substitutable sites of the substituted group are independently substituted by a group selected from halogen, hydroxy, amino, and cyano; r is independently selected from 0 and 1.

[0213] In some embodiments, wherein L4 is selected from Ring L 4Z is selected from 5-10 membered heterocyclic group (preferably 5-6 membered heterocyclic group), phenyl group, 6-8 membered monocyclic heteroaryl group; R L4z independently selected from hydrogen, fluorine, chlorine, bromine, oxo, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl; r is independently selected from 1.

[0214] In some embodiments, wherein L4 is selected from

[0215] The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0216] Alternatively, L4 is independently selected from The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0217] Alternatively, L4 is independently selected from The “#” end is the end connected to ring B, and the “##” end is the end connected to ring E.

[0218] In some embodiments, L4 is -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, The “#” end is the end connected to ring B, and the “##” end is the end connected to ring E.

[0219] In some embodiments, L4 is -NHC(O)NH-, The “#” end is the end connected to ring B, and the “##” end is the end connected to ring E.

[0220] In some embodiments, wherein Ring E is independently selected from C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0221] Alternatively, ring E is independently selected from C 3-8 Carbocyclyl, 3-8 membered heterocyclyl, phenyl, naphthyl, 5-10 membered heteroaryl;

[0222] Alternatively, ring E is independently selected from C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, phenyl, naphthyl, 5-10 membered heteroaryl; the heteroatom in the heterocyclic group and heteroaryl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0223] In some embodiments, wherein Ring E is independently selected from C 3-10 Carbocyclic group;

[0224] Alternatively, ring E is independently selected from C 3-6 Carbocyclic group.

[0225] In some embodiments, wherein Ring E is independently selected from 3-10 membered heterocyclyl;

[0226] Alternatively, Ring E is independently selected from a 3-6 membered heterocyclyl.

[0227] In some embodiments, wherein Ring E is independently selected from C 6-10 Aryl, 5-10 membered heteroaryl;

[0228] Alternatively, ring E is independently selected from phenyl, naphthyl, and 5-10 membered heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0229] Alternatively, ring E is independently selected from phenyl, naphthyl, and 8-9 membered bicyclic heteroaryl; the heteroatom in the heteroaryl is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0230] Alternatively, ring E is independently selected from a 9-membered bicyclic heteroaryl group; the heteroatom in the heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1, 2 or 3.

[0231] In some embodiments, wherein ring E is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered / 5-membered fused heteroaryl, 5-membered / 6-membered fused heteroaryl, 6-membered / 5-membered fused heteroaryl, 6-membered / 6-membered fused heteroaryl; the heteroatom in the heteroaryl is selected from N, O or S, and the number of heteroatoms is 1 or 2;

[0232] Alternatively, ring E is independently selected from a 5-membered / 6-membered fused heteroaryl group, or a 6-membered / 5-membered fused heteroaryl group; the heteroatom in the heteroaryl group is selected from N, O or S, and the number of heteroatoms is 1 or 2.

[0233] In some embodiments, wherein ring E is independently selected from phenyl, naphthyl, pyridyl, pyrrolyl, furanyl, thienyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, indazolyl;

[0234] Alternatively, Ring E is independently selected from indazolyl.

[0235] In some embodiments, wherein Ring E is independently selected from

[0236] Alternatively, Ring E is independently selected from

[0237] In some embodiments, wherein Ring E is independently selected from

[0238] Alternatively, Ring E is independently selected from

[0239] Alternatively, Ring E is independently selected from

[0240] In some embodiments, wherein R e are independently selected from deuterium, halogen, hydroxy, amino, nitro, cyano, -OR e1 、-SO2(R e1 ),-C(O)R e1 、-C(O)OR e1 、-OC(O)R e1 、-N(R e1 )(R e2 )、-C(O)N(R e1 )(R e2 )、-N(R e1 )C(O)(R e2 )、-S(O)N(R e1 )(R e2 )、-SO2N(R e1 )(R e2 )、-N(R e1 )SO2(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl (preferably C 3-5 cycloalkyl), 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means that one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 replaced by;

[0241] Or, R e Independently selected from deuterium, halogen, hydroxyl, amino, cyano, -OR e1 、-N(R e1 )(R e2 )、-SO2(R e1 ),-C(O)R e1 、-SO2N(R e1 )(Re2 )、-N(R e1 )SO2(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl (preferably C 3-5 cycloalkyl), 3-6 membered heterocyclyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 The heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2.

[0242] Or, R e Independently selected from halogen, hydroxy, amino, cyano, -OR e1 、-N(R e1 )(R e2 )、-SO2(R e1 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 The heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2;

[0243] Or, R e are independently selected from halogen, hydroxy, amino, cyano, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-4 Alkyl (preferably C 1-3 Alkyl), C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclic group; the optional substitution means that the unsubstituted or substituted group has one or more (for example, 2, 3, 4) substitutable sites independently substituted by a substituent selected from halogen, hydroxyl, and amino; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

[0244] In some embodiments, wherein R eare independently selected from halogen, hydroxy, amino, cyano, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently replaced by R e3 replaced.

[0245] Or, R e are independently selected from halogen, hydroxy, amino, cyano, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl; the optional substitution refers to unsubstituted or one or more (eg, 2, 3) substitutable sites of the substituted group are independently replaced by R e3 replaced.

[0246] In some embodiments, wherein R e independently selected from halogen, hydroxy, amino, cyano, or optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -N(C 1-4 Alkyl)2, -P(O)(C 1-4 alkyl) 2; the optional substitution means that one or more (e.g., 2, 3, 4) substitutable sites of the unsubstituted or substituted group are independently substituted by substituents selected from halogen, hydroxy, amino, cyclopropyl, and methyl.

[0247] In some embodiments, wherein R e are independently selected from halogen, methyl, cyclopropyl, -NH(CH3), -P(O)(C2H5)2; or, R e Independently selected from fluoro, methyl, cyclopropyl, -NH(CH3), -P(O)(C2H5)2.

[0248] In some embodiments, wherein R e It is fluorine, methyl, or cyclopropyl.

[0249] In some embodiments, wherein R e It is fluorine or cyclopropyl.

[0250] In some embodiments, wherein q is 2, R e fluoro and cyclopropyl, respectively.

[0251] In some embodiments, wherein, for

[0252] In some embodiments, wherein, for

[0253] In some embodiments, wherein, with the proviso that R e Not a methyl group.

[0254] In some embodiments, wherein, with the proviso that, when ring E is Ring A is When q is 2, the two R e Not methyl and fluorine.

[0255] In some embodiments, wherein two R e Together with the atoms to which they are attached, they form an optionally substituted 3-7 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, oxo, cyano, C 1-4 Alkyl, C 1-4 substituted with an alkoxy group;

[0256] Or, two R e Together with the atoms to which they are attached, they form an optionally substituted 3-7 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxy, amino, oxo, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy;

[0257] Or, two R e Together with the atoms to which they are attached, they form an optionally substituted 5-7 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy;

[0258] Or, two R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclyl, wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxy, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy;

[0259] Preferably, the heterocyclic group or heteroaryl group contains heteroatoms independently selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4; further preferably, preferably, the heterocyclic group or heteroaryl group contains heteroatoms independently selected from N or O, and the number of heteroatoms is 1 or 2;

[0260] Preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring (i.e., the heterocyclic group and ring E share one chemical bond (i.e., share two adjacent atoms) or two adjacent chemical bonds (i.e., share three adjacent atoms)); preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Wherein * represents an atom shared with ring E; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring selected from

[0261] In some embodiments, wherein, for

[0262] In some embodiments, wherein, Selected from

[0263] In some embodiments, wherein R e1 、R e2 are independently selected from hydrogen, deuterium, and optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0264] Or, R e1 、R e2 are independently selected from hydrogen, or optionally substituted C1-6 Alkyl, C 3-6 Cycloalkyl; the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxy, amino, and cyano;

[0265] Or, R e1 、R e2 are independently selected from hydrogen, or optionally substituted C 1-4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl), C 3-4 Cycloalkyl (e.g., cyclopropyl, cyclobutyl); the optionally substituted group means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from fluorine, chlorine and cyano.

[0266] In some embodiments, wherein R e1 、R e2 Each is independently selected from hydrogen, hydroxy, amino, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, -CH2CN, -CH2CH2CN, cyclopropyl, cyclobutyl;

[0267] Or, R e1 、R e2 are independently selected from hydrogen, methyl and ethyl.

[0268] In some embodiments, wherein R e3 are independently selected from deuterium, halogen, hydroxy, amino, nitro, cyano, -R e4 、-OR e4 、-S(O)2R e4 、-C(O)R e4 、-C(O)OR e4 、-OC(O)R e4 、-N(R e4 )(R e5 )、-C(O)N(R e4 )(R e5 )、-N(R e4 )C(O)R e5 、-S(O)N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )S(O)2R e5 、-P(O)(R e4 )R e5 ; R e4 、Re5 are independently selected from hydrogen, or optionally substituted by: C 1- 6 alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl (e.g., C 3-5 Cycloalkyl, C 3-4 cycloalkyl), 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2- 4-Alkynyl, C 3-6 substituted by a cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group;

[0269] Or, R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 , OR e4 、-SO2(R e4 ),-C(O)R e4 、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )R e5 ; R e4 、R e5 are independently selected from hydrogen, or arbitrarily substituted by one or more (e.g., 2, 3, 4, 5) of hydrogen, halogen, hydroxyl, amino, and cyano: C 1-6 Alkyl (preferably C 1-4 Alkyl; preferably C 1-3 Alkyl; for example, methyl, ethyl, propyl, isopropyl) or C 3-6 Cycloalkyl (e.g., C 3-5 Cycloalkyl, C 3-4 cycloalkyl).

[0270] In some embodiments, wherein q is independently selected from 0, 1, 2, 3;

[0271] Alternatively, q is independently selected from 1, 2 or 3;

[0272] Alternatively, q is 2 or 3.

[0273] In some embodiments, wherein L 5x, L 5y are independently selected from a bond, or an optionally substituted C 1-6 Alkylene; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0274] Or, L 5x , L 5y are independently selected from a bond, hydrogen, an optionally substituted methylene or an optionally substituted ethylene, wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, and oxo;

[0275] Or, L 5x , L 5y are each independently selected from a bond.

[0276] In some embodiments, wherein R 1 and R 2 Together with the atoms to which they are attached, they form C 3-10 Carbocyclic group; the C 3-10 The carbocyclyl group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R 3 Replaced by; R 3 are independently selected from hydrogen, halogen or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 3-6 substituted by a cycloalkyl group or a 3-6 membered heterocyclic group;

[0277] Or, R 1 and R 2 Together with the atoms to which they are attached, they form C 3-8 Carbocyclic group (preferably C 3-6 Carbocyclic group; further preferably C 3-5 carbocyclic group, for example, cyclopropyl, cyclobutyl, cyclopentyl); said C 3-8 The carbocyclyl group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R 3 Replaced by; R 3are independently selected from hydrogen, halogen or optionally substituted: C 1-5 Alkyl, C 1-5 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) groups selected from halogen, hydroxy, amino, cyano;

[0278] Or, R 1 and R 2 Together with the atoms to which they are attached, they form a group optionally substituted by one or more (e.g., 2, 3, 4, 5) R 3 The following groups substituted by: 3-membered carbocyclyl, 4-membered carbocyclyl, 3-membered / 3-membered spirocarbocyclyl, 3-membered / 4-membered spirocarbocyclyl, 3-membered / 5-membered spirocarbocyclyl, 3-membered / 6-membered spirocarbocyclyl; wherein R 3 independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl;

[0279] Or, R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0280] Or, R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0281] Or, R 1 and R 2 Together with the atoms to which they are attached, the carbon rings formed are The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end.

[0282] In some embodiments, wherein R f Independently selected from -C(O)OR f1 、-C(O)N(R f1 )(R f2 );

[0283] Or, R f Independently selected from -C(O)OR f1 ;

[0284] Or, R f Independently selected from the following groups: -COOH.

[0285] In some embodiments, wherein R f Independently selected from

[0286] Or, R f Independently selected from

[0287] In some embodiments, wherein R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substitution with cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

[0288] Or, R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 Alkoxy group substitution;

[0289] Or, R f1 、R f2 、R f3 、Rf4 、R f5 、R f6 、R f7 are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, cyano, oxo, C 1-4 Alkyl, C 1-4 Alkoxy group substitution;

[0290] Or, R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, cyano, oxo, C 1-3 Alkyl, C 1-3 Alkoxy groups are substituted.

[0291] In some embodiments, wherein R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 Each is independently selected from hydrogen, deuterium, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy.

[0292] In some embodiments, wherein R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R f7 are each independently selected from hydrogen.

[0293] In some embodiments, the compound is required to have the following conditions:

[0294] a) Ring C is not The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end; and / or

[0295] b) L4 is not The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E; and / or

[0296] c) When the compound structure shown in formula (I) is (Among them, R xx is H or CH3, R e can be substituted on any ring of the bicyclic system), for When R e is selected from halogen, optionally substituted C 3-6 Cycloalkyl; q is 1 or 2; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 Replaced by; R e3 Independently selected from deuterium, halogen, hydroxyl, amino, cyano, OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e3 )(R e4 )、-SO2N(R e4 )(R e5 )、-N(R e4 )S(O)2R e5 、-P(O)(R e4 )(R e5 );R e4 、R e5 are independently selected from hydrogen or optionally substituted C 1-6 Alkyl, the optional substitution means unsubstituted or substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, cyano; or two Re together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group (preferably a 3-10 membered heterocyclic alkyl, more preferably a 5-7 membered heterocyclic alkyl), the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substituents selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14aryl and 5-12 membered heteroaryl groups; and / or

[0297] d) When the compound structure shown in formula (I) is (Among them, R xx When H or CH3, for

[0298] In some embodiments, wherein Ring A is selected from phenyl, 3-6 membered heterocyclyl;

[0299] Ring B is selected from 8-9 membered bicyclic heterocyclyl, 8-9 membered bicyclic heteroaryl;

[0300] Ring C is selected from 9-membered bicyclic heteroaryl;

[0301] Ring D is selected from 6-membered heterocyclyl and 6-membered heteroaryl;

[0302] Ring E is selected from C 6-8 Aryl, 5-10 membered heteroaryl;

[0303] R a Each occurrence is independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)(R a2 ), and optionally substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from hydrogen, halogen, hydroxyl, amino;

[0304] R b Each occurrence is independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl;

[0305] R c Each occurrence is independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-6 alkyl;

[0306] R d Each occurrence is independently selected from halogen, hydroxy, amino, cyano, oxo, or optionally substituted: C 1-4 Alkyl, C 1- 4 alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxyl, and amino;

[0307] R e Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, cyano, -OR e1 、-SO2(R e1 ),-C(O)R e1 、-N(R e1 )(R e2 )、-SO2N(R e1 )(R e2 )、-N(R e1 )SO2(R e2 )、-P(O)(R e1 )(R e2 ), optionally substituted C 1-6 Alkyl, or optionally substituted C 3-6 Cycloalkyl; R e1 、R e2 are independently selected from hydrogen, methyl, ethyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable sites of the unsubstituted or substituted group are independently replaced by R e3 Taken; R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 , OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )(R e5 );R e4 、R e5 are independently selected from hydrogen, or arbitrarily substituted by one or more (e.g., 2, 3, 4, 5) of hydrogen, halogen, hydroxyl, amino, and cyano: C 1-6 Alkyl, C 3-6 Cycloalkyl (preferably C 3-5 Cycloalkyl, preferably C 3-4 cycloalkyl, e.g., cyclopropyl, cyclobutyl);

[0308] R 1 and R 2 Together with the atoms to which they are attached, they form C 3-8 Carbocyclic group; the C 3-8 The carbocyclic group is optionally substituted with one or more R 3 Replaced by; R 3are independently selected from hydrogen, halogen or optionally substituted: C 1-5 Alkyl, C 1-5 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) groups selected from hydrogen, halogen, hydroxyl, amino, and cyano;

[0309] R f Selected from -COOH,

[0310] L1 is selected from a bond, -CH2-;

[0311] L2 is selected from a bond, -CH2-, -C(O)-;

[0312] L3 is selected from a bond, -CH2-, -C(O)-;

[0313] L 5x , L 5y are each independently selected from a bond;

[0314] m, n, o, p, q, and r are each independently 0, 1, 2, or 3;

[0315] L4 is selected from -NHC(O)NH-, -NHC(S)NH-, -NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH- The “#” end is the end connected to ring B, and the “##” end is the end connected to ring E.

[0316] In some embodiments, wherein Ring A is selected from phenyl, 3-6 membered heterocyclyl;

[0317] Ring B is selected from a 9-membered bicyclic heterocyclic group and a 9-membered bicyclic heteroaryl group;

[0318] Ring C is selected from 9-membered bicyclic heteroaryl;

[0319] Ring D is selected from a 6-membered heterocyclic group and a 6-membered heteroaryl group; the heteroatom in the 6-membered heterocyclic group is O, and the number of heteroatoms is 1; the heteroatom in the 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2;

[0320] Ring E is selected from phenyl, 5-membered / 6-membered fused heteroaryl, and 6-membered / 5-membered fused heteroaryl; the heteroatom contained in the 5-membered / 6-membered fused heteroaryl or 6-membered / 5-membered fused heteroaryl is N, and the number of heteroatoms is 1, 2, or 3;

[0321] R a Each occurrence is independently selected from halogen, hydroxy, amino, cyano, and optionally substituted groups: C1-4 Alkyl, C 1-4 Alkoxy, C 3-4 Cycloalkyl, 4-5 membered heterocyclyl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from hydrogen, halogen, hydroxyl, amino;

[0322] R b Each occurrence is independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 alkyl;

[0323] R c Each occurrence is independently selected from halogen, hydroxy, amino, cyano, oxo, C 1-4 alkyl;

[0324] R d Each occurrence is independently selected from halogen, hydroxy, amino, cyano, or optionally substituted: C 1-4 Alkyl, C 1-4 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxyl, and amino;

[0325] R e Each occurrence is independently selected from halogen, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), optionally substituted C 1-6 Alkyl, or optionally substituted C 3- 6-cycloalkyl; R e1 、R e2 are independently selected from hydrogen, methyl, ethyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable sites of the unsubstituted or substituted group are independently replaced by R e3 Replaced by; R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )R e5 ; R e4、R e5 are independently selected from hydrogen or optionally substituted: C 1-6 Alkyl, C 3-6 Cycloalkyl (preferably C 3-5 Cycloalkyl, preferably C 3-4 cycloalkyl, such as cyclopropyl, cyclobutyl); the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxyl, amino, and cyano;

[0326] R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0327] R f Selected from -COOH,

[0328] L1 is selected from a bond, -CH2-;

[0329] L2 is selected from a bond, -CH2-, -C(O)-;

[0330] L3 is selected from a bond, -CH2-, -C(O)-;

[0331] L4 is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH- The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0332] L 5x , L 5y are each independently selected from a bond;

[0333] m, n, o, p, q, and r are each independently 0, 1, 2, or 3.

[0334] In some embodiments, wherein Ring A is selected from phenyl, 3-6 membered heterocyclyl;

[0335] Ring B is selected from a 9-membered cyclic heterocyclic group and a 9-membered bicyclic heteroaryl group; the heteroatom in the 9-membered cyclic heterocyclic group and the 9-membered bicyclic heteroaryl group is selected from N, and the number of heteroatoms is 1, 2 or 3;

[0336] Ring C is selected from a 9-membered bicyclic heteroaryl group; the heteroatom in the 9-membered bicyclic heteroaryl group is selected from N, and the number of heteroatoms is 1 or 2;

[0337] Ring D is selected from tetrahydropyranyl and pyridyl;

[0338] Ring E is selected from phenyl, indazolyl;

[0339] R a Each occurrence is independently selected from halogen, methyl, cyclopropyl;

[0340] R b Each occurrence is independently selected from fluoro, chloro, oxo, methyl;

[0341] R c Each occurrence is independently selected from fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0342] R d Each occurrence is independently selected from optionally substituted C 1-4 Alkyl and optionally substituted C 1-4 Alkoxy; the C 1-4 Alkyl or C 1-4 The alkoxy group is optionally substituted with one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxy, and amino;

[0343] R e are independently selected from halogen, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), optionally substituted C 1-6 Alkyl and optionally substituted C 3-6 Cycloalkyl; R e1 、R e2 are independently selected from hydrogen, methyl, ethyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable sites of the unsubstituted or substituted group are independently replaced by R e3 Replaced by; R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e3 )(R e4 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )(R e5 );R e4 、Re5 are independently selected from hydrogen or optionally substituted: C 1-6 Alkyl (preferably C 1-3 Alkyl, e.g., methyl, ethyl), C 3-6 Cycloalkyl (preferably C 3-5 Cycloalkyl, preferably C 3-4 Cycloalkyl, such as cyclopropyl, cyclobutyl), the optional substitution means unsubstituted or substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, cyano;

[0344] R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0345] R f Selected from -COOH,

[0346] L1 is selected from a bond, -CH2-;

[0347] L2 is selected from -C(O)-;

[0348] L3 is selected from a bond;

[0349] L4 is selected from -NHC(O)NH-, The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0350] L 5x , L 5y are each independently selected from a bond;

[0351] m, n, o, p, q, and r are each independently 0, 1, or 2.

[0352] In some embodiments, wherein Ring A is selected from phenyl;

[0353] Ring B is selected from The "*" end is connected to L1, the "**" end is connected to L2, and the "***" end is connected to L4;

[0354] Ring C is selected from the following groups:

[0355] The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end;

[0356] Ring D is

[0357] Ring E is

[0358] L1 is selected from a bond;

[0359] L2 is selected from -C(O)-;

[0360] L3 is selected from a bond;

[0361] L4 is selected from -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0362] L 5x , L 5y are each independently selected from a bond;

[0363] R a Each occurrence is independently selected from halogen, methyl, C 3-5 Cycloalkyl-(CH2) w -;

[0364] R b Each occurrence is independently selected from fluoro, chloro, oxo, methyl;

[0365] R c Each occurrence is independently selected from hydrogen, fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0366] R d Each occurrence is independently selected from optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, deuterium, halogen, hydroxyl, and amino;

[0367] R e is independently selected at each occurrence from fluoro, or an optionally substituted group: C 1-3 Alkyl (e.g., methyl, ethyl), C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C 3-5 Cycloalkyl-(CH2) w -; The condition is that when L4 is When R a or a substituent on ring E (or R e ) is C 3-5 Cycloalkyl-(CH2)w -;

[0368] Or, two R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group (e.g., a 5-, 6-, or 7-membered heterocyclic group) containing 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, or S; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 replaced by;

[0369] R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0370] R f Selected from

[0371] m is 2 or 3; q is 1, 2 or 3;

[0372] n, o, and p are each independently 0, 1, or 2;

[0373] w is 0, 1, or 2;

[0374] The R e3 As defined in the compound of formula (I);

[0375] Provided that it does not contain the following compounds:

[0376] In some embodiments, both R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring (i.e., the heterocyclic group and ring E share 1 chemical bond (i.e., share 2 adjacent atoms) or 2 adjacent chemical bonds (i.e., share 3 adjacent atoms)); preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Wherein * represents an atom shared with ring E; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring selected from

[0377] In some embodiments, the compound represented by formula (I) is a compound represented by the following formula:

[0378] Ring D, Ring E, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, q are as defined for the compound of formula (I).

[0379] In some embodiments, L4 is -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH-, The "#" end is connected to the end of the ring B, and the "##" end is connected to the end of the ring E; when L4 is R a The substitution position on the benzene ring is When R e is selected from halogen, optionally substituted C 3-6 Cycloalkyl; q is 1 or 2; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 replaced by;

[0380] R e3 Independently selected from deuterium, halogen, hydroxyl, amino, cyano, OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e3 )(R e4 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )(R e5 );R e4 、R e5 are independently selected from hydrogen or optionally substituted C 1-6Alkyl, wherein the optional substitution refers to being unsubstituted or substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, cyano; or two R e Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl (preferably a 3-10 membered heterocycloalkyl, more preferably a 5-7 membered heterocycloalkyl), wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 aryl and 5-12 membered heteroaryl groups.

[0381] In some embodiments, the compound represented by formula (I) is a compound represented by the following formula:

[0382] Ring C, Ring E, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, q are as defined for the compounds of formula (I), formula (II) or formula (I-1) to formula (I-8);

[0383] Among them, ring F is C 3-6 Cycloalkyl.

[0384] In some embodiments, Ring F is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably, Ring F is cyclopropyl.

[0385] In some embodiments, the compound represented by formula (I) is a compound represented by the following formula:

[0386] Ring C, Ring B, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, q are as defined for compounds of formula (I), formula (II) or formula (I-1) to formula (I-8); wherein ring F is C 3-6Cycloalkyl.

[0387] In some embodiments, Ring F is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably, Ring F is cyclopropyl.

[0388] In some embodiments, the compound represented by formula (I) is a compound represented by the following formula:

[0389] Ring C, Ring E, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, and q are as defined for the compounds of formula (I) and formula (I-1) to formula (I-8).

[0390] In some embodiments, the compound represented by formula (II), wherein ring C is selected from the following groups: The "+" end is connected to the end of -C(=O)-, the "++" end is connected to the end of tetrahydropyran, and the "+++" end is connected to one end; provided that, when ring C is L4 does not Alternatively, when ring C is L4 is R a The substitution position on the benzene ring is When R e is selected from halogen, optionally substituted C 3-6 Cycloalkyl, substituted C 1-3 Alkyl, q is 1 or 2; the optional substitution means that one or more (e.g., 2, 3, 4, 5) substitutable positions of the unsubstituted or substituted group are independently replaced by R e3 Substituted, wherein the substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, 5) substitutable sites of the substituted group are independently replaced by R e3 replaced by;

[0391] R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e3 )(R e4 )、-SO2N(Re4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )(R e5 );R e4 、R e5 are independently selected from hydrogen or optionally substituted: C 1-6 Alkyl (preferably C 1-3 Alkyl, such as methyl, ethyl) or C 3-6 Cycloalkyl (preferably C 3-5 Cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl), wherein the optional substitution means unsubstituted or substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, cyano;

[0392] Or two R e Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl (preferably a 5-7 membered heterocyclyl, such as a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 7-membered heterocyclyl; further preferably a 5-7 membered heterocycloalkyl, such as a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, a 7-membered heterocycloalkyl), wherein the optionally substituted group is unsubstituted or replaced by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl (preferably C 1-3 Alkyl, e.g., methyl, ethyl), C 1-6 Alkoxy (preferably C 1-3 Alkoxy, for example, methoxy, ethoxy), C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 The heterocyclic group or heterocycloalkyl group is substituted by an aryl group and a 5-12 membered heteroaryl group; preferably, the heteroatoms in the heterocyclic group or heterocycloalkyl group are independently selected from N, O or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0393] In some embodiments, Ring C is selected from the following groups: The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end; or,

[0394] Ring C is selected from the following groups: The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end.

[0395] In some embodiments, the compound represented by formula (I), formula (I-1) to (I-8), formula (II), formula (II-1) or formula (II-2) as described above, wherein,

[0396] Ring E is selected from phenyl, indazolyl;

[0397] R a Each occurrence is independently selected from halogen, methyl, cyclopropyl;

[0398] R b Each occurrence is independently selected from fluoro, chloro, oxo, methyl;

[0399] R c Each occurrence is independently selected from fluoro, chloro, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl;

[0400] R d Each occurrence is independently selected from C 1-4 Alkyl and C 1-4 Alkoxy; the C 1-4 Alkyl or C 1-4 The alkoxy group is optionally substituted with one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxy, and amino;

[0401] R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end of the "~~" is connected to L 5y one end;

[0402] L4 is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH-, The "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E;

[0403] m, n, o, p, q, and r are each independently 0, 1, or 2.

[0404] In some embodiments, the compound represented by formula (I), formula (I-1) to (I-8) or formula (II) as described above, wherein L4 is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-, -N(methyl)C(O)N(methyl)-, -NHC(S)NH-, -NH-, The “#” end is the end connected to ring B, and the “##” end is the end connected to ring E.

[0405] In some embodiments, the compound represented by formula (I), formula (I-1) to (I-8) or formula (II) as described above is a compound represented by the following formula:

[0406] wherein Y1 is N, Y2 and Y3 are both C, and Y4 is C or CH; or, Y1 is C, Y2 is N, Y3 is C or CH, and Y4 is C; or, Y1 is C, Y2 is C, Y3 is C or CH, and Y4 is N; or, Y1 is C, Y2 is N, Y3 is N, and Y4 is C;

[0407] Ring E, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, q are as defined in the compound of formula (I), formula (I-1) to formula (I-8) or formula (II).

[0408] In some embodiments, the compound represented by formula (I), formula (I-1) to (I-8) or formula (II) as described above is a compound represented by the following formula:

[0409] Among them, ring E, R a 、R b 、R c 、R d 、R e 、R 1 、R 2 , L 1 , L 4 , m, n, o, p, q are as defined in the compound of formula (I), formula (I-1) to formula (I-8) or formula (II).

[0410] In some embodiments, the proviso is that the following compounds are not included:

[0411] In some embodiments, the compound represented by formula (I), formula (II), or formula (I-1) to formula (I-8) is a compound represented by formula (III):

[0412] Ring D is independently selected from

[0413] Ring E is selected from

[0414] R a is selected from fluoro, methyl, cyclopropyl;

[0415] R b selected from methyl;

[0416] R c selected from fluorine and chlorine;

[0417] R d Selected from methyl, methoxy, ethoxy;

[0418] R e Selected from halogen, -N(R e1 )(R e2 )、-P(O)(R e1 )(R e2 ), or optionally substituted by: C 1-6 Alkyl (preferably C 1-3 Alkyl, e.g., methyl, ethyl), C 3-6 Cycloalkyl (preferably C 3-5 cycloalkyl, e.g., cyclopropyl, cyclobutyl); R e1 、R e2 are independently selected from hydrogen, methyl, and ethyl; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3 Replaced by; R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )R e5 ; R e4 、R e5 are independently selected from hydrogen or substituted by one or more of hydrogen, halogen, hydroxyl, amino, and cyano: C 1-6 Alkyl or C 3-6 cycloalkyl;

[0419] Or, two R eTogether with the atoms to which they are attached, they form an optionally substituted 5-7 membered heterocyclyl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3 or 4) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, methoxy, and cyclopropyl;

[0420] L1 is independently selected from a bond;

[0421] m, n, o, p, q, and r are each independently 0, 1, 2, or 3.

[0422] In some embodiments, R e is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; preferably, R e It is cyclopropyl.

[0423] In some embodiments, wherein Ring D is independently selected from

[0424] Ring E is selected from

[0425] R a is selected from fluoro, methyl, cyclopropyl;

[0426] R b selected from methyl;

[0427] R c Selected from H;

[0428] R d selected from methyl;

[0429] R e is selected from halogen, or optionally substituted by: C 1-6 Alkyl (preferably C 1-3 Alkyl, e.g., methyl, ethyl), C 3-6 Cycloalkyl (preferably C 3-5 Cycloalkyl, for example, cyclopropyl, cyclobutyl); the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3 Replaced by R e3 are independently selected from deuterium, halogen, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5)、-P(O)(R e4 )R e5 ; R e4 、R e5 are independently selected from hydrogen or substituted by one or more of hydrogen, halogen, hydroxyl, amino, and cyano: C 1-6 Alkyl or C 3-6 cycloalkyl;

[0430] Or, two R e Together with the atoms to which they are attached, they form an optionally substituted 5-7 membered heterocyclyl, wherein the optionally substituted group is unsubstituted or substituted by one or more (e.g., 2, 3 or 4) groups selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, methoxy, and cyclopropyl;

[0431] L1 is independently selected from a bond;

[0432] m, n, o, p, q, and r are each independently 0, 1, 2, or 3;

[0433] The condition is that when q is 2, R e are F and methyl respectively, and when m is 3, Not for

[0434] In some embodiments, the compound represented by formula (III) is a compound represented by formula (III-1):

[0435] Among them, ring E, ring D, R a 、R c 、R d 、R e , L 1 , m, o, p, q are as defined for the compound of formula (III).

[0436] In some embodiments, the compound represented by formula (III) is a compound represented by formula (III-2):

[0437] Among them, ring E, R a 、R c 、R d 、R e , L 1 , m, o, p, q are as defined for the compound of formula (III).

[0438] In some embodiments, in the aforementioned compounds (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula III-1, Formula III-2), with the proviso that when L4 is When R a or a substituent on ring E (or R e ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when R a and the substituents on ring E (or R e ) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, the two R e (Preferably, two R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl, said heterocyclyl (preferably a heterocycloalkyl) containing 1-3 (e.g. 1, 2 or 3) heteroatoms each independently selected from N, O or S;

[0439] The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3 substituted; said R e3 As defined in the compound of formula (I);

[0440] Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; more preferably cyclopropyl;

[0441] Provided that it does not contain the following compounds:

[0442] In some embodiments, in the aforementioned compounds (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula III-1, Formula III-2), with the proviso that R a or a substituent on ring E (or Re ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when R a and the substituents on ring E (or R e ) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, the two R e (Preferably, two R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl, said heterocyclyl (preferably a heterocycloalkyl) containing 1-3 (e.g. 1, 2 or 3) heteroatoms each independently selected from N, O or S;

[0443] The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3 substituted; said R e3 As defined in the compound of formula (I);

[0444] Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; more preferably cyclopropyl.

[0445] In some embodiments, both R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring (i.e., the heterocyclic group and ring E share 1 chemical bond (i.e., share 2 adjacent atoms) or 2 adjacent chemical bonds (i.e., share 3 adjacent atoms)); preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Wherein * represents an atom shared with ring E; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring selected from

[0446] In some embodiments, the compound represented by formula (I), formula (II), or formula (I-1) to formula (I-8) is a compound represented by formula (IV):

[0447] Ring E is selected from

[0448] R a Each occurrence is independently selected from fluoro, methyl and C 3-5 Cycloalkyl;

[0449] m is 2 or 3;

[0450] q is 2 or 3;

[0451] R e is independently selected at each occurrence from fluoro, or an optionally substituted group: C 1-3 Alkyl (e.g., methyl, ethyl), C 3- 5-cycloalkyl; provided that R a or R e at least one (e.g., one or two) of the groups is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene, or cyclopentyl-ethylene;

[0452] Or, two R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl containing 1-3 (e.g., 1, 2, or 3) heteroatoms each independently selected from N, O, or S;

[0453] The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3 replaced by;

[0454] R e3 are independently selected from deuterium, halogen (eg, fluorine, chlorine), hydroxy, amino, oxo, cyano, -R e4 、-OR e4 、-S(O)2R e4 、-C(O)R e4 、-N(R e4 )(R e5 )、-S(O)2N(R e4 )(R e5 )、-N(R e4 )S(O)2R e5 、-P(O)(R e4 )R e5 ; R e4 、R e5are independently selected from hydrogen or substituted by one or more (e.g., 2 or 3) of hydrogen, deuterium, halogen (e.g., fluorine or chlorine), hydroxyl, amino, cyano, oxo, and methoxy: C 1-3 Alkyl (e.g., methyl, ethyl, propyl) or C 3-6 cycloalkyl (preferably 3-5 membered cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl);

[0455] Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; more preferably cyclopropyl.

[0456] In some embodiments, both R e (Preferably, two adjacent R e ; Further preferably, two adjacent R e ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring (i.e., the heterocyclic group and ring E share 1 chemical bond (i.e., share 2 adjacent atoms) or 2 adjacent chemical bonds (i.e., share 3 adjacent atoms)); preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Wherein * represents an atom shared with ring E; preferably, the 6-7 membered heterocyclic group and ring E form a fused three-membered ring selected from

[0457] In some embodiments, the proviso is that the following compounds are not included:

[0458] In some embodiments, wherein, for Preferably, for

[0459] In some embodiments, wherein, for

[0460] In some embodiments, wherein, when for hour, for Preferably, for

[0461] when for hour, for

[0462] In some embodiments, the compound represented by formula (IV) is a compound represented by formula (IV-1):

[0463] Among them, ring E, m, q, R a 、R e The definition of is the same as that of the compound represented by formula (IV).

[0464] In some embodiments, the compound represented by formula (I), formula (II), or formula (I-1) to formula (I-8) is a compound represented by formula (V) to (VIII):

[0465] in, Indicates whether the key exists or not;

[0466] Indicates the presence or absence of ring G; when ring G exists, ring G is C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl);

[0467] L is a key, C 1-3 Alkylene (e.g., methylene, ethylene, propylene; preferably methylene) or C 1-3 Alkyl (e.g., methyl, ethyl, propyl; preferably methyl);

[0468] Alternatively, L and its adjacent R3 are cyclized to form an optionally substituted 5-7 membered heterocyclic group containing 1-3 (e.g., 1, 2 or 3) heteroatoms independently selected from N, O or S, in which case ring G is absent;

[0469] R3 is selected from H, F or methyl;

[0470] R4 is selected from C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl);

[0471] Ring F is an optionally substituted 5-7 membered heterocyclic group containing 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S;

[0472] The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable sites of the substituted group are independently replaced by R e3Replaced by; R e3 are independently selected from deuterium, halogen (eg, fluorine, chlorine), oxo, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 ),-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )R e5 ; R e4 、R e5 are independently selected from hydrogen or substituted by one or more (e.g., 2 or 3) of hydrogen, halogen (e.g., fluorine or chlorine), hydroxyl, amino, cyano, oxo, and methoxy: C 1-3 Alkyl (e.g., methyl, ethyl, propyl) or C 3-6 cycloalkyl (preferably 3-5 membered cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl).

[0473] In some embodiments, the L and its adjacent R3 are cyclized to form an optionally substituted 6-7 membered heterocyclic group containing 1-3 (e.g., 1, 2, or 3) heteroatoms each independently selected from N, O, or S; preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Where * indicates shared atoms.

[0474] In some embodiments, ring F is an optionally substituted 6-7 membered heterocyclic group containing 1-3 (e.g., 1, 2, or 3) heteroatoms each independently selected from N, O, or S; preferably, the 6-7 membered heterocyclic group is selected from Preferably, the 6-7 membered heterocyclic group is selected from Where * indicates shared atoms.

[0475] In some embodiments, in Formula (VIII) or Formula (VIII-1), for

[0476] In some embodiments, the compounds represented by formulas (V) to (VIII) and (V-1) to (VIII-1) are compounds represented by formulas (V-2) to (VIII-2):

[0477] Wherein, R, R3, L, and ring F are as defined for the compounds represented by formulae (V) to (VIII) and (V-1) to (VIII-1).

[0478] 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.

[0479] In some embodiments, the present invention provides the following compound, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0480] In a second aspect, the present invention provides a method for preparing a compound represented by formula (I) or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof.

[0481] The method can be prepared, for example, using the method shown in the following scheme,

[0482] The hydrazine group of intermediate 1.1 reacts with intermediate 1.2 to produce intermediate 1.3, which is then alkylated to produce intermediate 1.4. The amino group of intermediate 1.3 reacts to produce intermediate 1.5. Intermediate 2.1 is alkylated to produce intermediate 2.2. The cyano group of intermediate 3.1 is converted to intermediate 3.2. There are two methods for the synthesis of intermediate 4.1:

[0483] Method 1: The amino group of intermediate 1.3 or 1.4 reacts with the amino group of intermediate 2.1 or 2.2 to obtain intermediate 4.1;

[0484] Method 2: Intermediate 1.5 and intermediate 2.3 are reacted via Ullmann reaction to give intermediate 4.1;

[0485] Intermediate 4.1 reacts with the carboxyl group of intermediate 3.2 to obtain the target compound;

[0486] Note: The partial protection and deprotection reaction steps involved in this step have been omitted;

[0487] P1 is a protecting group (e.g., Boc, Bn, Cbz, etc.), X1 is a leaving group (e.g., I, Cl, Br, etc.);

[0488] Ring A, Ring B, Ring C, Ring D, Ring E, R a 、R b 、R c 、Rd 、R e 、R 1 、R 2 , L1, L2, L3, R f 、R e 、L4、L 5x , L 5y , m, n, o, p, q, etc. are as defined for the compound of formula (I).

[0489] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient.

[0490] Administration of the compounds of the present invention (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration for providing drugs of similar use. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be formulated into a solid, semi-solid, liquid, or gaseous formulation. Generally, the pharmaceutical composition can be prepared using conventional excipients in the pharmaceutical field by conventional preparation methods.

[0491] In a fourth aspect, the present invention provides a compound as described above (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or its tautomers, stereoisomers or pharmaceutically acceptable Use of a salt or a pharmaceutical composition of the present invention as a drug or in the preparation of a drug; preferably, the drug is a GLP-1R agonist; further preferably, the drug is a drug for treating and / or preventing GLP-1R-related disorders; further preferably, the drug is a drug for treating and / or preventing disorders mediated by GLP-1R; further preferably, the drug is a drug for treating and / or preventing disorders caused by or mediated by decreased GLP-1R activity; further preferably, the drug is a drug for preventing and / or treating disorders by stimulating GLP-1R-mediated cascade signals; further preferably, the disorders include diabetes, overweight or obesity, non-alcoholic fatty liver disease, Alzheimer's disease, etc.; further preferably, the diabetes is type 2 diabetes.

[0492] In some embodiments, the use, wherein the drug is a drug for treating and / or preventing diabetes, overweight or obesity, non-alcoholic fatty liver disease or Alzheimer's disease; preferably, the drug is a drug for treating and / or preventing diabetes, overweight or obesity; further preferably, the diabetes is type 2 diabetes.

[0493] In a fifth aspect, the present invention provides the compounds as described above (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII- 2, Formula VIII-2, compound 1-65) or its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition, for treating and / or preventing a disease; preferably, the disease is a GLP-1R-related disease; further preferably, the disease is a disease mediated by GLP-1R; further preferably, the disease is a disease caused or mediated by decreased GLP-1R activity; further preferably, the disease includes diabetes, overweight or obesity, non-alcoholic fatty liver disease, Alzheimer's disease, etc.; further preferably, the disease includes diabetes, overweight or obesity; further preferably, the diabetes is type 2 diabetes.

[0494] In a sixth aspect, the present application provides a method for treating a disease, comprising: administering to an individual in need thereof a therapeutically effective amount of a compound as described above (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VI II-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or its tautomers, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention; preferably, the disease is a GLP-1R-related disease; further preferably, the disease is a disease mediated by GLP-1R; further preferably, the disease is a disease caused or mediated by decreased GLP-1R activity; further preferably, the disease includes diabetes, overweight or obesity, non-alcoholic fatty liver disease, Alzheimer's disease, etc.; further preferably, the disease includes diabetes, overweight or obesity; further preferably, the diabetes is type 2 diabetes.

[0495] In some embodiments, the present invention provides a use or method, wherein the compound of the present invention (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula I I-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or its tautomers, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition of the present invention is used in combination with another, two or more compounds or drugs with the same or similar indications.

[0496] The present invention also provides a composition comprising a compound of the present invention (Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, Formula I-8, Formula I-9, Formula I-10, Formula I-11, Formula I-12, Formula I-13, Formula I-14, Formula I-15, Formula I-16, Formula I-17, Formula I-18, Formula I-19, Formula I-20, Formula II, Formula II-1, Formula II-2, Formula III, Formula IV, Formula IV-1, Formula V, Formula VI, Formula VII, Formula VIII, Formula V-1, Formula VI-1, Formula VII-1, Formula VIII-1, Formula V-2, Formula VI-2, Formula VII-2, Formula VIII-2, Compound 1-65) or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention and another, two or more compounds having the same or similar indications.

[0497] definition

[0498] Unless otherwise specified, the following terms used in this invention have the following meanings. A specific term should not be construed as ambiguous or unclear unless otherwise defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0499] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0500] When any variable (such as R a) occurs more than once in the composition or structure of a compound, its definition is independent on each occurrence. Thus, for example, if a group, a site or an atom is represented by two R a is replaced, then each R a There are independent options.

[0501] "Multiple" herein refers to 2-10, for example, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 2, 3, 4, 5, 6, 7, 8 or 9; preferably 2, 3, 4, 5, 6, 7 or 8; preferably 2, 3, 4 or 5; preferably 2 or 3.

[0502] “R b Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl", should be understood as "R b Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 1-6 Alkylamino, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic group, optionally substituted C 6-14 Other similar expressions in the present invention should be understood in the same manner as above.

[0503] The terms "optional," "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0504] The term "oxo" refers to a group in which two hydrogen atoms at the same substitution position are replaced by the same oxygen atom to form a double bond.

[0505] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 alkyl), more preferably containing 1 to 4 carbon atoms (i.e., C 1-4 Alkyl), more preferably containing 1-3 carbon atoms (ie C 1-3 Alkyl) such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0506] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 alkenyl), further preferably containing 2 to 8 carbon atoms (C 2-8 alkenyl), more preferably containing 2 to 6 carbon atoms (ie, C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example, "C 2-6 The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0507] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl), more preferably containing 2-6 carbon atoms (ie, C 2-6 Alkynyl), 2-5 carbon atoms (ie C 2-5 Alkynyl), 2-4 carbon atoms (ie C 2-4 Alkynyl), 2-3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl), for example, "C2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0508] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6), more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0509] Unless otherwise specified, the term "alkylamino" refers to -NR'R", R' and R" are the same or different and may be H or an alkyl group as defined above, wherein the alkyl group is as defined above, i.e., contains 1-20 carbon atoms, preferably, contains 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6), more preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. Representative examples include, but are not limited to, -NH(CH3), -N(CH3)(CH3), -N(CH2CH3)(CH3), -N(CH2CH3)[CH(CH3)2], etc.

[0510] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0511] Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon radical ("C 3- 15 In some embodiments, the carbocyclyl group has 3-15 ring carbon atoms ("C 3-15 carbocyclyl”), 3-14 ring carbon atoms (“C 3-14carbocyclyl”), 3-12 ring carbon atoms (“C 3-12 carbocyclyl”), or 4-12 ring carbon atoms (“C 4-12 carbocyclyl”), or 3 to 10 ring carbon atoms (“C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl”), or 5 to 7 ring carbon atoms (“C 5-7 carbocyclyl”), or 3 to 5 ring carbon atoms (“C 3-5 Carbocyclyl”). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is a monocyclic ("monocyclic carbocyclyl") or a fused (and carbocyclyl), bridged (bridged cyclyl) or spiro-fused (spirocyclyl) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused by one or more aryl groups, wherein the point of attachment is on the carbocyclyl or aryl ring, and in such cases, the number of atoms of the carbocyclyl ring system is the number of carbons in the carbocyclyl system after fusion. In certain embodiments, each example of a carbocyclyl group is independently optionally substituted, for example, unsubstituted (a "unsubstituted carbocyclyl") or substituted by one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0512] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-7 carbon atoms (C 3-7 Cycloalkyl), 3-6 carbon atoms (C 3-6 Cycloalkyl), 3-5 carbon atoms (C 3-5 Cycloalkyl) 3-4 carbon atoms (C 3-4 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0513] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it contains 3 to 12 ring atoms (3-12 membered heterocyclyl), more preferably 3 to 10 ring atoms (3-10 membered heterocyclyl), or 3 to 8 ring atoms (3-8 membered heterocyclyl), or 3 to 6 ring atoms (3-6 membered heterocyclyl), or 4 to 6 ring atoms (4-6 membered heterocyclyl), or 4 to 5 ring atoms (4-5 membered heterocyclyl), or 3 to 5 ring atoms (3-5 membered heterocyclyl), or 5 to 7 ring atoms (5-7 membered heterocyclyl), or 5 to 6 ring atoms (5-6 membered heterocyclyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include paracyclic, spirocyclic, and bridged heterocyclic groups. A "heterocyclic group" may be monocyclic ("monocyclic heterocyclic group") or a fused (paracyclic heterocyclic group), bridged ("heterobridged heterocyclic group" or "bridged heterocyclic group") or spirocyclic ("heterospirocyclic group," "spiroheterocyclic group," or "spirocyclic heterocyclic group") ring system, such as a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused or fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused or fused to one or more aryl or heteroaryl groups, or cycloalkyl ring, as defined above, is fused or fused to one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, cycloalkyl ring, aryl ring, or heteroaryl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiolanyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexanyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazacyclohexanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0514] Unless otherwise specified, the term "paracyclic" refers to a non-aromatic, saturated or partially unsaturated ring system formed by two or more cyclic structures sharing two adjacent atoms, including paracarbocyclyl and paraheterocyclyl. The term "non-aromatic" means that the entire ring system is non-aromatic.

[0515] The carbocyclyl group may contain 5-14 ring atoms, preferably 6-12 ring atoms, more preferably 7-10 ring atoms (e.g., 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms). The carbocyclyl group includes a bicyclic, tricyclic, tetracyclic or polycyclic carbocyclyl group, preferably a bicyclic, tricyclic or tetracyclic carbocyclyl group, more preferably a bicyclic or tricyclic carbocyclyl group. Illustrative examples of carbocyclyl groups include (but are not limited to) wait.

[0516] The heterocyclic group may contain 5-14 ring atoms, preferably 6-12 ring atoms, more preferably 7-10 ring atoms (e.g., 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms), wherein the heterocyclic group contains 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2, or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O, and S. The heterocyclic group includes a bicyclic, tricyclic, tetracyclic, or polycyclic heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic heterocyclic group, more preferably a bicyclic or tricyclic heterocyclic group. Illustrative examples of heterocyclic groups include (but are not limited to) wait.

[0517] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, or 6 to 8 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0518] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing 5-14 members, or preferably 5-12 members, or preferably 5-10 members, or preferably 5-9 members, or preferably 5-8 members, and more preferably 5-6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms being preferably 1, 2 or 3. Polycyclic heteroaryl is a fused heteroaryl. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0519] Unless otherwise specified, the term "fused heteroaryl" refers to an aromatic ring system formed by two or more cyclic structures sharing two adjacent atoms, each ring in the fused heteroaryl is an unsaturated aromatic ring, which may contain 5-20 ring atoms, preferably 6-14 ring atoms, more preferably 7-10 ring atoms (e.g., 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms), including 1-4 ring heteroatoms, preferably 1-3 (i.e., 1, 2 or 3) ring heteroatoms, and the heteroatoms are independently selected from N, O and S. Fused heteroaryl includes bicyclic, tricyclic, tetracyclic or polycyclic fused heteroaryl, preferably bicyclic, tricyclic or tetracyclic fused heteroaryl, more preferably bicyclic or tricyclic fused heteroaryl. Illustrative examples of fused heteroaryl include (but are not limited to)

[0520] wait.

[0521] In this article, It means that q Re can be substituted at any position in the bicyclic system as long as a stable structure can be formed. For example, It can be expressed as This rule applies to any ring system of the present invention and is used here for exemplary purposes.

[0522] In various parts of the present invention, referring to the connecting substituents (such as L 4x , L 4y Those skilled in the art will understand that when a linking group is clearly required in a compound structure, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively. Therefore, when used as a linking group, "alkyl" and "alkylene" have equivalent definitions, for example, "alkyl" and "alkylene" have equivalent definitions.

[0523] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0524] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, rotational isomers, and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher-order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents higher-order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers.

[0525] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0526] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0527] The compounds of the present invention also include their isotopic derivatives. Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically labeled or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest atom found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes, 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds. Isotope derivatives are preferably deuterated derivatives.

[0528] The compounds of the present invention also include solvates or solvates thereof. Unless otherwise specified, the terms "solvate" and "solvate" refer to the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0529] The compounds of the present invention also include co-crystals thereof. Unless otherwise specified, the term "co-crystal" is used to describe a situation in which the neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutically acceptable co-crystals enables the crystalline form of the active pharmaceutical ingredient to be altered, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters and L. Quere, RSC Publishing, 2012).

[0530] The compounds of the present invention also include their polymorphs. Unless otherwise specified, the term "polymorph" refers to the different arrangements of chemical drug molecules, generally manifesting as the solid state forms of the drug substance. A drug can exist in multiple crystalline forms. Different crystalline forms of the same drug may dissolve and be absorbed differently in the body, thus affecting the dissolution and release of the formulation.

[0531] The compounds of the present invention also include their metabolites. Unless otherwise specified, the term "metabolite" refers to products resulting from the in vivo metabolism of a specific compound or its salt. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by contacting the compounds of the present invention with a mammal for a sufficient period of time.

[0532] The compounds of the present invention also include prodrugs thereof. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they may be bioavailable orally, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limited to, of a prodrug is any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0533] The word "comprise" or "include" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0534] The term "individual" may also be referred to as "object" or "subject" and refers to a cell or an animal, including but not limited to mammals, such as laboratory animals or humans.

[0535] Some compounds of the present invention are optically active. The compounds of the present invention may be racemates, optical isomers or mixtures thereof. The synthesis of optical isomers in the compounds of the present invention may be prepared from starting materials of optical isomers or by separation of racemates.

[0536] The above embodiments represent exemplary embodiments of the present invention, but the present invention is not limited to the above embodiments. In addition, the various technical features in the above embodiments of the present invention can be combined with each other to form one or more new technical solutions, which also fall within the scope of the present invention as long as such new technical solutions are technically feasible.

[0537] Unless otherwise specified, the term "treat," "treatment," "treatment," or "treating" encompasses any treatment of a disease, disorder, or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder, or condition, i.e., arresting its development; or (b) relieving the symptoms of the disease, disorder, or condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder, or condition or one or more symptoms associated with the disease.

[0538] Abbreviations used in the Preparation Examples, Examples, and elsewhere herein are: DCM dichloromethane DCE 1,2-dichloroethane DIPEA N,N-diisopropylethylamine DMF N,N-dimethylformamide HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate NMP N-methylpyrrolidone THF tetrahydrofuran

[0539] This application designs a class of structurally novel compounds, which provide a new direction for the treatment of diseases such as diabetes, non-alcoholic fatty liver disease, Alzheimer's disease and weight loss.

[0540] The beneficial effects of the present invention are:

[0541] The compounds of the present invention achieve one or more of the following beneficial effects:

[0542] (1) Enzyme tests showed that the compounds of the present application have a strong agonist effect on GLP-1R;

[0543] (2) In vivo pharmacokinetic studies in mice and / or rats showed that the compounds of the present application have good oral performance.

[0544] (3) The in vivo efficacy in mice showed that the compound of the present application has an excellent weight-reducing effect.

[0545] (4) The in vivo efficacy in mice showed that the compound of the present application has excellent hypoglycemic effect.

[0546] (5) Safety assessment tests have shown that the compounds of the present application have no off-target risk or very low off-target risk and have good safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0547] Figure 1: H NMR spectrum (temperature: 60°C) of Example 10 (Compound 10).

[0548] Figure 2: H NMR spectrum (temperature: 80°C) of Example 8 (Compound 8).

[0549] Figure 3: H NMR spectrum (temperature: 80°C) of Example 15 (Compound 65).

[0550] Figure 4: Weight gain rate graph of Experimental Example 4. DETAILED DESCRIPTION

[0551] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0552] The following are examples of the preparation of exemplary compounds of the present application.

[0553] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS), or / and liquid chromatography (HPLC), or / and high-resolution mass spectrometry (HRMS). The NMR measurements were performed using a Bruker Avance neo 400 MHz (temperature: 60°C) or / and a Bruker AVANCE III 600; the LC-MS measurements were performed using an Agilent 1260 Infinity II-6120 / 6125 MSD or / and a Waters ACQUITY QDa; the HPLC measurements were performed using a Waters e2695-2998 (column: Waters XBridge C18 4.6*250 mm, 5 μm; column temperature: 40°C; flow rate: 1 mL / min; wavelength: 216 nm; mobile phase A: water (containing 0.1% trifluoroacetic acid); mobile phase B: methanol); and the HRMS measurements were performed using an Aglient Accurate-Mass Q-TOF 6530.

[0554] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0555] Preparation Example 1: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(methylamino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.4-A)

[0556] (S)-tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (150 mg) was dissolved in THF (5 mL), followed by the addition of iodomethane (62 mg) and sodium hydroxide (32 mg), and stirred at room temperature for two hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 1:1, volume ratio) to afford Intermediate 1.4-A (115 mg). ESI-MS (m / z): 389.2 [M+H]. + .

[0557] Preparation Example 2: Synthesis of (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-A)

[0558] Step 1: Synthesis of tert-butyl (S)-3-(3-(2-chloroethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0559] (S)-tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2 g), chloroethyl isocyanate (734 mg), and tetrahydrofuran (40 mL) were added to a flask. Triethylamine (1.6 g) was added and the mixture was heated to 60°C and stirred for 8 hours. After the reaction was completed, the temperature was lowered and the mixture was added to water (40 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 3:1) to obtain the product (700 mg). ESI-MS (m / z): 480.2 [M+H]. + ;

[0560] Step 2: Synthesis of (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxoimidazolin-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0561] The product from step 1 (700 mg) and N,N-dimethylformamide (10 mL) were added to a flask, followed by the addition of NaH (88 mg) and stirring at room temperature for 4 hours. After the reaction was complete, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (300 mg). ESI-MS (m / z): 444.2 [M+H] + ;

[0562] Step 3: Synthesis of intermediate 1.5-A

[0563] The product from step 2 (60 mg), 5-bromo-4-fluoro-1-methyl-1H-indazole (62 mg), cuprous iodide (24 mg), (1S,2S)-(+)-N,N-dimethylcyclohexanediamine (18 mg), potassium phosphate (61 mg), and dioxane (5 mL) were added to a flask and heated to 120°C under a nitrogen atmosphere with stirring for 4 hours. After the reaction, the mixture was cooled and water (40 mL) was added. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin-layer chromatography (hexane:ethyl acetate = 1:2) to obtain Intermediate 1.5-A (50 mg). ESI-MS (m / z): 592.3 [M+H]. + .

[0564] Preparation Example 3: Synthesis of (S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-9-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-B)

[0565] Step 1: Synthesis of 3-((5-bromo-2-nitrobenzyl)amino)propan-1-ol

[0566] 5-Bromo-2-nitrobenzaldehyde (100 mg) and 3-amino-1-propanol (144 mg) were dissolved in ethanol (10 mL), and tetraisopropyl titanate (1 g) was added. After stirring at room temperature for 1 hour, sodium borohydride (50 mg) was added and stirred at room temperature for two hours. Ammonia water (6 mL) was added to quench the mixture, and the reaction solution was filtered. The filtrate was dried and concentrated. The crude product was purified by column chromatography (ethyl acetate) to obtain the product (78 mg). ESI-MS (m / z): 290.1 ​​[M+H] + ;

[0567] Step 2: Synthesis of 9-bromo-3,4-dihydro-2H-[1,3]oxazinyl[3,2-b]indazole

[0568] The product from step 1 (78 mg) was dissolved in a mixed solvent of tert-butanol and water (15 mL / 5 mL). Potassium hydroxide (61 mg) was added and the mixture was reacted at 85°C for 5 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (ethyl acetate) to obtain the product (54 mg). ESI-MS (m / z): 253.2 [M+H] + ;

[0569] Step 3: Synthesis of intermediate 1.5-B

[0570] The product from step 2 (54 mg), (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (47 mg), cuprous iodide (8 mg), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (12 mg), and potassium carbonate (87 mg) were dissolved in N-methylpyrrolidone (2 mL) and stirred at 130°C for 4 hours under nitrogen. After the reaction, the reaction solution was directly concentrated, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1.5-B (27 mg). ESI-MS (m / z): 614.4 [M+H]. + .

[0571] Preparation Example 4: Synthesis of (S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-C)

[0572] Referring to intermediate 1.5-B, intermediate 1.5-C (24 mg) was obtained using 4-bromo-2-nitrobenzaldehyde (100 mg) as the starting material. ESI-MS (m / z): 614.4 [M+H] + .

[0573] Preparation Example 5: Synthesis of (S)-3-(3-(2,3-dihydro-[1,4]oxazino[2,3,4,hi]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-D)

[0574] Step 1: Synthesis of 5-bromo-7-hydroxy-1H-indazole

[0575] 5-Bromo-7-methoxy-1H-indazole (200 mg) was dissolved in dichloromethane (10 mL), and boron tribromide (440 mg) was added dropwise at 0°. After stirring at room temperature for 1 hour, the mixture was quenched with water (40 mL), extracted with dichloromethane (30 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and concentrated. The crude product was purified by column chromatography (n-hexane: ethyl acetate = 5:1) to give 5-bromo-7-hydroxy-1H-indazole (150 mg). ESI-MS (m / z): 213.1 [M+H] + .

[0576] Step 2: Synthesis of 8-bromo-2,3-dihydro-[1,4]oxazino[2,3,4,hi]indazole

[0577] 5-Bromo-7-hydroxy-1H-indazole (150 mg) was dissolved in N,N-dimethylformamide (20 mL). 1-Bromo-2-chloroethane (102 mg) was added and allowed to react at room temperature for 4 hours. The temperature was then raised to 70°C and the reaction continued for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (hexane:ethyl acetate = 10:1) to afford 8-bromo-2,3-dihydro-[1,4]oxazinyl[2,3,4]indazole (100 mg). ESI-MS (m / z): 239.2 [M+H]. + .

[0578] Step 3: Synthesis of intermediate 1.5-D

[0579] Referring to intermediate 1.5-B, 8-bromo-2,3-dihydro-[1,4]oxazino[2,3,4,hi]indazole (100 mg) was used as the starting material to obtain intermediate 1.5-D (30 mg). ESI-MS (m / z): 600.4 [M+H] + .

[0580] Preparation Example 6: Synthesis of (S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-E)

[0581] Step 1: Synthesis of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-3-(((2-(methoxycarbonyl)hydrazino)methylene)amino)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0582] (S)-tert-Butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5 g) and triethyl orthoformate (2.57 g) were added to a flask. The mixture was reacted at 90°C for 1 hour. After the reaction, the temperature was lowered and the solvent was removed under reduced pressure. Methyl hydrazinecarboxylate (2.4 g) and p-toluenesulfonic acid (634 mg) were added and stirred at 50°C for 2 hours. After the reaction, the temperature was lowered and water (100 mL) was added. Extraction was performed with ethyl acetate (50 mL x 3). The solvent was removed under reduced pressure and column chromatography (n-hexane:ethyl acetate = 1:1) was performed to obtain the product (5.4 g). ESI-MS (m / z): 475.2 [M+H]. + .

[0583] Step 2: Synthesis of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0584] The product from step 1 (5.4 g) and methanol (100 mL) were added to a flask, and a methanol solution of sodium methoxide (5 M, 4.5 mL) was added dropwise. The mixture was stirred at room temperature for 12 h. After the reaction was completed, most of the methanol was removed under reduced pressure, water (100 mL) was added, and the mixture was filtered and dried to obtain the crude product (4.2 g). ESI-MS (m / z): 443.2 [M+H] + ;

[0585] Step 3: Synthesis of intermediate 1.5-E

[0586] Referring to Intermediate 1.5-A, the product of step 2 (100 mg) was used as the starting material to obtain Intermediate 1.5-E (42 mg), ESI-MS (m / z): 591.3 [M+H] + .

[0587] Preparation Example 7: Synthesis of (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-F)

[0588] Step 1: Synthesis of 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole

[0589] 5-Bromo-4-fluoro-1H-indazole (1 g), cyclopropylboronic acid (0.8 g), anhydrous copper acetate (0.85 g), bipyridine (0.73 g), sodium carbonate (1 g), and 1,2-dichloroethane (20 mL) were added to a flask, heated to 70°C and stirred for two hours, filtered, and the filtrate was diluted with dichloromethane, washed with water (40 mL), and the solvent was removed under reduced pressure. Column chromatography (n-hexane: ethyl acetate = 5:1) gave the product (0.8 g). ESI-MS (m / z): 254.9 [M+H] + ;

[0590] Step 2: Synthesis of intermediate 1.5-F

[0591] Referring to Intermediate 1.5-A, the product of step 1 (220 mg) and (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (200 mg) were used as raw materials to obtain Intermediate 1.5-F (250 mg). ESI-MS (m / z): 616.3 [M+H] + ;

[0592] Preparation Example 8: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-G)

[0593] Step 1: Synthesis of 3-cyclopropyl-4-fluoroaniline

[0594] 3-Bromo-4-fluoroaniline (10 g), cyclopropylboronic acid (5.9 g), potassium phosphate (39.1 g), palladium acetate (1.2 g), triphenylphosphine (1.4 g), toluene (200 mL), and water (20 mL) were added to a flask. The mixture was heated to 100°C and stirred under a nitrogen atmosphere for 15 hours. After the reaction, water (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane:ethyl acetate = 10:1) to obtain the product (6.9 g). ESI-MS (m / z): 152.1 [M+H] + .

[0595] Step 2: Synthesis of (3-cyclopropyl-4-fluorophenyl)hydrazine

[0596] The product from step 1 (900 mg) was added to a flask with concentrated hydrochloric acid (30 mL). An aqueous solution of sodium nitrite (0.12 M, 60 mL) was added dropwise at 0°C and stirred at 0°C for 1 hour. Subsequently, a concentrated hydrochloric acid solution of stannous chloride (0.33 M, 50 mL) was added dropwise at 0°C and stirred at 0°C for 1 hour. After the reaction, water (150 mL) was added and the pH was adjusted to 8 with saturated aqueous sodium hydroxide solution. Ethyl acetate (200 mL) was added and the insoluble matter was removed by filtration. The layers were separated and the ethyl acetate layer was concentrated under reduced pressure to obtain the crude product. Finally, the product (210 mg) was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain ESI-MS (m / z): 167.1 [M+H]. + .

[0597] Step 3: Synthesis of tert-butyl (S)-3-amino-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0598] The product from step 2 (190 mg), tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylate (227 mg), ethanol (5 mL), and aqueous hydrochloric acid (2M, 100 μL) were added to a flask and stirred at 50°C. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane:ethyl acetate = 3:2) to obtain the product (258 mg). ESI-MS (m / z): 387.2 [M+H] + .

[0599] Step 4: Synthesis of tert-butyl (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0600] The product from step 3 (87 mg) was added to a flask with dichloromethane (2 mL). Triphosgene (22 mg) and N,N-diisopropylethylamine (58 mg) were dissolved in dichloromethane (2 mL) and added dropwise to the flask. The mixture was stirred at room temperature for 1 hour. 2,2-dimethoxyethylamine (94 mg) was added dropwise and the mixture was stirred at room temperature. After the reaction, water (20 mL) was added and the mixture was extracted with dichloromethane (20 mL x 3). The mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (85 mg). ESI-MS (m / z): 518.3 [M+H] + .

[0601] Step 5: Synthesis of (S)-2-(3-cyclopropyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester

[0602] The product from step 4 (80 mg), trifluoromethanesulfonic acid (35 mL), and tetrahydrofuran (2 mL) were added to a flask and stirred at 60°C for 1 hour. The reaction solution was cooled to room temperature, and triethylamine (47 mg) and di-tert-butyl dicarbonate (51 mg) were added and stirred at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (65 mg). ESI-MS (m / z): 454.2 [M+H] + .

[0603] Step 6: Synthesis of intermediate 1.5-G

[0604] Referring to the last step of intermediate 1.5-A, 5-bromo-1-methyl-4-fluoro-1H-indazole (39 mg) and the product of step 5 (50 mg) were used as raw materials to obtain intermediate 1.5-G (40 mg). ESI-MS (m / z): 602.3 [M+H] + .

[0605] Preparation Example 9: Synthesis of (S)-3-(3-(1-cyclopropylmethyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-H)

[0606] Referring to the synthesis of intermediate 1.5-F, bromomethylcyclopropane (200 mg) was used as the starting material to obtain intermediate 1.5-H (90 mg). ESI-MS (m / z): 630.3 [M+H] + .

[0607] Preparation Example 10: Synthesis of (S)-3-(3-(1-cyclopropyl-4-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-I)

[0608] Referring to the synthesis of intermediate 1.5-F, 5-bromo-4-methyl-1-H-indazole (140 mg) was used as the starting material to obtain intermediate 1.5-I (48 mg). ESI-MS (m / z): 612.2 [M+H] + .

[0609] Preparation Example 11: Synthesis of (S)-3-(3-(1-cyclopropyl-7-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-J)

[0610] Referring to the synthesis of intermediate 1.5-F, 5-bromo-7-methyl-1-H-indazole (150 mg) was used as the starting material to obtain intermediate 1.5-J (280 mg). ESI-MS (m / z): 612.2 [M+H] + .

[0611] Preparation Example 12: Synthesis of (S)-3-(3-(2-cyclopropylmethyl-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-K)

[0612] Referring to the synthesis of intermediate 1.5-F, (3.15g) was used as the starting material to obtain intermediate 1.5-K (4.20g), ESI-MS (m / z): 630.3 [M+H] + .

[0613] Preparation Example 13: Synthesis of 4-fluoro-1-methyl-1H-indazol-5-amine (Intermediate 2.1-A)

[0614] Step 1: Synthesis of N-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,1-diphenylmethaneimine

[0615] 5-Bromo-4-fluoro-1-methyl-1H-indazole (150 mg), benzophenone imine (142 mg), bis(dibenzylideneacetone)palladium (60 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (152 mg), and cesium carbonate (429 mg) were added to a flask. Toluene (20 mL) was added and the mixture was heated to 130°C and stirred for 4 hours. After the reaction was completed, the temperature was lowered and the mixture was added to water (40 mL). Extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product (120 mg) was isolated by column chromatography (n-hexane:ethyl acetate = 5:1). ESI-MS (m / z): 330.1 [M+H]. + ;

[0616] Step 2: Synthesis of Intermediate 2.1-A

[0617] The product from step 1 (120 mg) was added to a flask, followed by 10 mL each of tetrahydrofuran and water. Citric acid (200 mg) was added under ice-cooling, and the mixture was stirred overnight at room temperature. After completion of the reaction, the pH was adjusted to 9-10 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Intermediate 2.1-A (42 mg) was isolated by column chromatography (n-hexane:ethyl acetate = 5:1). ESI-MS (m / z): 166.1 [M+H] + .

[0618] Preparation Example 14: Synthesis of N,1-dimethyl-1H-indazol-5-amine (Intermediate 2.2-A)

[0619] 1-Methyl-1H-indazol-5-amine (150 mg) was dissolved in THF (5 mL), followed by the addition of iodomethane (160 mg) and sodium hydroxide (81 mg), and stirred at room temperature for two hours. After the reaction, water (40 mL) was added and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (n-hexane:ethyl acetate = 5:1) to afford Intermediate 2.2-A (103 mg). ESI-MS (m / z): 162.1 [M+H] + .

[0620] Example 1: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)urea (Compound 1)

[0621] Step 1: Synthesis of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(3-(1-methyl-1H-indazol-5-yl)ureido)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0622] 1-Methyl-1H-indazol-5-amine (50 mg) was dissolved in dichloromethane (5 mL), followed by the addition of triphosgene (30 mg) and triethylamine (68 mg). After stirring at room temperature for two hours, (S)-tert-butyl 3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (127 mg, 0.34 mmol) was added and the reaction was stirred at room temperature overnight. After completion of the reaction, water (40 mL) was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by thin-layer chromatography (dichloromethane:methanol = 30:1, volume ratio) to afford the product (153 mg). ESI-MS (m / z): 548.3 [M+H]. + ;

[0623] Step 2: Synthesis of (S)-1-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)urea

[0624] The product from step 1 (153 mg) was dissolved in a 4M solution of hydrochloric acid in dioxane (10 mL) and stirred at room temperature for two hours. After the reaction, the mixture was concentrated to give the crude product (105 mg). ESI-MS (m / z): 448.2 [M+H] + ;

[0625] Step 3: 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(1-methyl-1H-indazol-5-yl)urea

[0626] The product from step 2 (50 mg) and 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (46 mg) were dissolved in anhydrous DMF (2 mL), followed by the addition of HATU (85 mg) and DIPEA (29 mg). The reaction was stirred at room temperature overnight. After completion of the reaction, water (40 mL) was added and extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by thin-layer chromatography (dichloromethane:methanol=20:1) to afford compound 1 (65 mg). ESI-MS (m / z): 841.4 [M+H]. + ; HRMS (m / z): [M+H] + Calcd.for C 46 H 49 N 10 O5F:841.3944.Found:841.3950. HPLC retention time: 18.820min. Confirmed by H NMR spectrum ( 1 H NMR (600 MHz, DMSO-d6) confirmed the correct structure.

[0627] Example 2: Synthesis of 3-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-1-(1-methyl-1H-indazol-5-yl)urea (Compound 2)

[0628] According to the method of Example 1, N,1-dimethyl-1H-indazol-5-amine (Intermediate 2.2-A) (50 mg) was used as the starting material to obtain compound 2 (60 mg). ESI-MS (m / z): 855.4 [M+H]+ ; HRMS (m / z): [M+H] + Calcd.For C 47 H 51 N 10 O5F:855.4101.Found:855.4098.HPLC retention time:19.002min.

[0629] Example 3: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1-methyl-3-(1-methyl-1H-indazol-5-yl)urea (Compound 3)

[0630] Referring to the method of Example 1, compound 3 (63 mg) was obtained using (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(methylamino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.4-A) (50 mg) as a starting material. ESI-MS (m / z): 855.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 47 H 51 N 10 O5F:855.4101.Found:855.4100.HPLC retention time:19.101min.

[0631] Example 4: Synthesis of 1-((S)-5-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)urea (Compound 4)

[0632] According to the method of Example 1, 4-fluoro-1-methyl-1H-indazol-5-amine (Intermediate 2.1-A) (50 mg) was used as the starting material to obtain compound 4 (53 mg). ESI-MS (m / z): 859.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 46 H 48 N 10 O5F2:859.3850.Found:859.3843.HPLC retention time:18.912min.

[0633] Example 5: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 5)

[0634] Step 1: Synthesis of (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)imidazolin-2-one

[0635] (S)-tert-Butyl 3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxoimidazolin-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 1.5-A) (66 mg) and dichloromethane (10 mL) were added to a flask. Trifluoroacetic acid (3 mL) was added and the mixture was stirred at room temperature. After the reaction, the solvent was concentrated and the crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give the product (50 mg). ESI-MS (m / z): 492.2 [M+H]. + ;

[0636] Step 2: Synthesis of compound 5

[0637] 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (93 mg) and N,N-dimethylformamide (5 mL) were added to a flask. HATU (125 mg), triethylamine (56 mg), and the product from step 1 (54 mg) were added and stirred at room temperature for 6 hours. After the reaction, water (40 mL) was added to the mixture and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain compound 5 (22 mg). ESI-MS (m / z): 885.4 [M+H]. + ; HRMS (m / z): [M+H] + Calcd.for C 48 H 50 N 10 O5F2:885.4006.Found:885.4001; 1 H NMR (600MHz, DMSO-d6) δ11.80(s,1H),8.25(s,1H),7.58(d,J=8.8Hz,1H),7.54(s,1H),7.50-7.44(m,1H),7.40(d,J =8.4Hz,1H),7.31(d,J=5.7Hz,2H),7.27(d,J=8.0Hz,1H),6.94(s,1H),5.68-5.63(m,1H),4.39-4.33(m,1H),4.09(s ,3H),4.06-4.02(m,1H),3.96-3.86(m,2H),3.66-3.60(m,2H),3.18-3.10(m,1H),3.08-3.00(m,2H),2.90-2.80(m,2H),2.32(s,6H),1.75-1.62(m,4H),1.55-1.52(m,3H),1.29-1.22(m,5H),1.21-1.16(m,7H).HPLC retention time: 20.381min.

[0638] Example 6: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-9-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 6)

[0639] Referring to the method of Example 5, compound 6 (43 mg) was obtained using (S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-9-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-B) (27 mg) as a starting material. ESI-MS (m / z): 907.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 50 H 51 N 10 O6F:907.4050.Found:907.4058.HPLC retention time: 22.250 min.

[0640] Example 7: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 7)

[0641] Referring to the method of Example 5, compound 7 (10 mg) was obtained using (S)-3-(3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-C) (24 mg) as a starting material. ESI-MS (m / z): 907.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 50 H 51 N 10 O6F:907.4050.Found:907.4044.HPLC retention time:22.262min.

[0642] Example 8: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 8)

[0643] Referring to the method of Example 5, compound 8 (42 mg) was obtained using (S)-3-(3-(2,3-dihydro-[1,4]oxazino[2,3,4-hi]indazol-8-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-D) (30 mg) as a starting material. ESI-MS (m / z): 893.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 49 H 49 N 10 O6F:893.3893.Found:893.3884.HPLC retention time:20.210min. 1 H NMR (400 MHz, DMSO-d6, 80°C): see Figure 2.

[0644] Example 9: Synthesis of 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl))-2-((S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 9)

[0645] Referring to the method of Example 5, compound 9 (13 mg) was obtained using (S)-3-(1-(4-fluoro-1-methyl-1H-indazol-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-E) (42 mg) as a starting material. ESI-MS (m / z): 884.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 47 H 47 N 11 O5F2:884.3802.Found:884.3812.HPLC retention time:20.090min.

[0646] Example 10: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 10)

[0647] Referring to the method of Example 5, compound 10 (196 mg) was obtained using (S)-3-(3-(1-cyclopropyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-F) (250 mg) as a starting material. ESI-MS (m / z): 909.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 50 H 50 N 10 O5F2:909.4006.Found:909.4008. 1 The results of H NMR (600 MHz, DMSO-d6, 60°C) are shown in Figure 1. HPLC retention time: 21.060 min.

[0648] Example 11: Synthesis of 3-((1S,2S)-1-(5-((4S)-2,2-dimethyloxan-4-yl)-2-((4S)-2-(4-fluoro-3-cyclopropylphenyl)-3-(3-(4-fluoro-1-cyclopropylindazol-5-yl)-2-oxoimidazol-1-yl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl)indol-1-yl)-2-methylcyclopropyl)-4H-1,2,4-oxadiazol-5-one (Compound 61)

[0649] Referring to the method of Example 5, compound 61 (41 mg) was obtained using (S)-2-(3-cyclopropyl-4-fluorophenyl)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-G) (40 mg) as a starting material. ESI-MS (m / z): 895.3 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 49 H 48 N 10 O5F2:895.3850.Found:895.3846.HPLC retention time:19.834min.

[0650] Example 12: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropylmethyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 62)

[0651] Referring to the method of Example 5, compound 62 (40 mg) was obtained using (S)-3-(3-(1-cyclopropylmethyl-4-fluoro-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-H) (50 mg) as a starting material. ESI-MS (m / z): 923.4 [M+H]. + ; HRMS (m / z): [M+H] + Calcd.for C 51 H 52 N 10 O5F2: 923.4163. Found: 923.4170. HPLC retention time: 21.515 min.

[0652] Example 13: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-4-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 63)

[0653] Referring to Example 5, (S)-3-(3-(1-cyclopropyl-4-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-I) (83 mg) was used as a starting material to obtain compound 63 (82 mg). ESI-MS (m / z): 905.4 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 51 H 53 N 10 O5F2:905.4257.Found:905.4266.HPLC retention time:20.586min.

[0654] Example 14: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(1-cyclopropyl-7-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 64)

[0655] Referring to Example 5, compound 64 (130 mg) was obtained using (S)-3-(3-(1-cyclopropyl-7-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-J) (140 mg) as a starting material. ESI-MS (m / z): 905.3 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 51 H 53 N 10 O5F:905.4257.Found:905.4251.HPLC retention time:21.285min.

[0656] Example 15: Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(2-cyclopropylmethyl-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (Compound 65)

[0657] Referring to the method of Example 5, compound 65 (5.22 g) was obtained using (S)-3-(3-(2-cyclopropylmethyl-4-fluoro-2H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (Intermediate 1.5-K) (3.71 g) as a starting material. ESI-MS (m / z): 923.3 [M+H] + ; HRMS (m / z): [M+H] + Calcd.for C 51 H 52 N 10 O5F2: 923.4163. Found: 923.4169. HPLC retention time: 20.656 min. 1 H NMR (400 MHz, DMSO-d6, 80°C): see Figure 3.

[0658] With reference to the preparation methods of the above related examples, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0659] Specifically, referring to Example 1, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0660] Specifically, referring to Example 5, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0661] Specifically, referring to Example 9, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0662] Specifically, referring to Example 8, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0663] Specifically, referring to Example 10, and / or in combination with the preparation methods described in the literature, the following compounds were prepared, and their structures and characterization data are as follows:

[0664] Test Example 1: In vitro enzymatic test

[0665] GLP1R-cAmp-Luc cells were used to determine the agonist effect of the test compound on GLP-1R. 1) Dissolve the test compound in DMSO and mix thoroughly until the test compound is completely dissolved. The test compound was dissolved in DMSO and prepared into a solution with a stock concentration of 10 mM. All test compounds were cultured in DMEM medium (high glucose, Puromycin + , Hygromycin B + ) was diluted to a starting concentration of 1250 nM and then diluted 5-fold to a total of 7 concentration gradients. GLP1R-cAmp-Luc cells were cultured in a white-walled 96-well cell culture plate at a density of 1×10 5 1) Cells were seeded at a density of 1 / mL, with 90 μL of cell suspension per well; 10 μL of the test compound was added to each well according to a seven-point concentration gradient, with the actual working starting concentration of the test compound being 125 nM. The cells were placed in a 37°C, 5% CO2 cell culture incubator for 4 h; 2) 100 μL of luciferin potassium salt solution diluted to 300 μg / mL in PBS was added to each well, with a working concentration of 150 μg / mL, and incubated at room temperature for 30 min; 3) The fluorescence signal of firefly luciferin was measured using a multifunctional microplate reader (PerkinElmer, Nivo); the fluorescence values ​​were processed using GraphPad Prism software, and the EC was calculated. 50 value.

[0666] The compounds of the present invention have good GLP-1R agonist activity, and the preferred compounds have an agonist activity (EC 50 ), more preferably the compound has an agonist activity (EC 50)More preferably, the compound has an agonist activity (EC 50 ), more preferably the compound has an agonist activity of less than or equal to 2 nM (EC 50 ), more preferably the compound has an agonist activity of less than or equal to 1 nM (EC 50 The activity results of the exemplary compounds are shown in the following table. Note: A stands for EC 50 ≤10nΜ.

[0667] Test Example 2: Pharmacokinetics test in mice

[0668] Experimental animals: ICR mice (female, 22-25 g) were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0669] Experimental procedures: ICR mice were injected with the test compound via tail vein or gavage. Whole blood samples were collected from the mice 5 min (intravenous only), 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h, 36 h, 48 h, and 72 h after administration. Plasma was separated by centrifugation and the compound concentration was detected by LC-MS / MS. The plasma clearance rate Cl and elimination half-life T were calculated using Winnolin software. 1 / 2 , peak time Tmax, peak concentration Cmax, area under the drug-dose curve AUC and other pharmacokinetic parameters.

[0670] Intravenous dose: 2 mg / kg; oral gavage dose: 10 mg / kg.

[0671] Determination method: After protein precipitation pretreatment, quantitative analysis was performed by LC / MS / MS system.

[0672] The compounds of the present invention have excellent oral administration properties. The PK parameters of exemplary compounds are listed in the following table. Compared with LY 3502970, the compounds have better pharmacokinetic properties, especially better oral absorption properties. Note: 24h test results. Note: 72 hours of test results. Note: 24-hour test results Note: 24-hour test results Note: 24-hour test results Note: 24-hour test results Note: 24-hour test results

[0673] Test Example 3: Pharmacokinetic Study in Rats

[0674] Experimental animals: SD rats (female, 20-25 g) were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0675] Experimental procedures: SD rats were administered the test compound via the tail vein or oral gavage. Whole blood samples were collected from the mice before administration and at 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. The plasma was separated by centrifugation and the compound concentration was detected by LC-MS / MS. The pharmacokinetic parameters such as plasma elimination half-life (T1 / 2), peak time (Tmax), peak concentration (Cmax), and area under the concentration-time curve (AUC) were calculated using Winnolin software.

[0676] Intravenous dose: 2 mg / kg, oral gavage dose: 10 mg / kg

[0677] The compounds of the present invention have excellent oral administration properties. The oral PK parameters of exemplary compounds are listed in the following table. Compared with LY 3502970, the compounds have better pharmacokinetic properties, especially better oral absorption properties.

[0678] Experimental Example 4: Weight Loss Efficacy Study in DIO C57BL / 6hGLP1R Mice

[0679] 1. Experimental purpose: To compare the weight-reducing effects of the test compound and LY 3502970 at the same dose of 0.3 mpk administered orally to obese mice.

[0680] 2. Experimental Animals

[0681] Animals (species: C57BL / 6 humanized transgenic (hGLP1R) mice; age: 6 weeks; sex: male) were purchased and fed a high-fat diet (60 kcal% Fat) for at least 12 weeks until the weight of the animals reached more than 40 g.

[0682] 3. Trial Grouping Note: ig stands for oral administration; qd stands for once a day.

[0683] 4. Test methods

[0684] Before administration, the mice were weighed and their daily food intake (one complete night + day) was measured. The mice were then divided into groups based on their body weight and food intake.

[0685] The weight of mice was measured at a fixed time point every day, and the weight change rate of mice was calculated. After the measurement, the mice were given the corresponding drugs according to their current weight based on their grouping.

[0686] The weight of mice was counted daily, and the weight change rate was calculated, recorded and graphed.

[0687] 5. Test results: After 18 days of continuous administration, the weight change rate of mice in each group was statistically analyzed. Compared with the Vehicle group, Compound 10 of the present invention achieved a significantly better weight loss effect (the average weight growth rate of Compound 10 was -20.2%, p < 0.001); compared with the LY3502970 group (the average weight growth rate of LY3502970 was -15.1%), Compound 10 of the present invention achieved a significantly better weight loss effect (p < 0.05).

[0688] After 20 days of continuous administration, the weight change rate of mice in each group was statistically analyzed. Compared with the Vehicle group, Compound 10 of the present invention achieved a significantly better weight loss effect (the average weight growth rate of Compound 10 was -20.3%, p < 0.001); compared with the LY3502970 group (the average weight growth rate of LY3502970 was -15.7%), Compound 10 of the present invention achieved a significantly better weight loss effect (p < 0.05). The weight growth rate graph is shown in Figure 4.

[0689] Experimental Example 5: Study on the efficacy of intraperitoneal glucose tolerance test (IPGTT) in hGLP-1R transgenic mice

[0690] 1. Experimental purpose: To examine the effects of different doses of the test compound on blood glucose levels at different times after glucose loading in hGLP-1R transgenic mice after a single oral gavage.

[0691] 2. Experimental animals: C57BL / 6JSmoc-Glp1rem2 (hGLP1R) Smoc mice, male, approximately 23 g.

[0692] 3. Experimental grouping: Before the start of the experiment, the mice were fasted but not watered for about 16 hours. The basal blood glucose level of the mice was measured. The animals were randomly divided into balanced groups according to the basal blood glucose level and the weight of the mice, with 7 mice in each group.

[0693] 4. Test method: Each group was given the test compound by gavage at a volume of 10 mL / kg. The vehicle control group was given 2.5% DMSO + 10% EL + 15% PEG400 + 72.5% (100 mM glycine-NaOH buffer, pH = 10) was administered intraperitoneally (ip) with a glucose solution of 2 g / kg (based on mouse body weight) at 10 ml / kg 60 minutes after administration. Time of glucose administration was designated as time zero. Blood glucose levels were measured before, and 15, 30, 60, and 120 minutes after glucose administration.

[0694] 5. The specific groups are as follows:

[0695] 6. Test results:

[0696] Blood glucose test results showed that at a dose of 0.05 mg / kg, the blood glucose levels of mice in the compound 10 group at 15, 30, 60, and 120 min after glucose loading showed a downward trend and were significantly lower than those in the vehicle group (P<0.05, P<0.01, P<0.001). The results of area under the blood glucose curve showed that compared with the vehicle group, the blood glucose levels of mice in the compound 10 group after glucose loading (AUC 0-120min Glu The results were shown in the following table.

[0697] Test Example 6: Safety Assessment Test of 44 Off-Target Effects

[0698] 1. Purpose: This study mainly uses radioisotope binding methods, calcium flux detection methods, and enzyme fluorescence or chemiluminescence techniques to detect the off-target effects of the test compounds on 44 selected targets at the in vitro cellular or molecular levels, thereby evaluating the safety associated with the binding or activity inhibition of the test compounds to these targets.

[0699] 2. Test method: When the test compound 10 (free acid) is at a single concentration of 10 μM (the test concentration for Eta agonism is 12 μM), the binding, inhibitory or agonistic effects on 44 targets are detected.

[0700] 3. Experimental steps: Radioligand competition experiments were performed to detect the effects of the test compounds on 23 GPCRs (ADORA2A, Alpha1A, Alpha2A, Beta1, Beta2, CB1, CB2, CCKa, D1, D2L, H1, H2, op-delta, op-kappa, op-mu, M1, M2, M3, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B and V1A), 8 ion channels (nAChR-Alpha7, Cav1.2 (Dihydropyridine Site), GABAA (α1β3γ2), hERG, NMDA (MK-801), 5-HT3, Na + The compounds were tested for binding to three transporters (DAT, NET, and 5-HTT), as well as two nuclear receptors (AR and GR). Calcium flux assays were used to determine the agonist and antagonist effects of the test compounds on Eta receptors. In vitro biochemical platforms were used to assess the effects of the test compounds on seven enzyme targets.

[0701] 4. Test results:

[0702] At a test concentration of 10 μM, compound 10 had no significant binding or inhibitory effect (inhibition rate <50%) or agonist effect (agonist rate <50%) on 44 targets at a single concentration of 10 μM (the test concentration for Eta agonism was 12 μM).

[0703] At the tested concentration of 10 μM, LY3502970 had a significant effect on Ca 2+ -L, 5HT2B, and op-delta have mild inhibitory effects (inhibition rate > 50%), which may cause off-target risks of related targets.

[0704] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts: in, Ring A is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; Ring B is selected from 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; Ring C is selected from 9-membered bicyclic heteroaryl; Ring D is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; Ring E is selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; R a Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR a1 、-S(O)R a1 、-SO2(R a1 )、-C(O)R a1 、-C(O)OR a1 、-OC(O)R a1 、-N(R a1 )(R a2 )、-C(O)N(R a1 )(R a2 )、-N(R a1 )C(O)R a2 、-S(O)N(R a1 )(R a2 )、-SO2N(R a1 )(R a2 )、-N(R a1 )S(O)R a2 、-N(R a1 )S(O)2R a2 , and optionally one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R a3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; or two R a Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups; R a1 , R a2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R a3 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R a4 、-OR a4 、-SR a4 、-S(O)R a4 、-S(O)2R a4 、-C(O)R a4 、-C(O)OR a4 、-OC(O)R a4 、-N(R a4 )(R a5 )、-C(O)N(R a4 )(R a5 )、-N(R a4 )C(O)R a5 、-S(O)N(R a4 )(R a5 )、-S(O)2N(R a4 )(R a5 )、-N(R a4 )S(O)R a5 、-N(R a4 )S(O)2R a5 ; R a4 , R a5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R b Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R b1 replaced by; or two R b Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups; R b1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, -R b2 、-OR b2 、-SR b2 、-S(O)R b2 、-S(O)2R b2 、-C(O)R b2 、-C(O)OR b2 、-OC(O)R b2 、-N(R b2 )(R b3 )、-C(O)N(R b2 )(R b3 )、-N(R b2 )C(O)R b3 、-S(O)N(R b2 )(R b3 )、-S(O)2N(R b2 )(R b3 )、-N(R b2 )S(O)R b3 、-N(R b2 )S(O)2R b3 ; R b2 , R b3 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted by aryl or 5-12 membered heteroaryl groups; R c Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently replaced by R c1 replaced by; or two R c Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups; R c1 Each occurrence is independently selected from deuterium, halogen, hydroxy, amino, nitro, thiol, cyano, oxo, -R c2 、-OR c2 、-SR c2 、-S(O)R c2 、-S(O)2R c2 、-C(O)R c2 、-C(O)OR c2 、-OC(O)R c2 、-N(R c2 )(R c3 )、-C(O)N(R c2 )(R c3 )、-N(R c2 )C(O)R c3 、-S(O)N(R c2 )(R c3 )、-S(O)2N(R c2 )(R c3 )、-N(R c2 )S(O)R c3 、-N(R c2 )S(O)2R c3 ; R c2 , R c3 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted by aryl or 5-12 membered heteroaryl groups; R d Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR d1 、-S(O)R d1 、-S(O)2R d1 、-C(O)R d1 、-C(O)OR d1 、-OC(O)R d1 、-N(R d1 )(R d2 )、-C(O)N(R d1 )(R d2 )、-N(R d1 )C(O)R d2 、-S(O)N(R d1 )(R d2 )、-S(O)2N(R d1 )(R d2 )、-N(R d1 )S(O)R d2 、-N(R d1 )S(O)2R d2 , and optionally one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R d3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; or two R d Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl, an optionally substituted 3-7 membered cycloalkyl, or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted group is unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 substituted with aryl and 5-12 membered heteroaryl groups; R d1 , R d2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R d3 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R d4 、-OR d4 、-SR d4 、-S(O)R d4 、-S(O)2R d4 、-C(O)R d4 、-C(O)OR d4 、-OC(O)R d4 、-N(R d4 )(R d5 )、-C(O)N(R d4 )(R d5 )、-N(R d4 )C(O)R d5 、-S(O)N(R d4 )(R d5 )、-S(O)2N(R d4 )(R d5 )、-N(R d4 )S(O)R d5 、-N(R d4 )S(O)2R d5 ; R d4 , R d5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R e Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -OR e1 、-SR e1 、-S(O)R e1 、-S(O)2R e1 、-C(O)R e1 、-C(O)OR e1 、-OC(O)R e1 、-N(R e1 )(R e2 )、-C(O)N(R e1 )(R e2 )、-N(R e1 )C(O)R e2 、-S(O)N(R e1 )(R e2 )、-S(O)2N(R e1 )(R e2 )、-N(R e1 )S(O)R e2 、-N(R e1 )S(O)2R e2 、-C(O)N(R e1 )S(O)2N(R e1 )(R e2 )、-C(O)N(R e1 )S(O)2R e2 、-P(O)(R e1 )R e2 , and optionally one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R e3 Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; or two R e Together with the atoms to which they are attached, they form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl, wherein the optionally substituted means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6- 14 substituted with aryl and 5-12 membered heteroaryl groups; R e1 , R e2 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from hydrogen, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R e3 Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R e4 、-OR e4 、-SR e4 、-S(O)R e4 、-S(O)2R e4 、-C(O)R e4 、-C(O)OR e4 、-OC(O)R e4 、-N(R e4 )(R e5 )、-C(O)N(R e4 )(R e5 )、-N(R e4 )C(O)R e5 、-S(O)N(R e4 )(R e5 )、-S(O)2N(R e4 )(R e5 )、-N(R e4 )S(O)R e5 、-N(R e4 )S(O)2R e5 、-C(O)N(R e4 )S(O)2N(R e4 )(R e5 )、-C(O)N(R e4 )S(O)2R e5 、-P(O)(R e4 )R e5 ; R e4 , R e5 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Substituted by a cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R f selected from -C(O)OR f1 、-C(O)N(R f1 )(R f2 )、 R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R f7 Each occurrence is independently selected from hydrogen, deuterium, optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Substituted by a cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl substituent; R 1 and R 2 Together with the atoms to which they are attached, they form C 3-15 Carbocyclic group; the C 3-15 The carbocyclyl group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R 3 Replaced by; R 3 are independently selected from hydrogen, deuterium, halogen, hydroxyl or optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, cyano, oxo, C 3-10 substituted by cycloalkyl or 3-10 membered heterocyclic group; L1 is selected from a bond, -C(R L1 )2-、-O-、-C(R L1 )2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L1 )C(O)-、-C(O)N(R L1 )-or-N(R L1 )-;R L1 are independently selected from hydrogen, deuterium, or optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group; L2 is independently selected from a bond, -C(R L2 )2-、-O-、-C(R L2 )2O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L2 )C(O)-、-C(O)N(R L2 )-or-N(R L2 )-;R L2 are independently selected from hydrogen, deuterium, or optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group; L3 is independently selected from a bond, -C(R L3 )2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R L3 )C(O)-、-C(O)N(R L3 )-or-N(R L3 )-;R L3 are independently selected from hydrogen, deuterium, or optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by a cycloalkyl group or a 3-10 membered heterocyclic group; L4 is independently selected from a bond, -L 4x -C(R L4a )(R L4b )-L 4y -、-L 4x -OL 4y -、-L 4x -SL 4y -、-L 4x -C(O)-L 4y -、-L 4x -C(O)OL 4y -、-L 4x -OC(O)-L 4y -、-L 4x -N(R L4a )C(O)-L 4y -、-L 4x -C(O)N(R L4a )-L 4y -、-L 4x -N(R L4a )-L 4y -、-L 4x -N(R L4a )C(O)N(R L4b )-L 4y -、-L 4x -N(R L4a )C(S)N(R L4b )-L 4y -or L 4x , L 4y are independently selected from a bond, or an optionally substituted C 1-10 Alkylene; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by cycloalkyl or 3-10 membered heterocyclic group; R L4a , R L4b are independently selected from hydrogen, deuterium, or the following optionally substituted groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by cycloalkyl or 3-10 membered heterocyclic group; Ring L 4Z Selected from C 3-15 Carbocyclic group, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-12 membered heteroaryl; R L4z are independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, or optionally substituted with: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; the optional substitution means that one or more substitutable positions of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by cycloalkyl or 3-10 membered heterocyclic group; L 5x , L 5y are independently selected from a bond, or an optionally substituted C 1-10 Alkylene; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the unsubstituted or substituted group are independently selected from deuterium, halogen, hydroxyl, amino, nitro, thiol, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by cycloalkyl or 3-10 membered heterocyclic group; m, n, o, p, q, and r are each independently 0, 1, 2, or 3; Unless otherwise specified, the heteroatoms in the above heterocyclic groups and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: Ring A is selected from phenyl; Ring B is selected from The "*" end is connected to L1, the "**" end is connected to L2, and the "***" end is connected to L4; Ring C is selected from the following groups: The "+" end is connected to L2, the "++" end is connected to L3, and the "+++" end is connected to L 5x one end of Ring D is Ring E is L1 is selected from a bond; L2 is selected from -C(O)-; L3 is selected from a bond; L4 is selected from -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, The "#" end is the end connected to ring B, and the "##" end is the end connected to ring E; L 5x , L 5y are each independently selected from a bond; R a Each occurrence is independently selected from halogen, methyl, C 3-5 Cycloalkyl-(CH2) w -; R b Each occurrence is independently selected from fluoro, chloro, oxo, methyl; R c Each occurrence is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl; R d Each occurrence is independently selected from optionally substituted C 1-3 Alkyl and optionally substituted C 1-3 Alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, deuterium, halogen, hydroxyl, amino; R e is independently selected at each occurrence from fluorine, or an optionally substituted group: C 1-3 Alkyl (e.g., methyl, ethyl), C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C 3-5 Cycloalkyl-(CH2) w -; The condition is that when L4 is When R a or a substituent on ring E (or R e ) is C 3-5 Cycloalkyl-(CH2) w -; Or, two R e (Preferably, two adjacent R e ; Further preferably, two adjacent R located on different rings e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl (e.g., a 5-, 6- or 7-membered heterocyclyl) containing 1-3 (e.g., 1, 2 or 3) heteroatoms independently selected from N, O or S; the optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 replaced by; R 1 and R 2 The carbon rings formed together with the atoms to which they are attached are independently selected from The "~" end is connected to L 5x One end, "~~" end is connected to L 5y one end of R f Selected from m is 2 or 3; q is 1, 2 or 3; n, o, and p are each independently 0, 1, or 2; w is 0, 1, or 2; The R e3 As defined in claim 1; Provided that it does not contain the following compounds:

3. The compound according to claim 1 or 2, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The condition is that when L4 is When R a or a substituent on ring E (or R e ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when R a and the substituents on ring E (or R e ) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, the two R e (Preferably, two R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl, said heterocyclyl (preferably heterocycloalkyl) containing 1-3 (e.g. 1, 2 or 3) heteroatoms each independently selected from N, O or S; The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 replaced; said R e3 As defined in the compound of formula (I); Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; further preferably cyclopropyl; Provided that it does not contain the following compounds:

4. The compound according to any one of claims 1 to 3, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The condition is that R a or a substituent on ring E (or R e ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when R a and the substituents on ring E (or R e ) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, the two R e (Preferably, two R e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl, said heterocyclyl (preferably heterocycloalkyl) containing 1-3 (e.g. 1, 2 or 3) heteroatoms each independently selected from N, O or S; The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 replaced; said R e3 As defined in the compound of formula (I); Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; more preferably cyclopropyl.

5. The compound according to any one of claims 1 to 4, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The compound is a compound represented by the following formula: Ring E is selected from R a Each occurrence is independently selected from fluoro, methyl and C 3-5 Cycloalkyl; m is 2 or 3; q is 2 or 3; R e is independently selected at each occurrence from fluorine, or an optionally substituted group: C 1-3 Alkyl (e.g., methyl, ethyl), C 3- 5-cycloalkyl; provided that R a or R e at least one (e.g., one or two) of the groups is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene, or cyclopentyl-ethylene; Or, two R e (Preferably, two adjacent R e ; Further preferably, two adjacent R located on different rings e ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclyl containing 1-3 (e.g. 1, 2 or 3) heteroatoms each independently selected from N, O or S; The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 replaced by; R e3 are independently selected from deuterium, halogen (e.g., fluorine, chlorine), hydroxyl, amino, oxo, cyano, -R e4 、-OR e4 、-S(O)2R e4 、-C(O)R e4 、-N(R e4 )(R e5 )、-S(O)2N(R e4 )(R e5 )、-N(R e4 )S(O)2R e5 、-P(O)(R e4 )R e5 ; R e4 , R e5 are independently selected from hydrogen or one or more (e.g., 2 or 3) substituted by hydrogen, deuterium, halogen (e.g., fluorine or chlorine), hydroxyl, amino, cyano, oxo, methoxy: C 1-3 Alkyl (e.g., methyl, ethyl, propyl) or C 3-6 cycloalkyl (preferably 3-5 membered cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl); Preferably, the C 3-5 The cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; more preferably cyclopropyl.

6. The compound according to any one of claims 1 to 5, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: when for hour, for Preferably, for when for hour, for 7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The compound is a compound represented by the following formula:

8. The compound according to any one of claims 1 to 7, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The compound is a compound represented by the following formula: in, Indicates whether the key exists or not; Indicates the presence or absence of ring G; when ring G is present, ring G is C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl); L is a key, C 1-3 Alkylene (e.g., methylene, ethylene, propylene; preferably methylene) or C 1-3 Alkyl (e.g., methyl, ethyl, propyl; preferably methyl); Alternatively, L and its adjacent R3 are cyclized to form an optionally substituted 5-7 membered heterocyclic group, wherein the heterocyclic group contains 1-3 (e.g., 1, 2 or 3) heteroatoms independently selected from N, O or S, in which case, ring G does not exist; R3 is selected from H, F or methyl; R4 is selected from C 3-5 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl); Ring F is an optionally substituted 5-7 membered heterocyclic group containing 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S; The optional substitution means that the hydrogen on the substituted group is not replaced or one or more substitutable positions of the substituted group are independently replaced by R e3 Replaced by; R e3 are independently selected from deuterium, halogen (e.g., fluorine, chlorine), oxo, hydroxy, amino, cyano, -R e4 、-OR e4 、-SO2(R e4 )、-C(O)R e4 、-N(R e4 )(R e5 )、-SO2N(R e4 )(R e5 )、-N(R e4 )SO2(R e5 )、-P(O)(R e4 )R e5 ; R e4 , R e5 are independently selected from hydrogen or substituted by one or more (e.g., 2 or 3) of hydrogen, halogen (e.g., fluorine or chlorine), hydroxyl, amino, cyano, oxo, methoxy: C 1-3 Alkyl (e.g., methyl, ethyl, propyl) or C 3-6 The invention further comprises a 3- to 5-membered cycloalkyl group (preferably a 3- to 5-membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl).

9. The compound according to any one of claims 1 to 8, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The compound is a compound represented by the following formula:

10. The following compound, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein: The compound is selected from:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, its stereoisomer, tautomer or pharmaceutically acceptable salt, and optionally further comprising a pharmaceutically acceptable excipient.

12. Use of the compound according to any one of claims 1 to 10, its stereoisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 11 as a medicament or in the preparation of a medicament.

13. The use according to claim 12, wherein the drug is a GLP-1R agonist; further preferably, the drug is a drug for treating and / or preventing GLP-1R-related disorders; further preferably, the drug is a drug for treating and / or preventing disorders mediated by GLP-1R; further preferably, the drug is a drug for treating and / or preventing disorders caused by or mediated by decreased GLP-1R activity; further preferably, the drug is a drug for preventing and / or treating disorders by stimulating GLP-1R-mediated cascade signals; further preferably, the disorders include diabetes, overweight or obesity, non-alcoholic fatty liver disease, Alzheimer's disease, etc.; further preferably, the diabetes is type 2 diabetes.

14. The use according to claim 12, wherein The drug is a drug for treating and / or preventing diabetes, overweight or obesity, non-alcoholic fatty liver disease or Alzheimer's disease; preferably, the drug is a drug for treating and / or preventing diabetes, overweight or obesity; preferably, the diabetes is type 2 diabetes.