TW202527937A - Polycyclic compounds and use thereof - Google Patents

Abstract

The present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The compound of the invention acts as a GLP-1R agonist. The compound and pharmaceutical composition containing the same can be used in the preparation of medicaments for treating and/or preventing disorders mediated by GLP-1R.

Description

Polycyclic compounds and their uses

The present invention relates to the field of medical technology, and more specifically, to a class of polycyclic compounds, pharmaceutical compositions containing the same, and their use as GLP-1R agonists. The polycyclic compounds can prevent and/or treat diseases, disorders, and conditions mediated by GLP-1R.

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.

Diabetes mellitus is a common metabolic endocrine disorder characterized by disrupted 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 linked to unhealthy lifestyle, genetic factors, environmental factors, and the toxic effects of lipotoxicity and glucotoxicity on pancreatic beta cells. Furthermore, long-term poor glycemic control can lead to a variety of diabetic complications, including vascular complications (macrovascular disease (atherosclerosis) and microvascular disease (retinopathy and neuritis), renal complications (renal insufficiency and proteinuria), cardiac complications (myocarditis and heart failure), and urinary tract infections.

GLP-1 (glucagon-like peptide-1) is primarily synthesized and secreted by L cells located in the ileum and colon. Its 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 of the G protein-coupled receptor B cluster. Its hallmark features are a seven-transmembrane core domain and a relatively large extracellular domain.

In the pancreas, GLP-1 induces glucose-dependent insulin secretion, increasing insulin secretion and reducing glucagon. In the central nervous system, GLP-1R stimulation has the effects of increasing satiety, reducing food intake and nausea, and promoting nerve cell survival. In other tissue systems, GLP-1R stimulation also lowers blood pressure, improves microvascular function, reduces inflammation, slows gastric emptying, lowers blood sugar, increases insulin sensitivity, and reduces gluconeogenesis. Therefore, GLP-1R stimulation can lower blood sugar and/or reduce weight, thereby preventing and/or treating diabetes and/or obesity. Furthermore, GLP-1R stimulation can promote weight loss through a variety of biological mechanisms.

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

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by incurable cognitive impairment. The underlying mechanisms of AD development remain incompletely understood. 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 cell glycolysis becomes increasingly important for neuronal survival, serving as an energy substitute. GLP-1 can partially restore astrocyte glycolysis and increase lactate flux, which helps alleviate neuronal energy crises. The neuroprotective mechanism of GLP-1 is closely related to its promotion of aerobic glycolysis, mitigation of oxidative phosphorylation, and activation of the PI3K/Akt pathway. Therefore, GLP-1 agonists are a promising strategy for the prevention and treatment of AD.

Non-alcoholic fatty liver disease (NAFL) is divided into two main categories: non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis (NASH). With an oversupply of metabolic substrates, excess fat accumulates in liver cells, accompanied by the gradual production of potentially toxic lipid species and a progressive increase in de novo lipogenesis (DNL). NASH, characterized by cell damage and inflammatory cell infiltration, is considered a more aggressive form of NAFLD and can progress 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 NASH morbidity and mortality, and GLP-1 analogs can improve glycemic control, reduce weight, and activate liver enzymes in patients with T2DM. Some evidence suggests that liraglutide, acting directly on human hepatocytes in vitro, reduces steatosis by lowering DNL levels and increasing fatty acid oxidation. Notably, steatosis and hepatocyte swelling improved in the majority of patients after liraglutide treatment. Exciting experimental evidence is available in NASH patients suggesting the potential of liraglutide to reduce lipotoxicity by improving insulin sensitivity in adipose tissue. However, only a small percentage of NASH patients progress after liraglutide treatment. Semaglutide, a drug similar to liraglutide, has also been reported to reduce levels of alanine transaminase and inflammatory markers, with levels of inflammatory biomarkers significantly reduced after 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, lipotoxicity, and inflammation.

This invention claims the priority of: Patent Application No. 202311782864.9, filed with the National Intellectual Property Administration of China on December 22, 2023, entitled "A Class of Polycyclic Compounds and Their Uses"; Patent Application No. 202410173188.3, filed with the National Intellectual Property Administration of China on February 7, 2024, entitled "A Class of Polycyclic Compounds and Their Uses"; The entire text of each of these prior applications is incorporated herein by reference.

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: wherein Ring A is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring B is selected from a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring C is selected from a 9-membered bicyclic heteroaryl; Ring D is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring E is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; R ^a is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^a1 , -S(O)R ^a1 , -SO ₂ (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 ), -SO ₂ N(R ^a1 )(R ^a2 ), -N(R ^a1 )S(O)R ^a2 , -N(R ^a1 )S(O) ₂ R ^a2 , and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^a3 : 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 form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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; R ^a1 and R ^a2 are each independently selected from hydrogen, deuterium, an optionally substituted group: C _1-6 alkyl, C 1-6 alkoxy, C _{2-6 alkenyl, C 1-6} alkyl, C 1-6 alkoxy, C _3-10 cycloalkyl, a 3-10 membered heterocyclic group, a C 6-14 aryl and a 5-12 membered heteroaryl group; wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substituents selected from halogen, _hydroxyl , amino, nitro, _hydroxyl , nitrile, oxo, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; R ^a3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -R ^a4 R ^a4 , -OR a4 , -SR ^a4 , -S(O)R ^a4 , -S(O) ₂ R ^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) ₂ N(R ^a4 )(R ^a5 ), -N(R ^a4 )S(O)R ^a5 , -N(R ^a4 )S(O) ₂ R ^a5 ; R ^a4 , R ^a5 are each independently selected from hydrogen, deuterium, an optionally substituted C _1-6 alkyl, a C _1-6 alkoxy, a C _2-6 alkenyl, a C The optional substitution refers to being unsubstituted or substituted by one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substituents selected from halogen, hydroxyl, amino, nitro, hydroxyl, _nitrile , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, _3-7 membered heterocyclic group, phenyl, and 5-6 membered heteroaryl; R ^b is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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 heterocyclo, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions of the substituted group are independently substituted with R ^b1 ; or two R ^b together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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; R ^b1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -R ^b2 , -OR ^b2 , -SR ^b2 R b2 , -S(O)R ^b2 , -S(O) ₂ R ^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) ₂ N(R ^b2 )(R ^b3 ), -N(R ^b2 )S(O)R ^b3 , -N(R ^b2 )S(O) ₂ R ^b3 ; R ^b2 and R ^b3 are each independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 membered 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) groups selected from halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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 aryl, 5-12 membered heteroaryl; R ^c is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, or optionally substituted from 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; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted with R ^c1 ; or two R ^c together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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; R ^c1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -R ^c2 , -OR ^c2 , -SR ^c2 , -S(O)R ^c2 , -S(O) ₂ R ^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) ₂ N(R ^c2 )(R ^c3 ), -N(R ^c2 )S(O)R ^c3 , -N(R ^c2 )S(O) ₂ R ^c3 ; R ^c2 and R ^c3 are each independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 membered 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, 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 aryl, 5-12 membered heteroaryl; R ^d is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^d1 、-S(O)R ^d1 、-S(O) ₂ R ^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) ₂ N(R ^d1 )(R ^d2 、-N(R ^d1 )S(O)R ^d2 、-N(R ^d1 )S(O) ₂ R ^d2 、 and the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^d3 : C _1-6 alkyl, C or two R ^d together with the atoms to which they are attached form _an optionally substituted _{3-10 membered} heterocyclic group, an optionally substituted _3-7 membered cycloalkyl group or an optionally substituted _5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, _halogen , hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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 group; or two R d together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group, an optionally substituted 3-7 membered cycloalkyl group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 membered cycloalkyl, 3-10 membered heterocyclic group, C _6-14 aryl and 5-12 membered heteroaryl group; R ^d1 and R ^d2 are each independently selected from hydrogen, deuterium, and 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 heterocyclic group, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _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) ₂ N(R ^d4 )(R ^d5 ), -N(R ^d4 )S(O)R ^d5 , -N(R ^d4 )S(O) ₂ R ^d5 ; R ^d4 , R ^d5 are each independently selected from hydrogen, deuterium, an optionally substituted C _1-6 alkyl, a C _1-6 alkoxy, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 cycloalkyl, a 3-10 membered heterocyclic group, a C _6-14 membered 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) substituents selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3-7 membered heterocyclo, phenyl, 5-6 membered heteroaryl; R ^e is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^e1 , -SR ^e1 , -S(O)R ^e1 , -S(O) ₂ R ^e1 at each occurrence , -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) ₂ N(R ^e1 )(R ^e2 ), -N(R ^e1 )S(O)R ^e2 , -N(R ^e1 )S(O) ₂ R ^e2 , -C(O)N(R ^e1 )S(O) ₂ N(R ^e1 )(R ^e2 ), -C(O)N(R ^e1 )S(O) ₂ R ^e2 , -P(O)(R ^e1 )R ^e2 , and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^e3 of 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 form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, oxirane, nitrile, 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; R ^e1 and R ^e2 are each independently selected from hydrogen, deuterium, an optionally substituted group: C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C wherein the alkyl radical is an alkyl radical having _{a 2-6} member group, a C 2-6 alkynyl group, a C _3-10 cycloalkyl group, a 3-10 member heterocyclic group, a C _6-14 aryl group, or a 5-12 member heteroaryl group; wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substituents selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl group, a 3-6 member heterocyclic group, phenyl, or a 5-6 member heteroaryl group; wherein each occurrence of R ^e3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -R ^e4 , -OR ^e4 , -SR ^e4 , -S(O)R ^e4 , -S(O) ₂ R ^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) ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O)R ^e5 , -N(R ^e4 )S(O) ₂ R ^e5 , -C(O)N(R ^e4 )S(O) ₂ N(R ^e4 )(R ^e5 ), -C(O)N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 ) R ^e5 ; R ^e4 and R ^e5 are each independently selected from hydrogen, deuterium, and 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by a _3-7 membered cycloalkyl, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; R ^f is 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 are each 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted with a substituent of _{a 3-6} membered cycloalkyl, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; R ¹ and R ² together with the atoms to which they are attached form a C _3-15 carbocyclic group; the C _3-15 carbocyclic group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ³ ; R ³ is independently selected from hydrogen, deuterium, halogen, hydroxyl, or an optionally substituted group of the following groups: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-10 membered cycloalkyl, 3-10 membered heterocyclic group; the optional substitution means that the substituted group is unsubstituted or is substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions independently selected from deuterium, halogen, hydroxyl, amine, nitrile, oxo, C _3-10 cycloalkyl, 3-10 membered heterocyclic group; L ₁ is selected from a bond, -C( ^RL1 ) _2- , -O-, -C( ^RL1 ) _2O- , -S-, -C(O)-, -C(O)O-, -OC(O)-, -N( ^RL1 )C(O)-, -C(O)N( ^RL1 )- or -N( ^RL1 )-; R ^L1 is independently selected from hydrogen, deuterium, or an optionally substituted _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or a 3-10 membered heterocyclic group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, C3-10 cycloalkyl, or a _3-10 membered heterocyclic group; _L2 is independently selected from a bond, -C( ^RL2 ) ₂ -, -O-, -C(R ^L2 ) ₂ O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^L2 )C(O)-, -C(O)N(R ^L2 )-, or -N(R ^L2 )-; R ^L2 is 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 heterocyclic group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, C _1-6 alkyl, C L3 is independently selected from a bond, -C(RL3 _{) 2-} , -O-, _-S- , -C(O)-, -C( _O) O-, -OC(O ₎ -, -N(RL3)C(O)-, -C(O)N( ^RL3 )-, or -N(RL3)-; _RL3 is independently selected from hydrogen, deuterium, or the following optionally substituted groups: _{C1-6 alkyl} , C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or a 3-10 membered heterocyclic group; ^L3 is independently selected from a bond, -C( ^RL3 )2-, -O-, -S-, -C(O)-, -C(O ₎ O-, -OC(O)-, -N( ^RL3 )C(O)-, -C( _O) N( ^RL3 )-, or -N(RL3)-; RL3 is independently selected from hydrogen, deuterium, or the following optionally substituted groups: C1-6 alkyl, _C1-6 alkoxy, C2-6 alkenyl, _C2-6 alkynyl, C _3-10 membered 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) groups selected from deuterium, halogen, hydroxyl, amine, nitro, alkyl, nitrile, 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; L ₄ is independently selected from a bond, -L _4x -C( ^RL4a ) ( ^RL4b )-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 group; the optional substitution means that 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, amine, nitro, hydroxyl, nitrile, oxo, 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; ^RL4a , ^RL4b 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 The optional substitution means that the substituted group is unsubstituted or is substituted with one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substitutable positions independently selected from deuterium, halogen, _hydroxyl , amine, nitro, alkyl, nitrile, oxo, C 1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, or _3-10 membered heterocyclic group; Ring L _4Z is selected from C _3-15 carbocyclic group, 3-12 membered heterocyclic group, C _6-14 aryl, or 5-12 membered heteroaryl; R ^L4z is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, or optionally substituted _C1-6 alkyl, _C1-6 alkoxy, C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or _3-10 membered heterocyclic group; the optional substitution means that the group is unsubstituted or one or more substitutable positions of the substituted group are independently substituted with deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, _C1-6 alkyl, _C1-6 alkoxy, C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or _3-10 membered heterocyclic group; L _5x , L, _{and 5y} are each independently selected from a bond or an optionally substituted _C1-10 alkylene group; the optional substitution means that the group is 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, amine, nitro, hydroxyl, nitrile, oxo, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, C3-10 cycloalkyl, or a _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 heterocyclic and heteroaryl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; provided that the above definitions of the variables combined together form a stable chemical structure.

In some embodiments, each occurrence ^{of R} is independently selected from hydrogen, deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -ORd1, -S(O) ^Rd1 , -S(O) _2Rd1 , ^-C (O) ^Rd1 , -C(O) ^ORd1 , -OC(O) ^Rd1 , -N( ^Rd1 )( ^Rd2 ), -C(O)N( ^Rd1 )( ^Rd2 ), -N( ^Rd1 )C( ^O ) ^Rd2 , -S(O)N( ^Rd1 )( ^Rd2 ), -S(O) _2N ( ^Rd1 )( ^Rd2 ), -N( ^Rd1 )S(O) ^Rd2 , -N( ^Rd1 )S(O) ₂ R ^d2 , and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^d3 of 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, form an optionally substituted 3-10 membered heterocyclic group or 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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.

In some embodiments, wherein ring A is selected from C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; or, ring A is selected from C _3-8 carbocyclyl, 3-8 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl; or, ring A is selected from C _3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; wherein the hetero atom in the heterocyclyl and heteroaryl is selected from N, O or S, and the number of hetero atoms is 1 or 2.

In some embodiments, wherein Ring A is a C _3-10 carbocyclyl; or, Ring A is a C _3-6 carbocyclyl; or, Ring A is a C _3-6 carbocyclyl, provided that Ring A is not or cyclohexyl.

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.

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

In some embodiments, Ring A is pyridinyl.

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.

In some embodiments, wherein ^Ra is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -C(O) ^Ra1 , -C(O) ^ORa1 , -OC(O) ^Ra1 , -N( ^Ra1 )( ^Ra2 ), -C(O)N( ^Ra1 )( ^Ra2 ), -N( ^Ra1 )C(O)( ^Ra2 ), and the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) ^Ra3 : _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic, C _6-8 membered aryl, 5-6 membered heteroaryl; or, R ^a is independently selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -C(O)N(R ^a1 )(R ^a2 ), -N(R ^a1 )C(O)(R ^a2 ), and the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R ^a3 : 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; or, R ^a is independently selected from halogen, hydroxyl, amino, nitrile, and the following groups optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^a3 : C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, 4-5 membered heterocyclic group; the hetero atom in the heterocyclic group is O or N, and the number of hetero atoms is 1 or 2; or, R ^a is independently selected from halogen, hydroxyl, amino, nitrile, and the following groups optionally substituted by one or more (e.g., 2, 3) substituents: C _1-4 alkyl, C _1-4 alkoxy, C 3-4 cycloalkyl, 4-5 membered heterocyclic group; the hetero atom in the heterocyclic group is O or N, and the number of hetero atoms is 1 or 2; _3-4 membered cycloalkyl, 4-5 membered heterocyclic group; the substituent is selected from halogen, hydroxyl and amino; the hetero atom in the heterocyclic group is O, and the number of hetero atoms is 1.

In some embodiments, wherein ^Ra is independently selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -C(O)N( ^Ra1 )( ^Ra2 ), -N( ^Ra1 )C(O)( ^Ra2 ), _C1-6 alkyl, _C1-6 alkoxy; said _C1-6 alkyl, _C1-6 alkoxy is optionally substituted with one or more ^Ra3 ; or, ^Ra is independently selected from halogen, hydroxyl, amino, nitrile, _C1-4 alkyl, _C1-4 alkoxy; said _C1-4 alkyl, _C1-4 alkoxy is optionally substituted with one or more ^Ra3 .

In some embodiments, wherein ^Ra is independently selected from halogen, hydroxyl, amino, nitrile, optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, or ethoxy; the optional substitution means being unsubstituted or substituted with one or more (e.g., 2, 3, 4) substituents selected from deuterium, halogen, hydroxyl, and amino.

In some embodiments, wherein ^Ra is independently selected from halogen, methyl, and cyclopropyl; or, ^Ra is independently selected from fluoro, methyl, and cyclopropyl.

In some embodiments, wherein ^Ra is independently selected from fluoro, methyl, deuterated methyl (-CD ₃ ), -CF ₃ , methoxy, cyclopropyl, and -OCF ₃ .

In some embodiments, two R ^a together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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 group; or, two R ^a together with the atoms to which they are attached form an optionally substituted 3-6 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, and ethoxy groups.

In some embodiments, wherein ^Ra1 and ^Ra2 are independently selected from hydrogen, deuterium, and optionally substituted groups: _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; wherein 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, hydroxyl, amino, nitro, hydroxyl, nitrile, pentooxy, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; or, ^Ra1 and ^Ra2 are independently selected from hydrogen, _C1-6 alkyl (e.g., C3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl). _1-3 alkyl; preferably methyl or ethyl); the C _1-6 alkyl is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, and amino; or, R ^a1 and R ^a2 are each independently selected from hydrogen.

In some embodiments, wherein R ^a3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, 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 .

In some embodiments, wherein R ^a3 is independently selected from hydrogen, halogen, hydroxyl, amino, -R ^a4 ; wherein R ^a4 is 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 alkyl is optionally substituted with one or more substituents selected from hydrogen and halogen.

In some embodiments, wherein R ^a3 is independently selected from hydrogen and halogen; or, R ^a3 is independently selected from hydrogen, fluorine, and chlorine.

In some embodiments, wherein R ^a4 and R ^a5 are independently selected from hydrogen, an optionally substituted C _1-4 alkyl, a C _1-4 alkoxy, a C _3-6 cycloalkyl, a 3-6 membered heterocyclic group, a phenyl group, a 5-6 membered heteroaryl group; 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, hydroxyl, amino, nitrile, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy; or, R ^a4 and R ^a5 are independently selected from hydrogen, a C _1-4 alkyl group; the C _1-4 alkyl group is optionally substituted by one or more (e.g., 2, 3, 4) substituents selected from hydrogen and a halogen.

In some embodiments, wherein R ^a4 and R ^a5 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

In some embodiments, m is selected from 0, 1, 2, 3; or, m is selected from 2, 3.

In some embodiments, wherein L ₁ is selected from a bond, -C( ^RL1 ) _2- , -C( ^RL1 ) _2O- , -O-, -C(O)-, -N( ^RL1 )C(O)-, -C(O)N( ^RL1 )-; ^RL1 is selected from hydrogen, or an optionally substituted C _1-6 alkyl, C _1-6 alkoxy group; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitrile, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group; or, L ₁ is selected from a bond, -C( ^RL1 ) _2- , -C(R ^LR1 is selected from hydrogen, or optionally substituted _C1-4 alkyl, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., ₂ , 3) groups selected _{from halogen, hydroxyl, amine, and nitrile; Alternatively, L1} ^is selected from a bond, -C( ^LR1 ) _2- , -C( ^LR1 ) _2O- ; ^LR1 is selected from hydrogen, optionally substituted methyl, or optionally substituted ethyl, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3) groups selected from fluorine, chlorine, bromine, hydroxyl, amine, and nitrile; 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.

In some embodiments, L ₁ is not -CH(CH ₃ )-.

In some embodiments, wherein Ring B is selected from 3-10 membered heterocyclic groups, C _6-10 aryl groups, 5-10 membered heteroaryl groups; or, Ring B is selected from 4-6 membered monocyclic heterocyclic groups, 8-10 membered bicyclic heterocyclic groups, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl groups, 8-10 membered bicyclic heteroaryl groups; or, Ring B is selected from 8-10 membered bicyclic heterocyclic groups, 8-10 membered bicyclic heteroaryl groups; Alternatively, Ring B is selected from an 8-9 membered bicyclic heterocyclic group and an 8-9 membered bicyclic heteroaryl group; the heteroatom in the 8-9 membered bicyclic heterocyclic group and the 8-9 membered bicyclic heteroaryl group is selected from N or S, and the number of heteroatoms is 1, 2 or 3;

In some embodiments, Ring B is selected from a 9-membered paracyclic heterocyclic group and a 9-membered bicyclic heteroaryl group; wherein the paracyclic heterocyclic group is a heterocyclic paracyclic heteroaryl group, and the bicyclic heteroaryl group is a heteroaryl-fused heteroaryl group or a heteroaryl-fused aryl group; the hetero atom in the 9-membered paracyclic heterocyclic group is N, and the number of hetero atoms is 3; the hetero atom in the 9-membered bicyclic heteroaryl group is N, and the number of hetero atoms is 1 or 2.

In some embodiments, wherein Ring B is selected from 4-6 membered heterocyclic groups, 4-6 membered monocyclic heterocycloalkenyl groups, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl groups, 3-membered/5-membered heterocyclic groups, 5-membered/3-membered heterocyclic groups, 4-membered/4-membered heterocyclic groups, 4-membered/5-membered heterocyclic groups, 5-membered/4-membered heterocyclic groups, 5-membered/5-membered heterocyclic groups, 4-membered/6-membered heterocyclic group, 6-membered/4-membered heterocyclic group, 5-membered/6-membered heterocyclic group, 6-membered/5-membered heterocyclic group, 6-membered/6-membered heterocyclic group, 6-membered/7-membered heterocyclic group, 7-membered/6-membered heterocyclic group, 5-membered/5-membered fused heteroaryl group, 5-membered/6-membered fused heteroaryl group, 6-membered/5-membered fused heteroaryl group, 6-membered/6-membered fused heteroaryl group; Alternatively, Ring B is selected from a 5-membered/5-membered heterocyclic group, a 5-membered/6-membered heterocyclic group, a 6-membered/5-membered heterocyclic group, a 5-membered/5-membered fused heteroaryl group, a 5-membered/6-membered fused heteroaryl group, or a 6-membered/5-membered fused heteroaryl group; Alternatively, Ring B is selected from a 5-membered/5-membered heterocyclic group, a 5-membered/6-membered heterocyclic group, or a 6-membered/5-membered heterocyclic group, and the heteroatom in each of the 5-membered/5-membered heterocyclic group, the 5-membered/6-membered heterocyclic group, or the 6-membered/5-membered heterocyclic group is selected from N, and the number of heteroatoms is 1, 2, or 3; Alternatively, Ring B is selected from a 5-membered/6-membered heterocyclic group and a 6-membered/5-membered heterocyclic group, and the heteroatom in the 5-membered/6-membered heterocyclic group and the 6-membered/5-membered heterocyclic group is selected from N, and the number of heteroatoms is 3.

In some embodiments, wherein Ring B is selected from the following groups: .

In some embodiments, wherein Ring B is selected from the following groups: , wherein the "*" end is connected to L ₁ , the "**" end is connected to L ₂ , and the "***" end is connected to L ₄ ; Alternatively, Ring B is selected from the following groups: , where the "*" end is connected to _L1 , the "**" end is connected to _L2 , and the "***" end is connected to _L4 ; Or, Ring B is selected from , where the "*" end is connected to _L1 , the "**" end is connected to _L2 , and the "***" end is connected to _L4 .

In some embodiments, R ^b is independently selected from deuterium, halogen, hydroxyl, amine, nitro, oxirane, nitrile, oxirane, or optionally substituted from 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; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted by R ^b1 ; or, R ^b is independently selected from halogen, hydroxyl, amine, nitrile, oxirane, or optionally substituted from the following groups: C _1-6 alkyl, C The optional substitution means that one or more (e.g., _2, 3, 4, 5, 6, 7, or 8) substitutable positions of an unsubstituted or substituted group are each independently substituted by R ^b1 ; alternatively, R ^b is independently selected from a halogen, a hydroxyl, an amino, a nitrile, or an optionally substituted C _1-4 alkyl, a C _1-4 alkoxy group; the optional substitution means that one or more (e.g., 2, 3, 4, or 5) substitutable positions of an unsubstituted or substituted group are each independently substituted by R ^b1 ; alternatively, R ^b is independently selected from a C _1-4 alkyl group (preferably a C _1-3 alkyl group); alternatively, R ^b is independently selected from a methyl group.

In some embodiments, two R ^b together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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;

Alternatively, two R ^b together with the atoms to which they are attached form an optionally substituted 3-7 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, methyl, ethyl, methoxy, and ethoxy groups.

In some embodiments, wherein R ^b1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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 ); or, R ^b1 is independently selected from halogen, hydroxyl, amine, -R ^b2 ; or, R ^b1 is independently selected from halogen (e.g., fluorine, chlorine, bromine).

In some embodiments, R ^b2 and R ^b3 are independently selected from hydrogen, optionally substituted by the following groups: 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) groups selected from halogen, hydroxyl, amino, nitrile, C _1-6 alkyl, C _1-6 alkoxy; or, R ^b2 and R ^b3 are independently selected from hydrogen, optionally substituted by the following groups: C _1-4 alkyl, C _1-4 alkoxy groups; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5) groups selected from halogen, hydroxyl, amino, and nitrile groups; or, R ^b2 and R ^b3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

In some embodiments, n is independently selected from 0, 1, and 2; preferably, n is independently selected from 0 and 1; and more preferably, n is 1.

In some embodiments, wherein L ₂ is independently selected from a bond, -C( ^RL2 ) _2- , -O-, -C( ^RL2 ) _2O- , -C(O)-, -N( ^RL2 )C(O)-, -C(O)N( ^RL2 )-; ^RL2 is selected from hydrogen, or an optionally substituted C _1-6 alkyl, C _1-6 alkoxy; the optional substitution means that the optional substitution means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitrile, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group; or, L ₂ is independently selected from a bond, -C( ^RL2 ) ₂ -, -C( ^RL2 ) _2O- , -C(O)-; ^RL2 is selected from hydrogen, or _C1-4 alkyl optionally substituted by one or more (e.g., 2, 3, or 4) of halogen, hydroxyl, amino, or nitrile groups; or, _L2 is independently selected from a bond, -C( ^RL2 ) _2- , -C(O)-; ^RL2 is selected from hydrogen, or methyl or ethyl optionally substituted by one or more (e.g., 2, 3) of fluorine, chlorine, bromine, hydroxyl, amino, or nitrile groups.

In some embodiments, wherein L ₂ is independently selected from a bond, -CH ₂ -, -CH ₂ O-, -O-, -C(O)-, -NHC(O)-, -C(O)NH-; or, L ₂ is independently selected from a bond, -CH ₂ -, -C(O)-; or, L ₂ is -C(O)-.

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 hetero atom in the 9-membered bicyclic heteroaryl group is N, and the number of hetero atoms is 1, 2, or 3; or, ring C is independently selected from a 5-membered/6-membered fused heteroaryl group (e.g., a bicyclic ring composed of a heteroaryl group and a heteroaryl group fused together, or a bicyclic ring composed of an aryl group and a heteroaryl group fused together), the hetero atom in the 5-membered/6-membered fused heteroaryl group is selected from N, and the number of hetero atoms is 1 or 2; or, ring C is independently selected from the following groups: ; Alternatively, Ring C is selected from the following groups: , wherein the "+" end is connected to L ₂ , the "++" end is connected to L ₃ , and the "+++" end is connected to L _5x ; Alternatively, Ring C is independently selected from the following groups: , wherein the "+" end is connected to L ₂ , the "++" end is connected to L ₃ , and the "+++" end is connected to L _5x ; Alternatively, Ring C is selected from the following groups: , where the "+" end is connected to _L2 , the "++" end is connected to _L3 , and the "+++" end is connected to _L5x ;

In some embodiments, Ring C is independently selected from , where the "+" end is connected to _L2 , the "++" end is connected to _L3 , and the "+++" end is connected to _L5x .

In some embodiments, Ring C is , where the "+" end is connected to _L2 , the "++" end is connected to _L3 , and the "+++" end is connected to _L5x .

In some embodiments, wherein R ^c is independently selected from hydrogen, deuterium, halogen, hydroxyl, amine, nitro, alkyl, nitrile, oxo, or optionally substituted from 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, phenyl, _5-6 membered heteroaryl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted by R c1; or, R c is independently selected from hydrogen, halogen, hydroxyl, amine, nitrile, oxo, or optionally substituted from 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, phenyl, 5-6 membered heteroaryl; the optional substitution means that the unsubstituted or substituted group is independently substituted at ^{one or} more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions; _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 substituted by R ^c1 ; or, R ^c is independently selected from hydrogen, halogen, hydroxyl, amino, nitrile, pendoxy, or optionally substituted C _1-4 alkyl; the optional substitution means that one or more (e.g., 2, 3) substitutable positions of the unsubstituted or substituted group are independently substituted by R ^c1 ; or, R ^c is independently selected from hydrogen, halogen, hydroxyl, amino, nitrile, pendoxy, or optionally substituted C _1-4 alkyl (preferably C _1-3 alkyl); or, R ^{R c} is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl; or, R ^c is independently selected from hydrogen, fluorine, chlorine; or, R ^c is independently selected from hydrogen.

In some embodiments, two R ^c together with the atoms to which they are attached form an optionally substituted 3-6 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, pendoxy, C _1-6 alkyl (preferably C _1-3 alkyl), C _1-6 alkoxy (preferably C _1-3 alkoxy), C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl group; or, two R c ^c together with the atoms to which they are attached form an optionally substituted 3-6 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitrile, oxadioxy, methyl, ethyl, methoxy, and ethoxy groups.

In some embodiments, wherein R ^c1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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 ; or, R ^c1 is independently selected from halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -R ^c2 , -OR ^c2 ; or, R ^c1 is independently selected from halogen (e.g., fluorine, chlorine, bromine).

In some embodiments, R ^c2 and R ^c3 are independently selected from hydrogen, optionally substituted by the following groups: 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) groups selected from halogen, hydroxyl, amino, nitrile, C _1-6 alkyl, C _1-6 alkoxy; or, R ^c2 and R ^c3 are independently selected from hydrogen, optionally substituted by the following groups: C _1-4 alkyl (preferably C _1-3 alkyl), C _1-4 alkoxy (preferably C _1-3 alkoxy groups); the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from halogen, hydroxyl, amino, and nitrile groups; or, R ^c2 and R ^c3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

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.

In some embodiments, wherein L ₃ is independently selected from a bond, -C( ^RL3 ) _2- , -O-, -C(O)-, -N( ^RL3 )C(O)-, -C(O)N( ^RL3 )-; ^RL3 is selected from hydrogen, or an optionally substituted _C1-6 alkyl, _C1-6 alkoxy; the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amine, nitrile, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 3-6 membered heterocyclic group; or, L ₃ is independently selected from a bond, -C( ^RL3 ) _2- , -C(O)-; R ^L3 is selected from hydrogen, or optionally substituted _C1-4 alkyl, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from halogen, hydroxyl, amino, and nitrile; or, _L3 is independently selected from a bond, -C( ^RL3 ) _2- , or -C(O)-; ^RL3 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, or n-butyl; in some embodiments, wherein, _L3 is independently selected from a bond, _-CH2- , -CH( _CH3 )-, -O-, -C(O)-, -NHC(O)-, or -C(O)NH-; or, _L3 is independently selected from a bond, _-CH2- , or -C(O)-; or, _L3 is independently selected from a bond.

In some embodiments, wherein ring D is selected from C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; or, ring D is selected from C _3-8 carbocyclyl, 3-8 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl; or, ring D is selected from C _3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl; the hetero atom in the heterocyclyl or heteroaryl is selected from N, O or S, and the number of hetero atoms is 1, 2 or 3.

In some embodiments, wherein ring D is independently selected from C _3-10 carbocyclyl; or, ring D is independently selected from C _3-6 carbocyclyl.

In some embodiments, wherein Ring D is independently selected from a 3-10 membered heterocyclic group; Or, Ring D is independently selected from a 3-6 membered heterocyclic group.

In some embodiments, 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.

In some embodiments, Ring D is selected from tetrahydropyranyl, morpholinyl, piperidinyl, pyrazinyl, and tetrahydrofuranyl; Or, Ring D is selected from tetrahydropyranyl.

In some embodiments, wherein Ring D is independently selected from 、 、 ; Alternatively, Ring D is independently selected from .

In some embodiments, wherein Ring D is independently selected from 、 、 、 ; Alternatively, Ring D is independently selected from .

In some embodiments, wherein ring D is independently selected from C _6-10 aryl, 5-10 membered heteroaryl; or, ring D is independently selected from C _6-8 aryl, 5-8 membered heteroaryl, the hetero atom in the heteroaryl is selected from N, O or S, and the number of hetero atoms is 1 or 2; or, ring D is independently selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, the hetero atom in the heteroaryl is selected from N, O or S, and the number of hetero atoms is 1 or 2; or, ring D is independently selected from phenyl, pyridyl, pyrrolyl, furanyl, thienyl; or, ring D is independently selected from pyridyl.

In some embodiments, wherein ^Rd is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -C(O) ^Rd1 , -C(O) ^ORd1 , -OC(O) ^Rd1 , -N( ^Rd1 )( ^Rd2 ), -C( ^O )N( ^Rd1 )(Rd2), -N( ^Rd1 )C(O)( ^Rd2 ), optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) ^Rd3 , _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclic, C _6-8 membered aryl, 5-6 membered heteroaryl; or, R ^d is independently selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -N(R ^d1 )(R ^d2 ), -C(O)N(R ^d1 )(R ^d2 ), -N(R ^d1 )C(O)(R ^d2 ), or the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^d3 : 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; or, R ^d is independently selected from halogen, hydroxyl, amino, nitrile, the following groups optionally substituted by one or more (e.g., 2, 3) R ^d3 : C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, 4-5 membered heterocyclic group; the hetero atom in the heterocyclic group is O or N, and the number of hetero atoms is 1 or 2; or, R ^{d is independently selected from halogen, hydroxyl, amino, nitrile, the following groups optionally substituted by one or more (e.g., 2, 3) R d3} : C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, 4-5 membered heterocyclic group; the hetero atom in the heterocyclic group is O or N, and the number of hetero atoms is _{1 or 2} ; _3-4 membered cycloalkyl, 4-5 membered heterocyclic group; the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3) substituents selected from halogen, hydroxyl, and amino; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

In some embodiments, wherein R ^d is independently selected from halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -N(R ^d1 )(R ^d2 ), -C(O)N(R ^{d1 )(R d2 )} , -N(R ^d1 )C(O)(R ^d2 ), the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^d3 : C _1-6 alkyl, C _1-6 alkoxy; or, R ^d is independently selected from halogen, hydroxyl, amine, nitrile, the following groups optionally substituted with one or more (e.g., 2, 3, 4) R ^d3 : C _1-4 alkyl, C _1-4 alkoxy; or, R ^d is independently selected from halogen, hydroxyl, amino, nitrile, and optionally substituted _C1-4 alkyl (preferably _C1-3 alkyl), _C1-4 alkoxy (preferably _C1-3 alkoxy). The optional substitution means unsubstituted or substituted with one or more (e.g., 2 or 3) substituents selected from halogen, hydroxyl, and amino.

In some embodiments, R ^d is independently selected from halogen, hydroxyl, amino, nitrile, and optionally substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, and ethoxy; the optional substitution means unsubstituted or substituted with one or more (e.g., 2, 3) substituents selected from halogen, hydroxyl, and amino; preferably, R ^d is independently selected from methyl, methoxy, and ethoxy.

In some embodiments, two R ^d together with the atoms to which they are attached form an optionally substituted: 3-10 membered heterocyclic group, 3-7 membered cycloalkyl group or 5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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 group; or, two R ^d, together with the atoms to which they are attached, form an optionally substituted: 3-6 membered heterocyclic group (e.g., 3-, 4-, 5-, or 6-membered heterocyclic group), 3-6 membered cycloalkyl group (e.g., 3-, 4-, 5-, or 6-membered cycloalkyl group) or 5-6 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, or ethoxy.

In some embodiments, R ^d1 and R ^d2 are independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl (preferably C _1-3 alkyl), C _1-6 alkoxy (preferably C _1-3 alkoxy), C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, and 5-6 membered heteroaryl; wherein 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, hydroxyl, amino, nitro, alkyl, nitrile, pentooxy, C _{1-6 alkyl, C 1-6 alkoxy} , C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, and 5-6 membered heteroaryl; or, R ^d1 R d1 and R ^d2 are each 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, hydroxyl, and amino; or, R ^d1 and R ^d2 are each independently selected from hydrogen.

In some embodiments, R ^d3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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 .

In some embodiments, R ^d3 is independently selected from hydrogen, halogen, hydroxyl, amino, -R ^d4 ; R ^d4 is independently selected from C _1-6 alkyl, C _1-6 alkoxy; the C _1-6 alkyl, C _1-6 alkoxy is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from hydrogen and halogen; or, R ^d3 is independently selected from hydrogen, halogen, hydroxyl, amino, -R ^d4 ; R ^d4 is independently selected from C _1-4 alkyl, C _1-4 alkoxy; the C _1-4 alkyl, C _1-4 alkoxy is optionally substituted with one or more (e.g., 2, 3, 4 or 5) substituents selected from hydrogen and halogen; or, R ^d3 is independently selected from hydrogen, halogen, hydroxyl, amino, and ^-Rd4 ; ^Rd4 is independently selected from _C1-3 alkyl and _C1-3 alkoxy; and the _C1-3 alkyl and _C1-3 alkoxy groups are optionally substituted with one or more (e.g., 2 or 3) substituents selected from hydrogen and halogen.

In some embodiments, R ^d3 is independently selected from hydrogen and halogen; or, R ^d3 is independently selected from hydrogen, fluorine, and chlorine.

In some embodiments, R ^d4 and R ^d5 are independently selected from hydrogen, an optionally substituted C _1-4 alkyl group, a C _1-4 alkoxy group, a C _3-6 cycloalkyl group, a 3-6 membered heterocyclic group, a phenyl group, and a 5-6 membered heteroaryl group; 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, hydroxyl, amino, nitrile, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, and ethoxy; or, R ^d4 and R ^d5 are independently selected from hydrogen, a C _1-4 alkyl group; the C _1-4 alkyl group is optionally substituted by one or more (e.g., 2, 3, or 4) substituents selected from hydrogen and a halogen; Preferably, R ^d4 and R ^d5 are independently selected from hydrogen and C _1-3 alkyl; the C _1-3 alkyl is optionally substituted with one or more (e.g., 2, 3) substituents selected from hydrogen and halogen.

In some embodiments, R ^d4 and R ^d5 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl.

In some embodiments, p is independently selected from 0, 1, and 2; or, p is independently selected from 1 and 2; or, p is 2.

In some embodiments, wherein L ₄ 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 and L _4y are independently selected from a bond, or an optionally substituted C _1-6 alkylene (preferably C _1-3 alkylene), the optional substitution means that the unsubstituted or substituted group is substituted with one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substitutable positions independently selected from deuterium, halogen, hydroxyl, amino, nitrile, pendoxy, C _1-4 alkyl, C _1-4 alkoxy, C _3-16 cycloalkyl, 3-6 membered heterocyclic group; ^RL4a and ^RL4b 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 C _1-3 alkoxy), C The optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions of the substituted group are independently substituted with a substituent selected from _deuterium , halogen, hydroxyl, amino, nitrile, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or 3-6 membered heterocyclic group.

In some embodiments, wherein L ₄ is selected from -L _4x -N(R ^14a )-L _4y -, -L _4x -N(R ^14a )C(O)N(R ^14b )-L _4y -, -L _4x -N(R ^14a )C(S)N(R ^14b )-L _4y -; L _4x and L _4y are independently selected from a bond, or an optionally substituted methylene or ethylene, wherein the optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions are independently substituted with a substituent selected from fluorine, chlorine, bromine, hydroxyl, amino, nitrile, or pendoxy; R ^14a , R ^L4b is independently selected from hydrogen, or optionally substituted: methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropane, cyclobutane, wherein the optional substitution means that it is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted with a substituent selected from fluorine, chlorine, bromine, hydroxyl, amino, and nitrile.

In some embodiments, wherein _L 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-; or, _L is selected from -NHC(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, -N(methyl)C(O)NH-; or, _L is selected from -NHC(O)NH-.

In some embodiments, wherein _L4 is selected from ; Ring L _4Z is independently selected from C _3-10 carbocyclic group, 5-10 member heterocyclic group, C _6-8 aryl group, 5-10 member heteroaryl group; L _4x and L _4y are independently selected from a bond, or an optionally substituted C _1-6 alkylene group (preferably C _1-3 alkylene group, more preferably C _1-2 alkylene group); the optional substitution means that the substituted group is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions are independently substituted by a group selected from deuterium, halogen, hydroxyl, amino, nitrile, pendyloxy, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 member heterocyclic group; R ^L4z is independently selected from hydrogen, halogen, pendyloxy, or the following optionally substituted groups: _C1-6 alkyl, _C1-6 alkoxy; the optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions of the substituted group are independently substituted with a group selected from deuterium, halogen, hydroxyl, amino, nitrile, _C1-4 alkyl, _C1-4 alkoxy, C3-6 cycloalkyl, and _3-6 membered heterocyclic groups; r is independently selected from 0, 1, and 2.

In some embodiments, wherein _L4 is selected from ; Ring L _4Z is selected from 5-10 membered heterocyclic groups, phenyl groups, 6-8 membered monocyclic heteroaryl groups, 8-10 membered bicyclic heteroaryl groups; L _4x and 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 positions of the substituted group are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, nitrile, and oxo groups; R ^L4z are independently selected from hydrogen, halogen, oxo, or the following optionally substituted groups: C _1-4 alkyl, C _1-4 alkoxy groups, wherein the optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3) substitutable positions of the substituted group are independently substituted with a group selected from halogen, hydroxyl, amino, and nitrile; and r is independently selected from 0 and 1.

In some embodiments, wherein _L4 is selected from Ring L _4Z is selected from a 5-10 membered heterocyclic group (preferably a 5-6 membered heterocyclic group), a phenyl group, a 6-8 membered monocyclic heteroaryl group; R ^L4z is independently selected from hydrogen, fluorine, chlorine, bromine, a pendoxy group, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, and monochloromethyl; r is independently selected from 1.

In some embodiments, wherein _L4 is selected from , where the "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E; or, L ₄ is independently selected from , where the "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E; or, L ₄ is independently selected from , where the "#" end is connected to ring B, and the "##" end is connected to ring E.

In some embodiments, _L4 is -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E.

In some embodiments, _L4 is -NHC(O)NH-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E.

In some embodiments, wherein ring E is independently selected from C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; or, ring E is independently selected from C _3-8 carbocyclyl, 3-8 membered heterocyclyl, phenyl, naphthyl, 5-10 membered heteroaryl; or, ring E is independently selected from C _3-6 carbocyclyl, 3-6 membered heterocyclyl, phenyl, naphthyl, 5-10 membered heteroaryl; the hetero atom in the heterocyclyl or heteroaryl is selected from N, O or S, and the number of hetero atoms is 1, 2 or 3.

In some embodiments, wherein, Ring E is independently selected from C _3-10 carbocyclyl; or, Ring E is independently selected from C _3-6 carbocyclyl.

In some embodiments, wherein Ring E is independently selected from a 3-10 membered heterocyclic group; Or, Ring E is independently selected from a 3-6 membered heterocyclic group.

In some embodiments, wherein ring E is independently selected from C _6-10 aryl, 5-10 membered heteroaryl; or, ring E is independently selected from phenyl, naphthyl, 5-10 membered heteroaryl, the hetero atom in the heteroaryl is selected from N, O or S, and the number of hetero atoms is 1, 2 or 3; or, ring E is independently selected from phenyl, naphthyl, 8-9 membered bicyclic heteroaryl; the hetero atom in the heteroaryl is selected from N, O or S, and the number of hetero atoms is 1, 2 or 3; or, ring E is independently selected from 9 membered bicyclic heteroaryl; the hetero atom in the heteroaryl is selected from N, O or S, and the number of hetero atoms is 1, 2 or 3.

In some embodiments, 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, or 6-membered/6-membered fused heteroaryl; the heteroatom in the heteroaryl group is selected from N, O, or S, and the number of heteroatoms is 1 or 2. Alternatively, Ring E is independently selected from 5-membered/6-membered fused heteroaryl, or 6-membered/5-membered fused heteroaryl; the heteroatom in the heteroaryl group is selected from N, O, or S, and the number of heteroatoms is 1 or 2.

In some embodiments, Ring E is independently selected from phenyl, naphthyl, pyridyl, pyrrolyl, furanyl, thienyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, indazolyl; Or, Ring E is independently selected from indazolyl.

In some embodiments, wherein Ring E is independently selected from ; Alternatively, Ring E is independently selected from and .

In some embodiments, wherein Ring E is independently selected from ; Alternatively, Ring E is independently selected from 、 and ; Alternatively, Ring E is independently selected from and .

In some embodiments, wherein ^Re is independently selected from deuterium, halogen, hydroxyl, amine, nitro, nitrile, -OR ^e1 , -SO ₂ ( ^Re1 ), -C(O)Re1, -C(O)OR ^e1 , -OC(O) ^Re1 , -N( ^Re1 )( ^Re2 ), -C(O)N( ^Re1 )( ^Re2 ), -N( ^Re1 )C(O)( ^Re2 ), -S(O)N( ^Re1 )( ^Re2 ), -SO ₂ N( ^Re1 )( ^Re2 ), -N( ^Re1 )SO ₂ ( ^Re2 ), -P(O)( ^Re1 ) ^{(Re2 )} , or optionally substituted 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 heterocyclic group, phenyl, 5-6 membered heteroaryl; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted by R ^e3 ; or, R ^e is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -OR ^e1 , -N(R ^e1 )(R ^e2 ), -SO ₂ (R ^e1 ), -C(O) ^{R e1} , -SO ₂ N(R ^e1 )(R ^e2 ), -N(R ^e1 )SO ₂ (R ^e2 ), -P(O)(R ^e1 )(R ^e2 ), or the following optionally substituted groups: C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl (preferably C _3-5 cycloalkyl), 3-6 membered heterocyclic group; the optional substitution means that one or more (for example, 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted by R ^e3 ; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2; or, R ^e is independently selected from halogen, hydroxyl, amino, nitrile, -OR ^e1 , -N(R ^e1 )(R ^e2 ), -SO ₂ (R ^e1 ), -P(O)(R ^e1 )(R ^e2 ), or the following optionally substituted groups: C _1-4 alkyl, C _1-4 alkoxy, C _3-4 membered cycloalkyl, 4-5 membered heterocyclic group; 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 R ^e3 ; the heteroatom in the heterocyclic group is O or N, and the number of heteroatoms is 1 or 2; or, R ^e is independently selected from halogen, hydroxyl, amino, nitrile, -N(R ^e1 )(R ^e2 ), -P(O)(R ^e1 )(R ^e2 ), or the following optionally substituted groups: C _1-4 alkyl (preferably C _1-3 alkyl), C _1-4 alkoxy, C _3-4 membered cycloalkyl, 4-5 membered heterocyclic group; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4) substitutable positions of the substituted group are independently substituted with a substituent selected from halogen, hydroxyl, and amino groups; the heteroatom in the heterocyclic group is O, and the number of heteroatoms is 1.

In some embodiments, wherein R ^e is independently selected from halogen, hydroxyl, amine, nitrile, -N(R ^e1 )(R ^e2 ), -P(O)(R ^e1 )(R ^e2 ), or the following groups optionally substituted: C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl; the optional substitution means that one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted by R ^e3 ; or, R ^e is independently selected from halogen, hydroxyl, amine, nitrile, -N(R ^e1 )(R ^e2 ), -P(O)(R ^e1 )(R ^e2 ), or the following groups optionally substituted: C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl; the optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3) substitutable positions of the substituted group are independently substituted by R ^e3 .

In some embodiments, wherein R ^e is independently selected from halogen, hydroxyl, amino, nitrile, or the following optionally substituted groups: 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 the group is unsubstituted or one or more (e.g., 2, 3, 4) substitutable positions of the substituted group are independently substituted with a substituent selected from halogen, hydroxyl, amino, cyclopropyl, and methyl.

In some embodiments, wherein ^Re is independently selected from halogen, methyl, cyclopropyl, -NH(CH ₃ ), -P(O)(C ₂ H ₅ ) ₂ ; or, ^Re is independently selected from fluoro, methyl, cyclopropyl, -NH(CH ₃ ), -P(O)(C ₂ H ₅ ) ₂ .

In some embodiments, wherein, ^Re is fluoro, methyl, or cyclopropyl.

In some embodiments, wherein, ^Re is fluoro or cyclopropyl.

In some embodiments, wherein q is 2, ^Re is fluoro and cyclopropyl, respectively.

In some embodiments, wherein, for .

In some embodiments, wherein, for .

In some embodiments, wherein, with the proviso that ^Re is not methyl.

In some embodiments, wherein, the condition is that when ring E is or , Ring A is , and when q is 2, the two Re ^groups are not methyl and fluorine.

In some embodiments, wherein two R ^e together with the atoms to which they are attached form an optionally substituted 3-7 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, pendoxy, nitrile, C _1-4 alkyl, C _1-4 alkoxy groups; or, two R ^e together with the atoms to which they are attached form an optionally substituted 3-7 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxyl, amino, oxirane, nitrile, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy; or, two R ^e together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group or an optionally substituted 5-6 membered heteroaryl group, wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxyl, oxirane, amino, nitrile, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy; or, two ^Re (preferably, two adjacent ^Re ; further preferably, two adjacent Re located on different rings ⁾ ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4) groups selected from deuterium, fluorine, chlorine, bromine, hydroxyl, oxo, amino, nitrile, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy; 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, the heterocyclic group or heteroaryl group contains heteroatoms independently selected from N or O, and the number of heteroatoms is 1 or 2; 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 、 and Preferably, the 6-7 membered heterocyclic group is selected from 、 or , wherein * represents an atom shared with ring E; preferably, the combined three-membered ring formed by the 6-7 membered heterocyclic group and ring E is selected from 、 and .

In some embodiments, wherein, for 、 、 、 、 、 、 、 、 、 、 、 、 、 or .

In some embodiments, wherein, Selected from 、 、 、 and .

In some embodiments, wherein R ^e1 and R ^e2 are independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; or, R ^e1 and R ^e2 are independently selected from hydrogen, or optionally substituted C R e1 and R e2 are each 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 optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, and nitrile. Alternatively, R ^e1 and R ^e2 are each 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 optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from fluorine, chlorine, and nitrile.

In some embodiments, ^Re1 and ^Re2 are independently selected from hydrogen, hydroxyl, amino, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, _-CH2CN , _-CH2CH2CN , cyclopropyl, _cyclobutyl ; or, ^Re1 and ^Re2 are independently selected from hydrogen, methyl, ethyl.

In some embodiments, wherein R ^e3 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, nitrile, -R ^e4 , -OR ^e4 , -S(O) ₂ R ^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 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 )R ^e5 ; R ^e4 and R ^e5 are independently selected from hydrogen, or the following optionally substituted groups: C _1-6 alkyl, C wherein the substituted _1-6- membered alkyl radical is selected from the group consisting of C 1-4 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 heterocyclic group, phenyl, and 5-6-membered heteroaryl; wherein the substituted 1-6-membered alkyl radical is selected from the group consisting of C 1-4 alkoxy, C 2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclic group, phenyl, and 5-6-membered heteroaryl; wherein the substituted 1-6-membered alkyl radical is selected from the group consisting of C 1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclic group, phenyl, and 5-6-membered heteroaryl; or, R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^e4 )R ^e5 ; R ^e4 and 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, nitrile: 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 (for example, C _3-5 cycloalkyl, C _3-4 cycloalkyl).

In some embodiments, q is independently selected from 0, 1, 2, or 3; or, q is independently selected from 1, 2, or 3; or, q is 2 or 3.

In some embodiments, L _5x and L _5y are independently selected from a bond, or an optionally substituted C _1-6 alkylene group; 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 groups are independently selected from deuterium, halogen, hydroxyl, amino, nitrile, pendoxy, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclic groups; or, L _5x and L _{L 5x and L 5y} are each independently selected from a bond, hydrogen, an optionally substituted methylene, or an optionally substituted ethylene, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) selected from fluorine, chlorine, bromine, hydroxyl, amino, nitrile, and pendoxy groups; or, L _5x and L _5y are each independently selected from a bond.

In some embodiments, wherein R ¹ and R ² together with the atoms to which they are attached form a C _3-10 carbocyclic group; the C _3-10 carbocyclic group is optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ³ ; R ³ is independently selected from hydrogen, halogen, or an optionally substituted C _1-6 alkyl, C _1-6 alkoxy; the optional substitution means that the group is unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions of the substituted group are independently substituted by deuterium, halogen, hydroxyl, amino, nitrile, pentooxy, C _3-6 cycloalkyl, or 3-6 membered heterocyclic group; or, R ¹ and R ² together with the atoms to which they are attached form a C _3-8 carbocyclic group (preferably a C _3-6 carbocyclic group; further preferably a C _3-5 carbocyclic group, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group); the C _3-8 carbocyclic group is optionally substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) R ³ ; R ³ is independently selected from hydrogen, a halogen or an optionally substituted group of the following: C _1-5 alkyl, C _1-5 alkoxy; the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5) groups selected from halogen, hydroxyl, amino, nitrile; or, R ¹ and R ² together with the atoms to which they are attached form the following groups optionally substituted by one or more (e.g., 2, 3, 4, 5) R ³ : 3-membered carbocyclic group, 4-membered carbocyclic group, 3-membered/3-membered spirocarbocyclic group, 3-membered/4-membered spirocarbocyclic group, 3-membered/5-membered spirocarbocyclic group, 3-membered/6-membered spirocarbocyclic group; wherein R ³ is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl; or, R ¹ and R ² together with the atoms to which they are attached form a carbocyclic ring independently selected from , wherein the "~" end is connected to the end of L _5x , and the "~~" end is connected to the end of L _5y ; Alternatively, R ¹ and R ² together with the atoms to which they are connected form a carbon ring independently selected from , wherein the "~" end is connected to the end of L _5x , and the "~~" end is connected to the end of L _5y ; Alternatively, R ¹ and R ² together with the atoms to which they are connected form a carbon ring of , where the "~" end is connected to L _5x , and the "~~" end is connected to L _5y .

In some embodiments, wherein R ^f is independently selected from -C(O)OR ^f1 , -C(O)N(R ^f1 )(R ^f2 ); or, R ^f is independently selected from -C(O)OR ^f1 ; or, R ^f is independently selected from the following groups: -COOH.

In some embodiments, wherein ^Rf is independently selected from 、 、 、 ; Alternatively, R ^f is independently selected from .

In some embodiments, ^Rf1 , ^Rf2 , Rf3, ^Rf4 , ^Rf5 , ^Rf6 , and ^Rf7 are independently selected from hydrogen, deuterium, or ^the following optionally substituted groups: _C1-6 alkyl, _C1-6 alkoxy, _C3-6 carbocyclic group, 3-6 membered heterocyclic group, _C6-8 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, _C1-6 alkyl, _C1-6 alkoxy, _C2-4 alkenyl, _C2-4 alkynyl, C _3-6 membered cycloalkyl, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl group; or, R ^f1 , R ^f2 , R ^f3 , R ^f4 , R ^f5 , R ^f6 , R ^f7 are independently selected from hydrogen, deuterium, or the following groups optionally substituted: C _1-6 alkyl, C _1-6 alkoxy, C _3-6 carbocyclic group, 3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl group; the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitrile, pendyloxy, C _1-4 alkyl, C _1-4 alkoxy; or, R ^f1 , R ^f2 , R ^f3 , R ^{R f4} , R ^f5 , R ^f6 , and R ^f7 are independently selected from hydrogen, deuterium, or the following groups which are optionally substituted: C _1-4 alkyl, C _1-4 alkoxy, C _3-6 carbocyclic group, 3-6 membered heterocyclic group, 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) groups selected from halogen, hydroxyl, amino, nitrile, pendoxy, C _1-4 alkyl, C _1-4 alkoxy; or, R f1 , R ^f2 , R f3 , R ^f4 , R ^f5 , R ^f6 , and R ^f7 are independently selected from hydrogen, deuterium, or the following groups which are optionally substituted: C _1-3 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, phenyl, ^5-6 membered ^heteroaryl . The optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from halogen, hydroxy, amino, nitrile, pentooxy, C _{1-3 alkyl} , _{and C 1-3 alkoxy} .

In some embodiments, ^Rf1 , ^Rf2 , Rf3, ^Rf4 , ^Rf5 , ^Rf6 , and ^Rf7 are independently selected from hydrogen, deuterium ^, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, methyl, ethyl, n-propyl, isopropyl, methoxy, and ethoxy.

In some embodiments, ^Rf1 , ^Rf2 , ^Rf3 , ^Rf4 , ^Rf5 , ^Rf6 , and ^Rf7 are each independently selected from hydrogen.

In some embodiments, the compound must meet the following conditions: a) Ring C is not , wherein the "+" end is connected to the end of _L2 , the "++" end is connected to the end of _L3 , and the "+++" end is connected to the end of _L5x ; and/or b) _L4 is not , wherein the "#" end is connected to the end of ring B, and the "##" end is connected to the end of ring E; and/or c) when the compound structure represented by formula (I) is (wherein, R _xx is H or CH ₃ , and ^Re can be substituted on any ring of the bicyclic system), for or 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 substituted group are independently substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e3 )(R ^e4 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 )(R ^e5 ); R ^e4 and 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, and nitrile; 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, further 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, hydroxyl, nitrile, pentooxy, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C substituted with _6-14 membered aryl and 5-12 membered heteroaryl groups; and/or d) when the compound structure represented by formula (I) is (wherein R _xx is H or CH ₃ ), for .

In some embodiments, wherein Ring A is selected from phenyl, 3-6 membered heterocyclic group; Ring B is selected from 8-9 membered bicyclic heterocyclic group, 8-9 membered bicyclic heteroaryl group; Ring C is selected from 9 membered bicyclic heteroaryl group; Ring D is selected from 6 membered heterocyclic group, 6 membered heteroaryl group; Ring E is selected from C _6-8 aryl group, 5-10 membered heteroaryl group; ^Ra is independently selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, -C(O)N( ^Ra1 )( ^Ra2 ), -N( ^Ra1 )C(O)( ^Ra2 ), and optionally substituted following groups: C _1-6 alkyl, C _1-6 alkoxy, C _3-6 membered cycloalkyl, 3-6 membered heterocyclic group; 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; R ^b is independently selected from halogen, hydroxyl, amino, nitrile, oxo, C _1-6 alkyl at each occurrence; R ^c is independently selected from halogen, hydroxyl, amino, nitrile, oxo, C _1-6 alkyl at each occurrence; R ^d is independently selected from halogen, hydroxyl, amino, nitrile, oxo, or the following optionally substituted groups: 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; R ^e is independently selected at each occurrence from deuterium, halogen, hydroxyl, amino, nitrile, -OR ^e1 , -SO ₂ (R ^e1 ), -C(O)R ^e1 , -N(R ^e1 )(R ^e2 ), -SO ₂ N(R ^{e1 )(R e2 )} , -N(R ^e1 )SO ₂ (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, and ethyl; the optional substitution means that one or more (e.g., 2, 3, 4, or 5) substitutable positions of the unsubstituted or substituted groups are independently replaced by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (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 nitrile groups: C _1-6 alkyl, C _3-6 cycloalkyl (preferably C _3-5 cycloalkyl, preferably C _3-4 cycloalkyl, such as cyclopropyl and cyclobutyl); R ¹ and R ² together with the atoms to which they are attached form a C _3-8 carbocyclic group; the C _3-8 carbocyclic group is optionally substituted by one or more R ³ ; R ³ is independently selected from hydrogen, halogen, or the following optionally substituted groups: 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 nitrile; ^Rf is selected from -COOH, _L1 is selected from a bond, _-CH2- ; _L2 is selected from a bond, _-CH2- , -C(O)-; _L3 is selected from a bond, _-CH2- , -C(O)-; _L5x and _L5y are each independently selected from a bond; m, n, o, p, q, and r are each independently 0, 1, 2, or 3; _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- , where the "#" end is connected to ring B, and the "##" end is connected to ring E.

In some embodiments, Ring A is selected from phenyl and 3-6 membered heterocyclic groups; Ring B is selected from 9-membered bicyclic heterocyclic groups and 9-membered bicyclic heteroaryl groups; Ring C is selected from 9-membered bicyclic heteroaryl groups; Ring D is selected from 6-membered heterocyclic groups and 6-membered heteroaryl groups; the hetero atom in the 6-membered heterocyclic group is O, and the number of hetero atoms is 1; the hetero atom in the 6-membered heteroaryl group is N, and the number of hetero atoms is 1 or 2; 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; R ^a is independently selected from halogen, hydroxyl, amino, nitrile, and the following optionally substituted groups: C _1-4 alkyl, C _1-4 alkoxy, C _3-4 cycloalkyl, 4-5 membered heterocyclic group; 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, and amino; R ^b is independently selected from halogen, hydroxyl, amino, nitrile, oxo, and C _1-4 alkyl at each occurrence; R ^c is independently selected from halogen, hydroxyl, amino, nitrile, oxo, and C _1-4 alkyl at each occurrence; R ^d is independently selected from halogen, hydroxyl, amino, nitrile, or optionally substituted C _1-4 alkyl, C _1-4 alkoxy at each occurrence; the optional substitution means unsubstituted or substituted with one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxyl, and amino; R ^e 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 and R ^e2 are independently selected from hydrogen, methyl, and ethyl; the optional substitution refers to unsubstituted or one or more (e.g., 2, 3, 4, or 5) substitutable positions of the substituted group are independently substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), and -P(O)(R ^e4 )R ^e5 ; R ^e4 and 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 nitrile; R ¹ and R ² together with the atoms to which they are attached form a carbon ring independently selected from , wherein the "~" end is connected to the end of L _5x , and the "~~" end is connected to the end of L _5y ; R ^f is selected from -COOH, ; _L1 is selected from a bond, _-CH2- ; _L2 is selected from a bond, _-CH2- , -C(O)-; _L3 is selected from a bond, _-CH2- , -C(O)-; _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- , where the "#" end is connected to ring B, and the "##" end is connected to ring E; L _5x and L _5y are independently selected from keys; m, n, o, p, q, and r are each independently 0, 1, 2, and 3.

In some embodiments, wherein Ring A is selected from phenyl, 3-6 membered heterocyclic group; Ring B is selected from 9-membered paracyclic heterocyclic group, 9-membered bicyclic heteroaryl group; the hetero atom in the 9-membered paracyclic heterocyclic group and 9-membered bicyclic heteroaryl group is selected from N, and the number of hetero atoms is 1, 2 or 3; Ring C is selected from 9-membered bicyclic heteroaryl group; the hetero atom in the 9-membered bicyclic heteroaryl group is selected from N, and the number of hetero atoms is 1 or 2; Ring D is selected from tetrahydropyranyl and pyridyl; Ring E is selected from phenyl and indazolyl; ^Ra is independently selected from halogen, methyl and cyclopropyl at each occurrence; R ^b is independently selected from fluorine, chlorine, oxo, and methyl at each occurrence; R ^c is independently selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl at each occurrence; R ^d is independently selected from optionally substituted C _1-4 alkyl and optionally substituted C _1-4 alkoxy at each occurrence; the C _1-4 alkyl or C _1-4 alkoxy is optionally substituted with one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxy, and amino; R ^e is 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 positions of the unsubstituted or substituted group are independently substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e3 )(R ^e4 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^e4 )(R ^e5 ); R ^e4 and R ^e5 are independently selected from hydrogen or optionally substituted: C _1-6 alkyl (preferably C _1-3 alkyl, for example, methyl, ethyl), C _3-6 cycloalkyl (preferably C _3-5 cycloalkyl, preferably C _3-4 cycloalkyl, such as cyclopropyl, cyclobutyl), wherein the optional substitution means unsubstituted or substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, and nitrile; R ¹ and R ² together with the atoms to which they are attached form a carbon ring independently selected from , wherein the "~" end is connected to the end of L _5x , and the "~~" end is connected to the end of L _5y ; R ^f is selected from -COOH, ; L ₁ is selected from a bond, -CH ₂ -; L ₂ is selected from -C(O)-; L ₃ is selected from a bond; L ₄ is selected from -NHC(O)NH-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E; L _5x and L _5y are independently selected from keys; m, n, o, p, q, and r are each independently 0, 1, and 2.

In some embodiments, wherein Ring A is selected from phenyl; Ring B is selected from 、 , wherein the "*" end is connected to L ₁ , the "**" end is connected to L ₂ , and the "***" end is connected to L ₄ ; Ring C is selected from the following groups: , where the "+" end is connected to L ₂ , the "++" end is connected to L ₃ , and the "+++" end is connected to L _5x ; Ring D is ; Ring E is or ; L ₁ is selected from a bond; L ₂ is selected from -C(O)-; L ₃ is selected from a bond; L ₄ is selected from -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, , wherein the "#" end is the end connected to ring B, and the "##" end is the end connected to ring E; L _5x and L _5y are independently selected from a bond; ^Ra is independently selected from halogen, methyl, C _3-5 cycloalkyl-(CH ₂ ) _w - at each occurrence; R ^b is independently selected from fluorine, chlorine, oxo, and methyl at each occurrence; R ^c is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl at each occurrence; R ^d is independently selected from optionally substituted C _1-3 alkyl and optionally substituted C _1-3 alkoxy at each occurrence; 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; R ^e is independently selected at each occurrence from fluorine, or optionally substituted C _1-3 alkyl (e.g., methyl, ethyl), C _3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C _3-5 cycloalkyl-(CH ₂ ) _w -; provided that when L ₄ is When , at least one (e.g., 1 or 2) of ^Ra or the substituents on ring E (or ^Re ) is _C3-5 cycloalkyl -( _CH2 ) _w- ; or, two ^Re (preferably, two adjacent ^Re ; further preferably, two adjacent ^Re located on different rings) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group (e.g., a 5-membered, 6-membered or 7-membered heterocyclic group), the 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 substituted or one or more substitutable sites of the substituted group are independently substituted by ^Re3 ; ^R1 and R ² The carbon rings formed together with the atoms to which they are attached are independently selected from , where the "~" end is connected to L _5x , and the "~~" end is connected to L _5y ; R ^f is selected from m is 2 or 3; q is 1, 2 or 3; n, o, p are each independently 0, 1, 2; w is 0, 1 or 2; R ^e3 is as defined for the compound of formula (I); provided that the following compounds are not included: 、 .

In some embodiments, two ^Re (preferably, two adjacent ^Re ; more preferably, two adjacent ^Re located on different rings ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocyclic alkyl group) contains 1-3 (e.g., 1, 2, or 3) heteroatoms 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 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 、 and Preferably, the 6-7 membered heterocyclic group is selected from 、 or , wherein * represents an atom shared with ring E; preferably, the combined three-membered ring formed by the 6-7 membered heterocyclic group and ring E is selected from 、 and .

In some embodiments, the compound represented by formula (I) is a compound represented by the following formula: , , , , , , or Ring D, Ring E, ^Ra , ^Rb , ^Rc , ^Rd , Re, ^R1 , ^R2 , ^L1 , ^L4 , ^m , n, o, p, and q are as defined for the compound of formula (I).

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-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E; when L ₄ is , the substitution position of ^Ra on the benzene ring is or 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 substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e3 )(R ^e4 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^e4 )(R ^e5 ); R ^e4 and 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, and nitrile; 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, further 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, hydroxyl, nitrile, pentooxy, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 3-10 membered heterocyclic group, C substituted with _6-14 membered aryl and 5-12 membered heteroaryl groups.

In some embodiments, the compound represented by formula (I) is a compound represented by the following formula: Ring C, Ring E, ^Ra , ^Rb , ^Rc , ^Rd , Re, ^R1 , ^R2 , ^L1 , ^L4 , m, ⁿ , o, p, and q are as defined in the compounds of Formula (I), Formula (II), or Formulas (I-1) to (I-8); wherein Ring F is a _C3-6 cycloalkyl group.

In some embodiments, cycloF is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; preferably, cycloF is cyclopropyl.

In some embodiments, the compound represented by formula (I) is a compound represented by the following formula: Ring C, Ring B, ^Ra , ^Rb , ^Rc , ^Rd , ^Re , ^R1 , ^R2 , ^L1 , ^L4 , m, n, o, p, and q are as defined in the compounds of Formula (I), Formula (II), or Formulas (I-1) to (I-8); wherein Ring F is a _C3-6 cycloalkyl group.

In some embodiments, cycloF is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; preferably, cycloF is cyclopropyl.

In some embodiments, the compound represented by formula (I) is a compound represented by the following formula: Ring C, Ring E, ^Ra , ^Rb , ^Rc , ^Rd , Re, ^R1 , ^R2 , ^L1 , ^L4 , ^m , n, o, p, and q are as defined for the compounds of Formula (I) and Formula (I-1) to Formula (I-8).

In some embodiments, the compound represented by formula (II), wherein ring C is selected from the following groups: , where the "+" end is connected to -C(=O)-, the "++" end is connected to tetrahydropyran, and the "+++" end is connected to One end; the condition is that when ring C is , L ₄ is not ; or, when ring C is , L ₄ is , the substitution position of ^Ra on the benzene ring is or 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 an unsubstituted or substituted group are independently substituted by R ^e3 , and the substitution means that one or more (e.g., 2, 3, 4, 5) substitutable positions of an unsubstituted or substituted group are independently substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e3 )(R ^e4 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^{R e4} )(R ^e5 ); R ^e4 and 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 with one or more substituents selected from hydrogen, halogen, hydroxyl, amino, and nitrile; or two R ^e together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group (preferably a 5-7 membered heterocyclic group, such as a 5-membered heterocyclic group, a 6-membered heterocyclic group, or a 7-membered heterocyclic group; further preferably a 5-7 membered heterocycloalkyl group, such as a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, or a 7-membered heterocycloalkyl group), wherein the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, pentooxy, C _1-6 alkyl (preferably C _1-3 alkyl, such as methyl, ethyl), C _1-6 alkoxy (preferably C The present invention also provides _{a 3-} membered alkyl group, a C _1-3 alkoxy group, for example, a methoxy group, an ethoxy group), a C 3-10 cycloalkyl group, a 3-10 membered heterocyclic group, a C _6-14 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.

In some embodiments, Ring C is selected from the following groups: 、 、 , wherein the "+" end is connected to L ₂ , the "++" end is connected to L ₃ , and the "+++" end is connected to L _5x ; or, Ring C is selected from the following groups: 、 , where the "+" end is connected to _L2 , the "++" end is connected to _L3 , and the "+++" end is connected to _L5x .

In some embodiments, the compounds represented by formula (I), (I-1) to (I-8), (II), (II-1) or (II-2) as described above, wherein ring E is selected from phenyl and indazolyl; ^Ra is independently selected from halogen, methyl and cyclopropyl at each occurrence; ^Rb is independently selected from fluorine, chlorine, oxo and methyl at each occurrence; ^Rc is independently selected from fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl and n-butyl at each occurrence; ^Rd is independently selected from _C1-4 alkyl and _C1-4 alkoxy at each occurrence; the _C1-4 alkyl or _C1-4 alkoxy is optionally substituted with one or more (e.g., 2, 3, 4, 5) substituents selected from hydrogen, halogen, hydroxyl and amino; ^R1 and R ² The carbon rings formed together with the atoms to which they are attached are independently selected from , wherein the "~" end is connected to the end of L _5x , and the "~~" end is connected to the end of L _5y ; L ₄ 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-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E; m, n, o, p, q, and r are each independently 0, 1, and 2.

In some embodiments, the compound represented by formula (I), formula (I-1) to (I-8) or formula (II) as described above, wherein L ₄ 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-, , where the "#" end is connected to ring B, and the "##" end is connected to ring E.

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: 、 、 、 、 ,or , wherein Y ₁ is N, Y ₂ and Y ₃ are both C, and Y ₄ is C or CH; or, Y ₁ is C, Y ₂ is N, Y ₃ is C or CH, and Y ₄ is C; or, Y ₁ is C, Y ₂ is C, Y ₃ is C or CH, and Y ₄ is N; or, Y ₁ is C, Y ₂ is N, Y ₃ is N, and Y ₄ is C; Ring E, ^Ra , ^Rb , ^Rc , ^Rd , ^Re , ^R1 , ^R2 , ^L1 , ^L4 , m, n, o, p, and q are as defined in the compound of Formula (I), Formula (I-1) to Formula (I-8), or Formula (II).

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: 、 、 、 、 or wherein Ring E, ^Ra , ^Rb , ^Rc , ^Rd , Re, ^R1 , ^R2 , ^L1 , ^L4 , m, ⁿ , o, p, and q are as defined in the compound of Formula (I), (I-1) to (I-8), or (II).

In some embodiments, with the proviso that the following compounds are not included: 、 .

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): , Ring D is independently selected from 、 ; Ring E selected from 、 ; R ^a is selected from fluorine, methyl, and cyclopropyl; R ^b is selected from methyl; R ^c is selected from fluorine and chlorine; R ^d is selected from methyl, methoxy, and ethoxy; R ^e is selected from halogen, -N(R ^e1 )(R ^e2 ), -P(O)(R ^e1 )(R ^e2 ), or the following optionally substituted groups: C _1-6 alkyl (preferably C _1-3 alkyl, for example, methyl, ethyl), C _3-6 cycloalkyl (preferably C _3-5 cycloalkyl, for example, cyclopropyl, cyclobutyl); R ^e1 and R ^e2 are independently selected from hydrogen, methyl, and ethyl; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable positions of the substituted group are independently substituted by R ^e3 ; R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^e4 )R ^e5 ; R ^e4 and R ^e5 are independently selected from hydrogen or one or more of hydrogen, halogen, hydroxyl, amino, and nitrile groups, optionally substituted: C _1-6 alkyl or C _3-6 membered cycloalkyl; or, two R ^e together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the optional substitution means being unsubstituted or substituted with one or more (e.g., 2, 3, or 4) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, methyl, ethyl, methoxy, and cyclopropyl; L ₁ is independently selected from a bond; m, n, o, p, q, and r are each independently 0, 1, 2, or 3.

In some embodiments, ^Re is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; preferably, ^Re is cyclopropyl.

In some embodiments, wherein Ring D is independently selected from ; Ring E selected from ; ^Ra is selected from fluorine, methyl, and cyclopropyl; ^Rb is selected from methyl; ^Rc is selected from H; ^Rd is selected from methyl; ^Re is selected from a halogen, or an optionally substituted _C1-6 alkyl group (preferably a _C1-3 alkyl group, for example, methyl, ethyl), a _C3-6 cycloalkyl group (preferably a _C3-5 cycloalkyl group, for example, cyclopropyl, cyclobutyl); the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable positions of the substituted group are independently substituted by ^Re3 . R ^e3 is independently selected from deuterium, halogen, hydroxyl, amino, nitrile, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^e5 ), -P(O)(R ^e4 )R ^e5 ; R ^e4 and R ^e5 are independently selected from hydrogen or C _1-6 alkyl or C _3-6 membered cycloalkyl substituted with one or more of hydrogen, halogen, hydroxyl, amino, and nitrile; or, two R ^e together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, or 4) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, methyl, ethyl, methoxy, and cyclopropyl; L ₁ is independently selected from a bond; m, n, o, p, q, and r are each independently 0, 1, 2, or 3; provided that when q is 2, ^Re is F and methyl, respectively, and m is 3, Not for .

In some embodiments, the compound represented by formula (III) is a compound represented by formula (III-1): , wherein Ring E, Ring D, ^Ra , ^Rc , ^Rd , Re, ^L1 , ^m , o, p, and q are as defined for the compound of formula (III).

In some embodiments, the compound represented by formula (III) is a compound represented by formula (III-2): , wherein ring E, ^Ra , ^Rc , ^Rd , Re, ^L1 , m, o, p, and q are as defined for the compound ^of formula (III).

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 L ₄ is when at least one (e.g., one or two) of ^Ra or the substituents on ring E (or ^Re ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when neither Ra nor the substituents on ring E (or Re) are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, two ^Re (preferably, two ^Re located on different rings) are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl- ^ethylene , cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl- ^ethylene , ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 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 substituted or one or more substitutable positions of the substituted group are independently substituted by R ^e3 ; the R ^e3 is as defined in the compound of formula (I); preferably, the C _3-5 cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl; further preferably, it is cyclopropyl; provided that the following compounds are not included: 、 .

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 ^Ra 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 the substituents on ^Ra and ring E (or Re) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, ^two Re (preferably, two ^Re located on different rings) are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl- ^ethylene . ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 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 substituted or one or more substitutable positions of the substituted group are independently replaced by R ^e3 ; the R ^e3 is as defined for the compound of formula (I); preferably, the C _3-5 cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; further preferably, it is cyclopropyl.

In some embodiments, two ^Re (preferably, two adjacent ^Re ; more preferably, two adjacent ^Re located on different rings ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocyclic alkyl group) contains 1-3 (e.g., 1, 2, or 3) heteroatoms 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 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 、 and Preferably, the 6-7 membered heterocyclic group is selected from 、 or , wherein * represents an atom shared with ring E; preferably, the combined three-membered ring formed by the 6-7 membered heterocyclic group and ring E is selected from 、 and .

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): , Ring E selected from and ; ^Ra is independently selected at each occurrence from fluorine, methyl and _C3-5 cycloalkyl; m is 2 or 3; q is 2 or 3; ^Re is independently selected at each occurrence from fluorine, or an optionally substituted _C1-3 alkyl (e.g., methyl, ethyl), _C3-5 cycloalkyl; provided that at least one (e.g., one or two) of ^Ra or ^Re is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, two ^Re (preferably, two adjacent ^Re ; further preferably, two adjacent ^Re located on different rings) are selected from the group consisting of fluorine, methyl, and C3-5 cycloalkyl; ) together with the atoms to which they are attached 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; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable positions of the substituted group are independently replaced by R ^e3 ; R ^e3 is independently selected from deuterium, halogen (e.g., fluorine, chlorine), hydroxyl, amino, oxirane, nitrile, -R ^e4 , -OR ^e4 , -S(O) ₂ R ^e4 , -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -S(O) ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 )R ^e5 ; R ^e4 and R ^e5 are independently selected from hydrogen or C 1-3 alkyl (e.g., methyl, ethyl, propyl) or C _3-6 membered cycloalkyl (preferably 3-5 membered cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl) arbitrarily substituted by one or more (e.g., 2 or ₃ ) of hydrogen, deuterium, halogen (e.g., fluorine or chlorine), hydroxyl, amino, nitrile, oxo, or methoxy groups; preferably, the C _3-5 cycloalkyl is selected from cyclopropyl, cyclobutyl, and cyclopentyl; more preferably, it is cyclopropyl.

In some embodiments, two ^Re (preferably, two adjacent ^Re ; more preferably, two adjacent ^Re located on different rings ) together with the atoms to which they are attached form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocyclic alkyl group) contains 1-3 (e.g., 1, 2, or 3) heteroatoms 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 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 、 and Preferably, the 6-7 membered heterocyclic group is selected from 、 or , wherein * represents an atom shared with ring E; preferably, the combined three-membered ring formed by the 6-7 membered heterocyclic group and ring E is selected from 、 and .

In some embodiments, with the proviso that the following compounds are not included: .

In some embodiments, wherein, for 、 、 、 、 、 、 、 、 、 、 、 、 or ; preferably, for 、 、 、 or .

In some embodiments, wherein, for or .

In some embodiments, wherein for Hour, for 、 、 、 or ; preferably, for ; when for Hour, for 、 、 or .

In some embodiments, the compound represented by formula (IV) is a compound represented by formula (IV-1): , wherein ring E, m, q, ^Ra , and ^Re are defined the same as those for the compound represented by formula (IV).

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): 、 、 、 、 、 or , in, Indicates whether the key exists or not; Indicates the presence or absence of ring G; when ring G is present, ring G is a C _3-5 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl); L is a bond, a C _1-3 alkylene group (e.g., methylene, ethylene, propylene; preferably methylene) or a C _1-3 alkyl group (e.g., methyl, ethyl, propyl; preferably methyl); or, L is combined with its adjacent R ₃ to form an optionally substituted 5-7 membered heterocyclic group, the heterocyclic group containing 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S, in which case ring G is absent; R ₃ is selected from H, F or methyl; R ₄ is selected from C _3-5 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl); Ring F is an optionally substituted 5-7 membered heterocyclic group, the 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 substituted or one or more substitutable positions of the substituted group are independently replaced by R ^e3 ; R ^e3 is independently selected from deuterium, halogen (e.g., fluorine, chlorine), oxo group, hydroxyl group, amino group, nitrile group, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^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) arbitrarily substituted by hydrogen, halogen (e.g. fluorine or chlorine), hydroxyl, amino, nitrile, oxo, methoxy: C _1-3 alkyl (e.g. methyl, ethyl, propyl) or C _3-6 membered cycloalkyl (preferably 3-5 membered cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl).

In some embodiments, the L is combined with its adjacent R ₃ to form an optionally substituted 6-7 membered heterocyclic group, wherein the heterocyclic group contains 1-3 (e.g., 1, 2, or 3) heteroatoms independently selected from N, O, or S; preferably, the 6-7 membered heterocyclic group is selected from 、 or Preferably, the 6-7 membered heterocyclic group is selected from 、 or , where * indicates shared atoms.

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

In some embodiments, in Formula (VIII) or Formula (VIII-1), for or .

In some embodiments, the compounds represented by formula (V) to (VIII) and formula (V-1) to (VIII-1) are compounds represented by formula (V-2) to (VIII-2): 、 、 or , wherein R, R ₃ , L, and ring F are as defined for the compounds represented by formulas (V) to (VIII), (V-1) to (VIII-1).

Based on the common knowledge in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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: Compound structure and number Compound structure and number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 62 63 64 65

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.

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

The hydrazine group of intermediate 1.1 reacts with intermediate 1.2 to obtain intermediate 1.3, and intermediate 1.3 is alkylated to obtain intermediate 1.4; the amine group of intermediate 1.3 is reacted to obtain intermediate 1.5; intermediate 2.1 is alkylated to obtain intermediate 2.2; the nitrile group of intermediate 3.1 is converted into intermediate 3.2 through reaction; there are two methods for synthesizing intermediate 4.1: Method 1: The amine group of intermediate 1.3 or 1.4 reacts with the amine group of intermediate 2.1 or 2.2 to obtain intermediate 4.1; Method 2: Intermediate 1.5 and intermediate 2.3 undergo Ullmann reaction to obtain intermediate 4.1; Intermediate 4.1 reacts with the carboxyl group of intermediate 3.2 to obtain the target compound. Note: The partial protection and deprotection reaction steps involved in this step have been omitted. _P1 is a protecting group (e.g., Boc, Bn, Cbz, etc.), _X1 is a leaving group (e.g., I, Cl, Br, etc.); Ring A, Ring B, Ring ^C , Ring ^D , Ring E, Ra, ^Rb , Rc, ^Rd , ^Re , ^R1 , ^R2 , _L1 , _L2 , _L3 , ^Rf , Re, ^L4 , _L5x , _L5y , m _, n, o, p, q, etc. are as defined for the compound of formula (I).

In a third aspect, the present invention provides a pharmaceutical composition comprising 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 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 salts thereof, optionally, further comprising a pharmaceutically acceptable excipient.

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- Administration of compounds of 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 with similar uses. 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 above-mentioned pharmaceutical composition can be prepared using conventional excipients in the field of pharmaceutical preparations by conventional preparation methods.

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 the salt or the 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 diseases; further preferably, the drug is a drug for treating and/or preventing GLP-1R-mediated diseases; further preferably, the drug is a drug for treating and/or prevent diseases caused by or mediated by decreased GLP-1R activity; further preferably, the drug is a drug for preventing and/or treating diseases by stimulating cascade signals mediated by GLP-1R; further preferably, the diseases include diabetes, overweight or obesity, non-alcoholic fatty liver disease, Alzheimer's disease, etc.; further preferably, the diabetes is type 2 diabetes.

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.

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 said 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 by 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.

In a sixth aspect, the present invention provides a method for treating a disease, comprising administering to a subject 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 VIII III-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, or the pharmaceutical composition 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 by 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.

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 thereof, or the pharmaceutical composition of the present invention is used in combination with another, two or more compounds or drugs having the same or similar indications.

The present invention also provides a composition comprising 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 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, or the pharmaceutical composition of the present invention, and another, two or more compounds having the same or similar indications.

Definition

Unless otherwise specified, the following terms used in this invention have the following meanings. A specific term, unless specifically defined, should not be considered ambiguous or unclear and 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 product or its active ingredient.

As used herein, C _mn means that the moiety has an integer number of carbon atoms in the given range. For example, "C _1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When any variable (e.g., ^Ra ) occurs more than once in the composition or structure of a compound, its definition is independent in each instance. Thus, for example, if a group, site, or atom is substituted with two ^Ras , each ^Ra has a separate option.

The term "plurality" 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.

“R ^b is independently selected from deuterium, halogen, hydroxyl, amino, nitro, oxirane, nitrile, oxirane, 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 heterocyclo, C _6-14 aryl, 5-12 membered heteroaryl” should be understood as “R ^b is independently selected from deuterium, halogen, hydroxyl, amino, nitro, oxirane, nitrile, oxirane, 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 "Optionally substituted _C2-6 alkynyl, optionally substituted _C3-10 cycloalkyl, optionally substituted 3-10 membered heterocyclic group, optionally substituted _C6-14 aryl, optionally substituted 5-12 membered heteroaryl". Other similar expressions of the present invention should be understood in the same manner as above.

The terms "optional," "optionally," "optionally," or "arbitrarily" 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.

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

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., _C1-10 alkyl), further preferably containing 1 to 8 carbon atoms ( _C1-8 alkyl), more preferably containing 1 to 6 carbon atoms (i.e., _C1-6 alkyl), more preferably containing 1 to 4 carbon atoms (i.e., _C1-4 alkyl), and more preferably containing 1 to 3 carbon atoms (i.e., _C1-3 alkyl). For example, " _C1-6 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.

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. An alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., _C2-10 alkenyl), more preferably 2-8 carbon atoms ( _C2-8 alkenyl), more preferably 2-6 carbon atoms (i.e., _C2-6 alkenyl), 2-5 carbon atoms (i.e., _C2-5 alkenyl), 2-4 carbon atoms (i.e., _C2-4 alkenyl), 2-3 carbon atoms (i.e., _C2-3 alkenyl), or 2 carbon atoms (i.e., C2 _alkenyl ). For example, " _C2-6 alkenyl" means that the group is 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.

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. An alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., _C2-10 alkynyl), more preferably 2-8 carbon atoms ( _C2-8 alkynyl), more preferably 2-6 carbon atoms (i.e., _C2-6 alkynyl), 2-5 carbon atoms (i.e., _C2-5 alkynyl), 2-4 carbon atoms (i.e., _C2-4 alkynyl), 2-3 carbon atoms (i.e., _C2-3 alkynyl), or 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.

Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6), more preferably 1-4 carbon atoms, more preferably 1-3 carbon atoms, and even more preferably 1-2 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.

Unless otherwise specified, the term "alkylamino" refers to -NR'R", wherein R' and R" are the same or different and may be H or an alkyl group as defined above. The alkyl group is as defined above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6), more preferably 1-4 carbon atoms, more preferably 1-3 carbon atoms, and even more preferably 1-2 carbon atoms. Representative examples include, but are not limited to, -NH( _CH3 ), -N( _CH3 )( _CH3 ), _-N ( _CH2CH3 )( _CH3 ), -N( _CH2CH3 )[CH( _CH3 ) ₂ ], and _the like.

Unless otherwise specified, the term "halogen" or "halogenated" refers to F, Cl, Br, or I. The _term "haloalkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or _all hydrogen atoms, are replaced by a halogen. Representative examples of haloalkyl groups include CCl₃, _CF₃ , _CHCl₂ , _CH₂Cl , _CH₂Br , _CH₂I , _CH₂CF₃ , and _{CF₂CF₃ .}

Unless otherwise specified, the term "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon group having from 3 to 15 ring carbon atoms (" _C3-15 carbocyclyl") and no heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has 3 to 15 ring carbon atoms (" _C3-15 carbocyclyl"), 3 to 14 ring carbon atoms (" _C3-14 carbocyclyl"), 3 to 12 ring carbon atoms (" _C3-12 carbocyclyl"), or 4 to 12 ring carbon atoms (" _C4-12 carbocyclyl"), or 3 to 10 ring carbon atoms (" _C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“ _C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“ _C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“ _C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“ _C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“ _C5-10 carbocyclyl”), or 5 to 7 ring carbon atoms (“ _C5-7 carbocyclyl”), or 3 to 5 ring carbon atoms (“ _C3-5 carbocyclyl”). Exemplary _C3-6 carbocyclo 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. Exemplary _C3-8 carbocyclyl groups include, but are not limited to, the aforementioned _C3-6 carbocyclyl groups as well as cycloheptyl ( _C7 ), cycloheptenyl ( _C7 ), cycloheptadienyl ( _C7 ), cycloheptatrienyl (C7), cyclooctyl ( _C8 ), cyclooctenyl ( _C8 ), bicyclo[2.2.1]heptanyl ( _{C7 )} , bicyclo[2.2.2]octanyl ( _C8 ), and the like. Exemplary _C3-10 carbocyclyl groups include, but are not limited to, the aforementioned _C3-8 carbocyclyl groups as well as cyclononyl ( _C9 ), cyclononenyl ( _C9 ), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), octahydro-1H-indenyl ( _C9 ), decahydronaphthyl ( _C10 ), spiro[4.5]decyl ( _C10 ), and the like. As illustrated in the examples above, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or a fused (bicarbocyclyl), bridged (bridged) or spiro-fused (spirocyclyl) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment is on the carbocyclyl or aryl ring, and in such cases, the number of members of the carbocyclyl ring system is the number of carbon atoms in the carbocyclyl ring system after fusion. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted carbocyclyl") or substituted with one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted _C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted _C3-10 carbocyclyl.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic group having a specified number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., _C3-12 cycloalkyl), more preferably containing 3-10 carbon atoms ( _C3-10 cycloalkyl), further preferably 3-7 carbon atoms ( _C3-7 cycloalkyl), 3-6 carbon atoms ( _C3-6 cycloalkyl), 3-5 carbon atoms ( _C3-5 cycloalkyl), 3-4 carbon atoms (C3-4 cycloalkyl), _4-6 carbon atoms ( _C4-6 cycloalkyl), and 5-6 carbon atoms ( _C5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

Unless otherwise specified, the term "heterocyclic" 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 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, the ring contains 3 to 12 ring atoms (3-12 membered heterocyclic group), more preferably 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 4 to 5 ring atoms (4-5 membered heterocyclic group), or 3 to 5 ring atoms (3-5 membered heterocyclic group), or 5 to 7 ring atoms (5-7 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include bicyclic, spirocyclic, and bridged heterocyclic groups. A "heterocyclic group" may be a monocyclic ("monocyclic heterocyclic group") or a fused (heterocyclic group), bridged ("heterobridged heterocyclic group" or "bridged heterocyclic group"), or spiro ("heterospirocyclic group", "spiroheterocyclic group" or "spiroheterocyclic 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 hetero atoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is joined or fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or in which the heterocyclyl ring as defined above is joined or fused with one or more aryl or heteroaryl groups. In some embodiments, the present invention further includes a ring system in which a cycloalkyl ring is joined or fused to one or more heteroaryl groups, wherein the point of attachment is on the heterocycloalkyl ring, cycloalkyl ring, aryl ring, or heteroaryl ring, and in such cases, the number of members in the heterocycloalkyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of a heterocycloalkyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, oxolinyl, dithiolanyl, and dioxathiolanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexanyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azacycloheptanyl, oxadiazinyl, and thiacycloheptanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azacyclooctanyl, oxadiazinyl, and thiacyclooctanyl. Exemplary 5-membered heterocyclic groups fused to a C ₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

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

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.

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.

Unless otherwise specified, the term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, or 6-8 carbon atoms, preferably 6-10 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.

Unless otherwise specified, the term "heteroaryl" or "heteroarylcyclic group" refers to an aromatic monocyclic or polycyclic ring system having 5-14 members, or preferably 5-12 members, or preferably 5-10 members, or preferably 5-9 members, or preferably 5-8 members, or more preferably 5-6 members, wherein one, two, three 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 one, two or three. A polycyclic heteroaryl group is a fused heteroaryl group. 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, oxazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, 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]oxazinyl, [1,2,4]triazolo[4,3-b]oxazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

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 and may contain 5-20 ring atoms, preferably 6-14 ring atoms, and 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. The fused heteroaryl group includes a bicyclic, tricyclic, tetracyclic or polycyclic fused heteroaryl group, preferably a bicyclic, tricyclic or tetracyclic fused heteroaryl group, more preferably a bicyclic or tricyclic fused heteroaryl group. Illustrative examples of the fused heteroaryl group include (but are not limited to) wait.

In this article, 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 、 、 、 or ; This rule applies to any system of the present invention and is used here for illustrative purposes.

Throughout this disclosure, references to linking substituents (e.g., _L4x , _L4y , etc.) will be made. 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 the 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 the linking alkylene 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.

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 humans, without excessive toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. 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 an appropriate reagent.

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

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

Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., mirror isomers, non-mirror isomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing asymmetric centers, double-bonded (Z) and (E) isomers, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention or mixtures of mirror isomers, non-mirror isomers, or geometric isomers (or conformational isomers) thereof are within the scope of the present invention.

The compounds of the present invention also include isotopic derivatives thereof. Unless otherwise specified, the term "isotopic derivative" means that the compounds of the present invention may exist in an isotopically marked or enriched form, containing one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the atom found in the largest amount in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopic labels include hydrogen isotopes ( ^2H and ^3H ); carbon isotopes ( ^13C and ^14C ); chlorine isotopes ( ^35Cl and ^37Cl ); fluorine isotopes ( ^18F ); iodine isotopes ( ^123I and ^125I ); nitrogen isotopes ( ^13N and ^15N ); oxygen isotopes ( ^15O , ^17O , and ^18O ); and sulfur isotope ^(35S ). These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. ³ H and ¹³ C are particularly widely used due to their ease of labeling and detection. Substitution with certain heavy isotopes, such as dihydrogen ( ² H), can enhance metabolic stability and extend half-life, thereby reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from pre-labeled starting materials using known synthetic techniques similar to those used for non-isotope-labeled compounds. Deuterated derivatives are preferred.

The compounds of the present invention also include their solvates or solvates. Unless otherwise specified, the terms "solvate" and "solvate" refer to a physical association of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In certain 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 arrangement and/or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solventization methods are well known in the art.

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 allows for the modification of the crystalline form of the active pharmaceutical ingredient, 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).

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 forms of a pharmaceutical raw material. A drug can exist in multiple crystalline forms. Different crystalline forms of the same drug may dissolve and be absorbed differently in the body, thereby affecting the dissolution and release of the drug product.

The compounds of the present invention also include their metabolites. Unless otherwise specified, the term "metabolite" refers to a product obtained by metabolism of a specific compound or its salt in the body. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, 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 mammals for a sufficient period of time.

The compounds of the present invention also include prodrugs thereof. Unless otherwise specified, the term "prodrug" refers to a drug that is converted to the parent drug in vivo. Prodrugs are often 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 themselves may be related to physicochemical properties. For example, they may be bioavailable via oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in drug 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, and the compound is subsequently metabolized and 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.

The word "comprise" or "include" and its English variants such as comprises or comprising should be construed in an open and non-exclusive sense, i.e., "including but not limited to".

The term "individual" may also be referred to as "object" or "subject" and refers to cells or animals, including but not limited to mammals, such as experimental animals or humans.

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 of the compounds of the present invention may be prepared from optical isomer starting materials or by separation of racemates.

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.

Unless otherwise specified, the term "treatment" 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 condition; or (c) ameliorating or eliminating the disease, disorder or condition or one or more symptoms associated with the disease.

Abbreviations used in the Preparative 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

This invention designs a class of structurally novel compounds, providing a new direction for the treatment of diseases such as diabetes, non-alcoholic fatty liver disease, Alzheimer's disease, and weight loss.

The beneficial effects of the present invention are:

The compounds of the present invention have achieved one or more of the following beneficial effects: (1) Enzyme tests showed that the compounds of the present invention have a strong stimulating effect on GLP-1R; (2) Pharmacokinetic tests in mice and/or rats showed that the compounds of the present invention have good oral properties. (3) In vivo efficacy in mice showed that the compounds of the present invention have excellent weight loss effects. (4) In vivo efficacy in mice showed that the compounds of the present invention have excellent blood sugar lowering effects. (5) Safety assessment tests showed that the compounds of the present invention have no off-target risk or very low off-target risk and good safety.

The present invention is further described below with reference to 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 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 this field. In addition, any methods and materials that are similar or equivalent to those described herein may be used in the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

The following are examples of preparation of exemplary compounds of the present invention.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-mass spectrometry (HPLC), and/or high resolution mass spectrometry (HRMS). NMR measurements were performed using a Bruker Avance neo 400 MHz (temperature: 60°C) and/or a Bruker AVANCE III 600. LC-MS was performed using an Agilent 1260 Infinity II-6120/6125MSD and/or a Waters ACQUITY QDa. HPLC was 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). HRMS was performed using an Aglient Accurate-Mass Q-TOF 6530.

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

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 )

Tert-butyl (S)-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). Methyl iodide (62 mg) and sodium hydride (32 mg) were then added 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, concentrated by filtration, and separated by column chromatography (hexane:ethyl acetate = 1:1 by volume) to afford intermediate 1.4-A (115 mg). ESI-MS (m/z): 389.2 [M+H] ⁺ .

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 )

Step 1: (S)-3-(3-(2- chloroethyl ) urea group )-2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -2,4,6,7- Tetrahydrogen -5 H - Pyrazole [4,3- c ] Pyridine -5- Synthesis of tert-butyl carboxylate

(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 complete, 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, and concentrated by filtration. 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] ⁺ ;

Step 2: (S)-2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -3-(2- Pentoxyimidazoline -1- base )-2,4,6,7- Tetrahydrogen -5 H - Pyrazolo [4,3- c ] Pyridine -5- Synthesis of tert-butyl carboxylate

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, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:1) to yield the product (300 mg). ESI-MS (m/z): 444.2 [M+H] ⁺ ;

Step 3: Intermediate Products 1.5-A Synthesis

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. Under a nitrogen atmosphere, the mixture was heated to 120°C and stirred for 4 hours. After the reaction was complete, the temperature was lowered, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by thin-layer chromatography (n-hexane:ethyl acetate = 1:2) to give intermediate product 1.5-A (50 mg). ESI-MS (m/z): 592.3 [M+H] ⁺ .

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 )

Step 1: 3-((5- bromine -2- Nitrobenzyl ) Amine ) C -1- Synthesis of alcohols

5-Bromo-2-nitrobenzaldehyde (100 mg) and 3-amino-1-propanol (144 mg) were dissolved in ethanol (10 mL). Tetraisopropyl titanium dioxide (1 g) was then added. After stirring at room temperature for 1 hour, sodium borohydride (50 mg) was added and stirred for two hours. The mixture was quenched with aqueous ammonia (6 mL). The reaction mixture was filtered, dried, and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield the product (78 mg). ESI-MS (m/z): 290.1 [M+H] ⁺ ;

Step 2: 9- bromine -3,4- dihydrogen -2H-[1,3] Oxazinyl [3,2-b] Synthesis of indazole

The product from step 1 (78 mg) was dissolved in a mixture of tert-butanol and water (15 mL/5 mL). Potassium hydroxide (61 mg) was added and the reaction was incubated at 85°C for 5 hours. The mixture was diluted with water (40 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 (ethyl acetate) to obtain the product (54 mg). ESI-MS (m/z): 253.2 [M+H] ⁺ ;

Step 3: Intermediate Products 1.5-B Synthesis

The product from step 2 (54 mg), (S)-tert-butyl 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-carboxylate (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 under nitrogen at 130°C for 4 hours. 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 the intermediate product 1.5-B (27 mg). ESI-MS (m/z): 614.4 [M+H] ⁺ .

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 )

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

Preparation Example 5 : Synthesis of (S)-3-(3-(2,3- dihydro- [1,4] oxazino [2,3,4,1- i ] 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 )

Step 1: 5- bromine -7- Hydroxyl -1H- Synthesis of indazole

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

Step 2: 8- bromine -2,3- dihydrogen -[1,4] Oxazino [2,3,4, hi ] Synthesis of indazole

5-Bromo-7-hydroxy-1H-indazole (150 mg) was dissolved in N,N-dimethylformamide (20 mL), and 1-bromo-2-chloroethane (102 mg) was added. The reaction was allowed to proceed at room temperature for 4 hours, then the temperature was 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 obtain 8-bromo-2,3-dihydro-[1,4]oxazinyl[2,3,4]indazole (100 mg). ESI-MS (m/z): 239.2 [M+H] ⁺ .

Step 3: Intermediate Products 1.5-D Synthesis

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

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 )

Step 1: (S)-2-(4- fluorine -3,5- Dimethylphenyl )-3-(((2-( Methoxycarbonyl ) hydrazine ) Methylene ) Amine )-4- methyl -2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

(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 h. After the reaction was complete, the temperature was lowered, the solvent was removed under reduced pressure, and methyl hydrazinecarboxylate (2.4 g) and p-toluenesulfonic acid (634 mg) were added. The mixture was stirred at 50°C for 2 h. After the reaction was complete, the temperature was lowered, and the mixture was extracted with water (100 mL) and ethyl acetate (50 mL x 3). The solvent was removed under reduced pressure, and the product was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (5.4 g). ESI-MS (m/z): 475.2 [M+H] ⁺ .

Step 2: (S)-2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -3-(5- Pendyl group -1,5- dihydrogen -4H-1,2,4- triazole -4- base )-2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

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

Step 3: Intermediate Products 1.5-E Synthesis

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

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 )

Step 1: 5- bromine -1- Cyclopropyl -4- fluorine -1H- Synthesis of indazole

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. The mixture was heated to 70°C and stirred for two hours. The mixture was filtered, and the filtrate was diluted with dichloromethane and washed with water (40 mL). The solvent was removed under reduced pressure, and column chromatography (n-hexane:ethyl acetate = 5:1) was performed to obtain the product (0.8 g). ESI-MS (m/z): 254.9 [M+H] ⁺ ;

Step 2: Intermediate Products 1.5-F Synthesis

Referring to Intermediate 1.5-A, the product from 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 starting materials to obtain Intermediate 1.5-F (250 mg). ESI-MS (m/z): 616.3 [M+H] ⁺ ;

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)

Step 1: 3- Cyclopropyl -4- Synthesis of Fluoroaniline

3-Bromo-4-fluoroaniline (10 g), cyclopropylboronic acid (5.9 g), potassium phosphate (39.1 g), sodium 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, the mixture was extracted with water (200 mL) and ethyl acetate (150 mL x 3). The product 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] ⁺ .

Step 2: (3- Cyclopropyl -4- Fluorophenyl ) Synthesis of hydrazine

The product from Step 1 (900 mg) and concentrated hydrochloric acid (30 mL) were added to a flask. 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 solution of stannous chloride in concentrated hydrochloric acid (0.33 M, 50 mL) was added dropwise at 0°C and the reaction was stirred at 0°C for 1 hour. After the reaction, water (150 mL) was added, and the pH was adjusted to 8 with saturated sodium hydroxide solution. Ethyl acetate (200 mL) was added, and 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, it was purified by column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the product (210 mg). ESI-MS (m/z): 167.1 [M+H] ⁺ .

Step 3: (S)-3- Amine -2-(3- Cyclopropyl -4- Fluorophenyl )-4- methyl -2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

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 (2 M, 100 μL) were added to a flask and stirred at 50°C. After the reaction, the product 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] ⁺ .

Step 4: (S)-2-(3- Cyclopropyl -4- Fluorophenyl )-3-(3-(2,2- Dimethoxyethyl ) urea group )-4- methyl -2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

The product from Step 3 (87 mg) and dichloromethane (2 mL) were added to a flask. 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 then added dropwise, and the reaction was continued at room temperature. After the reaction, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The product was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain the product (85 mg). ESI-MS (m/z): 518.3 [M+H] ⁺ .

Step 5: (S)-2-(3- Cyclopropyl -4- Fluorophenyl )-4- methyl -3-(2- Pendyl group -2,3- dihydrogen -1H- Imidazole -1- base )-2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

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 mixture 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, the product 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] ⁺ .

Step 6: Intermediate Products 1.5-G Synthesis

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

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 )

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

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 )

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

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 )

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

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 )

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

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

Step 1: N-(4- fluorine -1- methyl -1H- Indazole -5- base )-1,1- Synthesis of diphenylmethane

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-dimethyloxanthracene (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 complete, the mixture was cooled and 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, concentrated, and separated by column chromatography (hexane:ethyl acetate = 5:1) to afford the product (120 mg). ESI-MS (m/z): 330.1 [M+H] ⁺ ;

Step 2: Intermediate Products 2.1-A Synthesis

The product from Step 1 (120 mg) was added to a flask. 10 mL each of tetrahydrofuran and water were added. Citric acid (200 mg) was added under ice-cooling, and the mixture was stirred overnight at room temperature. After 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. Separation by column chromatography (hexane:ethyl acetate = 5:1) afforded the intermediate product 2.1-A (42 mg). ESI-MS (m/z): 166.1 [M+H] ⁺ .

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

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). The mixture was stirred at room temperature for two hours. After the reaction, 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, concentrated by filtration, and separated by column chromatography (hexane:ethyl acetate = 5:1) to afford the intermediate 2.2-A (103 mg). ESI-MS (m/z): 162.1 [M+H] ⁺ .

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 )

Step 1: (S)-2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -3-(3-(1- methyl -1H- Indazole -5- base ) urea group )-2,4,6,7- Tetrahydrogen -5H- Pyrazolo [4,3-c] Pyridine -5- Synthesis of tert-butyl carboxylate

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). The mixture was stirred at room temperature for two hours, and then (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. The reaction was stirred at room temperature overnight. After 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 separated by thin-layer chromatography (dichloromethane:methanol = 30:1, volume ratio) to obtain the product (153 mg). ESI-MS (m/z): 548.3 [M+H] ⁺ ;

Step 2: (S)-1-(2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -4,5,6,7- Tetrahydrogen -2H- Pyrazolo [4,3-c] Pyridine -3- base )-3-(1- methyl -1H- Indazole -5- base ) Synthesis of urea

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

Step 3: 1-((S)-5-(5-((S)-2,2- dimethyltetrahydrogen -2H- pyran -4- base )-1-((1S,2S)-2- methyl -1-(5- Pendyl group -4,5- dihydrogen -1,2,4- Oxadiazole -3- base ) Cyclopropyl )-1H- Indole -2- carbonyl )-2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -4,5,6,7- Tetrahydrogen -2H- Pyrazolo [4,3-c] Pyridine -3- base )-3-(1- methyl -1H- Indazole -5- base ) urea

The product of 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). HATU (85 mg) and DIPEA (29 mg) were then added, and the reaction was stirred at room temperature overnight. After the reaction, 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, concentrated by filtration, 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 O ₅ F: 841.3944. Found: 841.3950. HPLC retention time: 18.820 min. The structure was confirmed by ¹ H NMR (600 MHz, DMSO-d ₆ ).

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 )

Following the method of Example 1, compound 2 (60 mg) was obtained using N,1-dimethyl-1H-indazol-5-amine (intermediate 2.2-A) (50 mg). ESI-MS (m/z): 855.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. For C ₄₇ H ₅₁ N ₁₀ O ₅ F: 855.4101. Found: 855.4098. HPLC retention time: 19.002 min.

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 )

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

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 )

Following the method of Example 1, compound 4 (53 mg) was obtained using 4-fluoro-1-methyl-1H-indazol-5-amine (intermediate 2.1-A) (50 mg). ESI-MS (m/z): 859.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₄₆ H ₄₈ N ₁₀ O ₅ F ₂ : 859.3850. Found: 859.3843. HPLC retention time: 18.912 min.

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 )

Step 1: (S)-1-(4- fluorine -1- methyl -1 H - Indazole -5- base )-3-(2-(4- fluorine -3,5- Dimethylphenyl )-4- methyl -4,5,6,7- Tetrahydrogen -2 H - Pyrazole [4,3- c ] Pyridine -3- base ) imidazoline -2- Synthesis of ketones

(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 obtain the product (50 mg). ESI-MS (m/z): 492.2 [M+H] ⁺ ;

Step 2: Compound 5 Synthesis

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 the mixture was stirred at room temperature for 6 hours. After the reaction, water (40 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was 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 O ₅ F ₂ : 885.4006. Found: 885.4001; ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.80 (s, 1H), 8.25 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.50-7.44 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 5.7 Hz, 2H), 7.27 (d, J = 8.0 Hz, 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), δ δ: 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: 20.381 min.

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 )

According to the method of Example 5, compound 6 (43 mg) was obtained using (S)-tert-butyl 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-carboxylate (Intermediate 1.5-B) (27 mg) as starting material. ESI-MS (m/z): 907.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₅₀ H ₅₁ N ₁₀ O ₆ F: 907.4050. Found: 907.4058. HPLC retention time: 22.250 min.

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 )

According to the method of Example 5, compound 7 (10 mg) was obtained using (S)-tert-butyl 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-carboxylate (Intermediate 1.5-C) (24 mg) as starting material. ESI-MS (m/z): 907.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₅₀ H ₅₁ N ₁₀ O ₆ F: 907.4050. Found: 907.4044. HPLC retention time: 22.262 min.

Example 8 : Synthesis of 3-((1S,2S)-1-(2-((S)-3-(3-(2,3- dihydro- [1,4] oxazino [ 2,3,4-1H ] 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 )

According to the method of Example 5, starting from (S)-3-(3-(2,3-dihydro-[1,4]oxazino[ 2,3,4-1H ]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) was compound 8 (42 mg). ESI-MS (m/z): 893.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₄₉ H ₄₉ N ₁₀ O ₆ F: 893.3893. Found: 893.3884. HPLC retention time: 20.210 min. ^1H NMR (400 MHz, DMSO-d6, 80°C): See Figure 2.

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 )

According to the method of Example 5, compound 9 (13 mg) was obtained using (S)-tert-butyl 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-carboxylate (Intermediate 1.5-E) (42 mg) as starting material. ESI-MS (m/z): 884.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₄₇ H ₄₇ N ₁₁ O ₅ F ₂ : 884.3802. Found: 884.3812. HPLC retention time: 20.090 min.

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 )

According to the method of Example 5, compound 10 (196 mg) was obtained using (S)-tert-butyl 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-carboxylate (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 O ₅ F ₂ : 909.4006. Found: 909.4008. ¹ H NMR (600 MHz, DMSO-d ₆ , 60°C) results are shown in Figure 1. HPLC retention time: 21.060 min.

Example 11 : Synthesis of 3-((1S,2S)-1-(5-((4S)-2,2 -dimethyloxacyclohexan -4- yl )-2-((4S)-2-(4- fluoro -3 -cyclopropylphenyl )-3-(3-(4- fluoro - 1- cyclopropylindazol -5- yl )-2 -oxoimidazole -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)

According to the method of Example 5, compound 61 (41 mg) was obtained using (S)-tert-butyl 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 -carboxylate (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 O ₅ F ₂ : 895.3850. Found: 895.3846. HPLC retention time: 19.834 min.

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 )

According to the method of Example 5, compound 62 (40 mg) was obtained using (S)-tert-butyl 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-carboxylate (Intermediate 1.5-H) (50 mg). ESI-MS (m/z): 923.4 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₅₁ H ₅₂ N ₁₀ O ₅ F ₂ : 923.4163. Found: 923.4170. HPLC retention time: 21.515 min.

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 )

Referring to Example 5, starting from (S)-tert-butyl 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-carboxylate (Intermediate 1.5-I) (83 mg) was 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 O ₅ F ₂ : 905.4257. Found: 905.4266. HPLC retention time: 20.586 min.

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 )

Referring to Example 5, starting from (S)-tert-butyl 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-carboxylate (Intermediate 1.5-J) (140 mg) was compound 64 (130 mg). ESI-MS (m/z): 905.3 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₅₁ H ₅₃ N ₁₀ O ₅ F: 905.4257. Found: 905.4251. HPLC retention time: 21.285 min.

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 )

According to the method of Example 5, compound 65 (5.22 g ) was obtained using (S)-tert -butyl 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 -carboxylate (intermediate 1.5-K) (3.71 g) as starting material. ESI-MS (m/z): 923.3 [M+H] ⁺ ; HRMS (m/z): [M+H] ⁺ Calcd. for C ₅₁ H ₅₂ N ₁₀ O ₅ F ₂ : 923.4163. Found: 923.4169. HPLC retention time: 20.656 min. ¹ H NMR (400 MHz, DMSO-d6, 80°C): See Figure 3.

With reference to the preparation methods of the above-mentioned 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:

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: No. Structural ESI-MS (m/z) 11 839.4[M+H] ⁺ 12 839.4[M+H] ⁺ 13 827.4[M+H] ⁺ 14 839.4[M+H] ⁺ 15 827.4[M+H] ⁺ 16 840.4[M+H] ⁺ 17 828.4[M+H] ⁺ 18 853.4[M+H] ⁺ 19 899.4[M+H] ⁺ 20 899.4[M+H] ⁺ twenty one 939.4[M+H] ⁺ twenty two 887.4[M+H] ⁺

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: No. Structural ESI-MS (m/z) twenty three 897.4[M+H] ⁺ twenty four 897.4[M+H] ⁺ 25 885.4[M+H] ⁺ 26 897.4[M+H] ⁺ 27 885.4[M+H] ⁺ 28 898.4[M+H] ⁺ 29 886.4[M+H] ⁺ 30 911.4[M+H] ⁺

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: No. Structural ESI-MS (m/z) 31 882.4[M+H] ⁺ 32 870.4[M+H] ⁺ 33 882.4[M+H] ⁺ 34 870.4[M+H] ⁺ 35 882.4[M+H] ⁺ 36 870.4[M+H] ⁺ 37 883.4[M+H] ⁺ 38 871.4[M+H] ⁺ 39 896.4[M+H] ⁺

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: No. Structural ESI-MS (m/z) 40 893.4[M+H] ⁺ 41 911.4[M+H] ⁺

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: No. Structural ESI-MS (m/z) 42 921.4[M+H] ⁺ 43 907.4[M+H] ⁺ 44 895.4[M+H] ⁺ 45 907.4[M+H] ⁺ 46 895.4[M+H] ⁺ 47 907.4[M+H] ⁺ 48 895.4[M+H] ⁺ 49 908.4[M+H] ⁺ 50 896.4[M+H] ⁺ 51 942.4[M+H] ⁺ 52 943.4[M+H] ⁺ 53 942.4[M+H] ⁺ 54 942.4[M+H] ⁺ 55 930.4[M+H] ⁺ 56 931.4[M+H] ⁺ 57 930.4[M+H] ⁺ 58 956.4[M+H] ⁺ 59 923.4[M+H] ⁺ 60 937.4[M+H] ⁺

Test Example 1 : In vitro enzymatic test

Using GLP1R-cAmp-Luc cells, test compounds were tested for their GLP-1R stimulatory effects. 1) Dissolve the test compound in DMSO and mix thoroughly until completely dissolved. Prepare a 10 mM stock solution using DMSO. All test compounds were diluted in DMEM (high glucose, Puromycin ⁺ , Hygromycin B ⁺ ) to a starting concentration of 1250 nM and then diluted five-fold to a total of seven concentration steps. GLP1R-cAmp-Luc cells were seeded at a density of 1 × 10 ⁵ /mL in white-walled 96-well cell culture plates, with 90 μL of cell suspension per well. 10 μL of the test compound was added to each well across all seven concentration gradients, with the actual working starting concentration of the test compound being 125 nM. The cells were incubated in a 37°C, 5% CO ₂ 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 the cells were incubated at room temperature for 30 min. 3) The firefly luciferin fluorescence signal was measured using a multifunctional microplate reader (PerkinElmer, Nivo). GraphPad Prism software was used to process the fluorescence values and calculate the _EC50 value.

The compounds of the present invention exhibit potent GLP-1R agonism, with preferred compounds exhibiting agonistic activity ( _EC50 ) of less than or equal to 20 nM, more preferred compounds exhibiting agonistic activity (EC50 ₎ of less than or equal to 10 nM, more preferred compounds exhibiting agonistic activity ( _EC50 ) of less than or equal to 5 nM, more preferred compounds exhibiting agonistic activity ( _EC50 ) of less than or equal to 2 nM, and even more preferred compounds exhibiting agonistic activity ( _EC50 ) of less than or equal to ₁ nM. The activity results for exemplary compounds are shown in the table below. Compound number Agonist activity ( EC ₅₀ : nM ) Compound number Agonist activity ( EC ₅₀ : nM ) 1 A 6 A 2 A 7 A 3 A 8 A 4 A 9 A 5 A 10 A 61 A 62 A 63 A 64 A 65 A LY35029770 A Note: A represents _EC50 ≤ 10 nM.

Test Example 2 : In vivo pharmacokinetic study in mice

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

Experimental procedures: ICR mice were administered the test compound via tail vein injection or oral gavage. Whole blood samples were collected from the mice at 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 compound concentrations were measured by LC-MS/MS. Pharmacokinetic parameters such as plasma clearance (Cl), elimination half-life (T _1/2 ), peak time (Tmax), peak concentration (Cmax), and area under the concentration-time curve (AUC) were calculated using Winnolin software.

Intravenous dose: 2 mg/kg; oral dose: 10 mg/kg.

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

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. Compound IV (2 mg/kg) Oral (10 mg/kg) AUC _inf (h*ng/mL) C _max (ng/mL) _Tmax (h) AUC _inf (h*ng/mL) 8 7706 5377 1.33 41197 Note: Test results are available within 24 hours. Compound IV (2 mg/kg) Oral (10 mg/kg) Cl (mL/h/kg) AUC _inf (h*ng/mL) T _1/2 (h) C _max (ng/mL) _Tmax (h) T _1/2 (h) AUC _inf (h*ng/mL) F (%) 10 92.7 21599 10 8197 1.67 9.56 103132 95.5 Note: 72-hour test results. Compound IV (2 mg/kg) Oral (10 mg/kg) Cl (mL/h/kg) AUC _inf (h*ng/mL) T _1/2 (h) C _max (ng/mL) _Tmax (h) T _1/2 (h) AUC _inf (h*ng/mL) F (%) 10 102 19736 7.14 8197 1.67 7.77 95629 96.9 Note: 24-hour test results Compound IV (2 mg/kg) Oral (10 mg/kg) AUC _inf (h*ng/mL) C _max (ng/mL) _Tmax (h) AUC _inf (h*ng/mL) 61 7077 5103 1.00 42906 Note: 24-hour test results Compound IV (2 mg/kg) Oral (10 mg/kg) AUC _inf (h*ng/mL) C _max (ng/mL) _Tmax (h) AUC _inf (h*ng/mL) 41 7207 4557 1.67 43702 Note: 24-hour test results Compound IV (2 mg/kg) Oral (10 mg/kg) AUC _inf (h*ng/mL) C _max (ng/mL) _Tmax (h) AUC _inf (h*ng/mL) F (%) 65 17341 7807 1.67 85040 98.1 Note: 24-hour test results Compound IV (2 mg/kg) Oral (10 mg/kg) AUC _inf (h*ng/mL) C _max (ng/mL) _Tmax (h) AUC _inf (h*ng/mL) F (%) LY3502970 10268 2660 1.17 23822 46.4 Note: 24-hour test results

Test Example 3 : In vivo pharmacokinetic study in rats

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

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. Plasma was separated by centrifugation, and compound concentrations were measured by LC-MS/MS. Pharmacokinetic parameters such as plasma elimination half-life (T _{1/2 )} , peak time (T max ), peak concentration (C max ), and area under the concentration-time curve (AUC) were calculated using Winnolin software.

Intravenous dose: 2 mg/kg, oral dose: 10 mg/kg

The compounds of the present invention have excellent oral administration properties. The oral PK parameters of exemplary compounds are listed in the table below. Compared with LY3502970, they have better pharmacokinetic properties, especially better oral absorption properties. Compound C _max (ng/mL) _Tmax (h) T _1/2 (h) AUC _inf (h*ng/mL) 8 2947 2.0 3.86 24500 65 3190 3.33 7.47 31480 LY3502970 1006 2.0 6.86 9190

Test Example 4 : DIO C57BL/6 hGLP1R Weight loss efficacy study in mice

1. Purpose: To compare the weight loss efficacy of the test compound and LY3502970 at a dose of 0.3 mpk administered orally to obese mice.

2. Experimental animals

Animals (species: C57BL/6 humanized transgenic (hGLP1R) mice; age: 6 weeks; sex: male) were fed a high-fat diet (60 kcal% Fat) for at least 12 weeks after purchase, until their body weight reached 40 g or more.

3. Trial Groups Group medication Number of animals per group Dosage Dosage concentration Medication volume Dosage method Frequency of medication solvent mg/kg mg/mL mL/kg G1 Vehicle 5 0 0 5 ig qd 10% DMSO + 10% EL35 + 15% PEG400 + 65% (100mM glycine-NaOH buffer, pH=10) G2 10 5 0.3 0.06 ig qd G3 LY3502970 5 0.3 0.06 ig qd Note: ig stands for oral administration; qd stands for once daily.

4. Test methods

Before drug administration, mice were weighed and their daily food intake (one complete night + day) was measured. Mice were then divided equally into groups based on body weight and food intake.

The mice's body weight was measured at a fixed time each day, and the weight change rate was calculated. After measurement, the mice were given the corresponding medication according to their current weight based on their grouping.

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

5. Experimental Results: Statistical analysis of the weight change rate of mice in each group after 18 days of continuous dosing revealed that Compound 10 of the present invention achieved significantly superior weight loss compared to the Vehicle group (average weight gain rate of Compound 10 was -20.2%, p < 0.001). Compound 10 of the present invention also achieved significantly superior weight loss compared to the LY3502970 group (average weight gain rate of LY3502970 was -15.1%) (p < 0.05).

After 20 days of continuous dosing, statistical analysis of the weight change rate of mice in each group revealed that Compound 10 of the present invention achieved a significantly superior weight loss effect compared to the Vehicle group (average weight gain rate of Compound 10 was -20.3%, p < 0.001). Compared to the LY3502970 group (average weight gain rate of LY3502970 was -15.7%), Compound 10 of the present invention also achieved a significantly superior weight loss effect (p < 0.05). The weight gain rate graph is shown in Figure 4.

Test Example 5 :right hGLP-1R Glucose tolerance test (GTT) in transgenic mice IPGTT ) Efficacy studies

1. 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.

2. Experimental animals: C57BL/6JSmoc-Glp1r ^{em2 (hGLP1R) Smoc} mice, male, approximately 23 g.

3. Experimental Grouping: Before the start of the experiment, the mice were fasted but not watered for approximately 16 hours. The basal blood glucose level of the mice was measured. The animals were then randomly divided into groups based on basal blood glucose and body weight, with 7 mice in each group.

4. Experimental Methods: Each group received the test compound by gavage at a volume of 10 mL/kg. The vehicle control (vehicle) group received 2.5% DMSO, 10% Kolliphor® EL, 15% PEG400, and 72.5% (100 mM glycine-NaOH buffer, pH 10) at the same frequency and volume. Sixty minutes after administration, mice were intraperitoneally (i.p.) injected with 2 g/kg of glucose solution based on body weight at a volume of 10 mL/kg. Time of glucose administration was designated as zero. Blood glucose levels were measured before, and 15, 30, 60, and 120 minutes after glucose administration.

5. The specific groups are as follows: Group medication Number of animals Dosage Dosage concentration Medication volume Dosage method Frequency of medication mg/kg mg/mL mL/kg G1 vehicle 6 0 - 10 ig Single G4 Compound 10 6 0.05 0.005 ig Single

6. Test results:

Blood glucose testing results showed that at a dose of 0.05 mg/kg, the blood glucose levels of mice in the Compound 10 group showed a downward trend at 15, 30, 60, and 120 minutes after glucose loading, and were significantly lower than those in the vehicle group ( P < 0.05, P < 0.01, P < 0.001). Calculation of the area under the blood glucose curve showed that compared with the vehicle group, the AUC _{0-120min Glu} level in the Compound 10 group after glucose loading was significantly lower ( P < 0.001). The results are shown in the table below. Average blood glucose AUC (mmol*min/L) (Mean±SD, n=5) Time point (min) G1 (Solvent) G4 (Compound 10) 0.05 mg/kg 0-120 1790.5±176.4 949.6±87.6

Test Example 6 :right 44 Safety assessment trial of off-target effects of a target

1. Study Objective: This study primarily utilizes radioisotope binding, calcium flux assays, and enzyme fluorescence or chemiluminescence techniques to detect the off-target effects of test compounds on 44 selected targets at the in vitro cellular or molecular level, thereby evaluating the safety profile associated with the binding or inhibitory effects of the test compounds on these targets.

2. Experimental Method: Test compound 10 (free acid) was tested at a single concentration of 10 μM (the test concentration for Eta agonism was 12 μM) for binding, inhibition, or agonism against 44 targets.

3. Experimental Procedure: Radioligand competition assays were used to assess the binding of test compounds to 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), eight ion channels (nAChR-Alpha7, Cav1.2 (Dihydropyridine Site), GABAA (α1β3γ2), hERG, NMDA (MK-801), 5-HT3, Na ⁺ , and Kv), three transporters (DAT, NET, and 5-HTT), and two nuclear receptors (AR and GR). Calcium flux assays were used to test the agonist and antagonist effects of the test compounds on Eta receptors. In vitro biochemical platforms were used to test the effects of the test compounds on seven enzyme targets.

4. Test results:

At a test concentration of 10 μM, compound 10 had no significant binding, inhibition (inhibition rate <50%), or agonism (agonism rate <50%) against any of the 44 targets at a single concentration of 10 μM (the test concentration for Eta agonism was 12 μM).

At a tested concentration of 10 μM, LY3502970 exhibited mild inhibitory effects on Ca ²⁺ -L, 5HT2B, and op-delta (inhibition rate > 50%). This may pose a risk of off-target effects on these targets.

The above describes the implementation of the present invention. However, the present invention is not limited to the above implementation. 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.

without

Figure 1: H NMR spectrum (temperature: 60°C) of Example 10 (Compound 10). Figure 2: H NMR spectrum (temperature: 80°C) of Example 8 (Compound 8). Figure 3: H NMR spectrum (temperature: 80°C) of Example 15 (Compound 65). Figure 4: Weight gain rate spectrum of Experimental Example 4.

Claims (14)

A compound represented by formula (I), its stereoisomers, tautomers or pharmaceutically acceptable salts: wherein Ring A is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring B is selected from a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring C is selected from a 9-membered bicyclic heteroaryl; Ring D is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; Ring E is selected from a C _3-15 carbocyclyl, a 3-12 membered heterocyclyl, a C _6-14 aryl, and a 5-12 membered heteroaryl; R ^a is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^a1 , -S(O)R ^a1 , -SO ₂ (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 ), -SO ₂ N(R ^a1 )(R ^a2 ), -N(R ^a1 )S(O)R ^a2 , -N(R ^a1 )S(O) ₂ R ^a2 , and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^a3 : 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 form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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; R ^a1 and R ^a2 are each independently selected from hydrogen, deuterium, an optionally substituted group: C _1-6 alkyl, C 1-6 alkoxy, C _{2-6 alkenyl, C 1-6} alkyl, C 1-6 alkoxy, C _3-10 cycloalkyl, a 3-10 membered heterocyclic group, a C 6-14 aryl and a 5-12 membered heteroaryl group; wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substituents selected from halogen, _hydroxyl , amino, nitro, _hydroxyl , nitrile, oxo, C _1-6 alkyl, C 1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclic group, phenyl, 5-6 membered heteroaryl; R ^a3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -R ^a4 R ^a4 , -OR a4 , -SR ^a4 , -S(O)R ^a4 , -S(O) ₂ R ^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) ₂ N(R ^a4 )(R ^a5 ), -N(R ^a4 )S(O)R ^a5 , -N(R ^a4 )S(O) ₂ R ^a5 ; R ^a4 , R ^a5 are each independently selected from hydrogen, deuterium, an optionally substituted C _1-6 alkyl, a C _1-6 alkoxy, a C _2-6 alkenyl, a C The optional substitution refers to being unsubstituted or substituted by one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substituents selected from halogen, hydroxyl, amino, nitro, hydroxyl, _nitrile , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, _3-7 membered heterocyclic group, phenyl, and 5-6 membered heteroaryl; R ^b is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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 heterocyclo, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substitutable positions of the substituted group are independently substituted with R ^b1 ; or two R ^b together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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; R ^b1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -R ^b2 , -OR ^b2 , -SR ^b2 R b2 , -S(O)R ^b2 , -S(O) ₂ R ^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) ₂ N(R ^b2 )(R ^b3 ), -N(R ^b2 )S(O)R ^b3 , -N(R ^b2 )S(O) ₂ R ^b3 ; R ^b2 and R ^b3 are each independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 membered 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) groups selected from halogen, hydroxyl, amino, nitro, alkyl, nitrile, 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 aryl, 5-12 membered heteroaryl; R ^c is independently selected at each occurrence from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, or optionally substituted from 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; the optional substitution means unsubstituted or one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions of the substituted group are independently substituted with R ^c1 ; or two R ^c together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, 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; R ^c1 is independently selected from deuterium, halogen, hydroxyl, amine, nitro, hydroxyl, nitrile, oxo, -R ^c2 , -OR ^c2 , -SR ^c2 , -S(O)R ^c2 , -S(O) ₂ R ^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) ₂ N(R ^c2 )(R ^c3 ), -N(R ^c2 )S(O)R ^c3 , -N(R ^c2 )S(O) ₂ R ^c3 ; R ^c2 and R ^c3 are each independently selected from hydrogen, deuterium, and optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 membered 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, 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 aryl, 5-12 membered heteroaryl; R ^d is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^d1 、-S(O)R ^d1 、-S(O) ₂ R ^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) ₂ N(R ^d1 )(R ^d2 、-N(R ^d1 )S(O)R ^d2 、-N(R ^d1 )S(O) ₂ R ^d2 、 and the following groups optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^d3 : C _1-6 alkyl, C or two R ^d together with the atoms to which they are attached form _an optionally substituted _{3-10 membered} heterocyclic group, an optionally substituted _3-7 membered cycloalkyl group or an optionally substituted _5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, _halogen , hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, 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 group; or two R d together with the atoms to which they are attached form an optionally substituted 3-10 membered heterocyclic group, an optionally substituted 3-7 membered cycloalkyl group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 membered cycloalkyl, 3-10 membered heterocyclic group, C _6-14 aryl and 5-12 membered heteroaryl group; R ^d1 and R ^d2 are each independently selected from hydrogen, deuterium, and 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 heterocyclic group, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means unsubstituted or substituted by one or more (for example, 2, 3, 4, 5, 6, 7 or 8) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _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) ₂ N(R ^d4 )(R ^d5 ), -N(R ^d4 )S(O)R ^d5 , -N(R ^d4 )S(O) ₂ R ^d5 ; R ^d4 , R ^d5 are each independently selected from hydrogen, deuterium, an optionally substituted C _1-6 alkyl, a C _1-6 alkoxy, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 cycloalkyl, a 3-10 membered heterocyclic group, a C _6-14 membered 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) substituents selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, 3-7 membered heterocyclo, phenyl, 5-6 membered heteroaryl; R ^e is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -OR ^e1 , -SR ^e1 , -S(O)R ^e1 , -S(O) ₂ R ^e1 at each occurrence , -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) ₂ N(R ^e1 )(R ^e2 ), -N(R ^e1 )S(O)R ^e2 , -N(R ^e1 )S(O) ₂ R ^e2 , -C(O)N(R ^e1 )S(O) ₂ N(R ^e1 )(R ^e2 ), -C(O)N(R ^e1 )S(O) ₂ R ^e2 , -P(O)(R ^e1 )R ^e2 , and optionally substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ^e3 of 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 form an optionally substituted 3-10 membered heterocyclic group or an optionally substituted 5-12 membered heteroaryl group, wherein the optional substitution means being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, oxirane, nitrile, 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; R ^e1 and R ^e2 are each independently selected from hydrogen, deuterium, an optionally substituted group: C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C wherein the alkyl radical is an alkyl radical having _{a 2-6} member group, a C 2-6 alkynyl group, a C _3-10 cycloalkyl group, a 3-10 member heterocyclic group, a C _6-14 aryl group, or a 5-12 member heteroaryl group; wherein the optional substitution refers to being unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) substituents selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl group, a 3-6 member heterocyclic group, phenyl, or a 5-6 member heteroaryl group; wherein each occurrence of R ^e3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxo, -R ^e4 , -OR ^e4 , -SR ^e4 , -S(O)R ^e4 , -S(O) ₂ R ^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) ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O)R ^e5 , -N(R ^e4 )S(O) ₂ R ^e5 , -C(O)N(R ^e4 )S(O) ₂ N(R ^e4 )(R ^e5 ), -C(O)N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 ) R ^e5 ; R ^e4 and R ^e5 are each independently selected from hydrogen, deuterium, and 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted by a _3-7 membered cycloalkyl, a 3-7 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; R ^f is 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 are each 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) groups selected from halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, oxirane, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C substituted with a substituent of _{a 3-6} membered cycloalkyl, a 3-6 membered heterocyclic group, a phenyl group, or a 5-6 membered heteroaryl group; R ¹ and R ² together with the atoms to which they are attached form a C _3-15 carbocyclic group; the C _3-15 carbocyclic group is optionally substituted with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R ³ ; R ³ is independently selected from hydrogen, deuterium, halogen, hydroxyl, or an optionally substituted group of the following groups: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-10 membered cycloalkyl, 3-10 membered heterocyclic group; the optional substitution means that the substituted group is unsubstituted or is substituted with one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substitutable positions independently selected from deuterium, halogen, hydroxyl, amine, nitrile, oxo, C _3-10 cycloalkyl, 3-10 membered heterocyclic group; L ₁ is selected from a bond, -C( ^RL1 ) _2- , -O-, -C( ^RL1 ) _2O- , -S-, -C(O)-, -C(O)O-, -OC(O)-, -N( ^RL1 )C(O)-, -C(O)N( ^RL1 )- or -N( ^RL1 )-; R ^L1 is independently selected from hydrogen, deuterium, or an optionally substituted _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or a 3-10 membered heterocyclic group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, C3-10 cycloalkyl, or a _3-10 membered heterocyclic group; _L2 is independently selected from a bond, -C( ^RL2 ) ₂ -, -O-, -C(R ^L2 ) ₂ O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^L2 )C(O)-, -C(O)N(R ^L2 )-, or -N(R ^L2 )-; R ^L2 is 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 heterocyclic group, wherein the optional substitution means unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) groups selected from deuterium, halogen, hydroxyl, amino, nitro, hydroxyl, nitrile, C _1-6 alkyl, C L3 is independently selected from a bond, -C(RL3 _{) 2-} , -O-, _-S- , -C(O)-, -C( _O) O-, -OC(O ₎ -, -N(RL3)C(O)-, -C(O)N( ^RL3 )-, or -N(RL3)-; _RL3 is independently selected from hydrogen, deuterium, or the following optionally substituted groups: _{C1-6 alkyl} , C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or a 3-10 membered heterocyclic group; ^L3 is independently selected from a bond, -C( ^RL3 )2-, -O-, -S-, -C(O)-, -C(O ₎ O-, -OC(O)-, -N( ^RL3 )C(O)-, -C( _O) N( ^RL3 )-, or -N(RL3)-; RL3 is independently selected from hydrogen, deuterium, or the following optionally substituted groups: C1-6 alkyl, _C1-6 alkoxy, C2-6 alkenyl, _C2-6 alkynyl, C _3-10 membered 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) groups selected from deuterium, halogen, hydroxyl, amine, nitro, alkyl, nitrile, 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; L ₄ is independently selected from a bond, -L _4x -C( ^RL4a ) ( ^RL4b )-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 group; the optional substitution means that 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, amine, nitro, hydroxyl, nitrile, oxo, 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; ^RL4a , ^RL4b 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 The optional substitution means that the substituted group is unsubstituted or is substituted with one or more (e.g., ₂ , 3, 4, 5, 6, 7, or 8) substitutable positions independently selected from deuterium, halogen, _hydroxyl , amine, nitro, alkyl, nitrile, oxo, C 1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, or _3-10 membered heterocyclic group; Ring L _4Z is selected from C _3-15 carbocyclic group, 3-12 membered heterocyclic group, C _6-14 aryl, or 5-12 membered heteroaryl; R ^L4z is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, or optionally substituted _C1-6 alkyl, _C1-6 alkoxy, C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or _3-10 membered heterocyclic group; the optional substitution means that the group is unsubstituted or one or more substitutable positions of the substituted group are independently substituted with deuterium, halogen, hydroxyl, amino, nitro, alkyl, nitrile, oxo, _C1-6 alkyl, _C1-6 alkoxy, C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, _C3-10 cycloalkyl, or _3-10 membered heterocyclic group; L _5x , L, _{and 5y} are each independently selected from a bond or an optionally substituted _C1-10 alkylene group; the optional substitution means that the group is 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, amine, nitro, hydroxyl, nitrile, oxo, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 alkylamino, _C2-6 alkenyl, _C2-6 alkynyl, C3-10 cycloalkyl, or a _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 heterocyclic and heteroaryl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4. The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof as described in claim 1, wherein Ring A is selected from phenyl; Ring B is selected from 、 , wherein the "*" end is connected to L ₁ , the "**" end is connected to L ₂ , and the "***" end is connected to L ₄ ; Ring C is selected from the following groups: , where the "+" end is connected to L ₂ , the "++" end is connected to L ₃ , and the "+++" end is connected to L _5x ; Ring D is ; Ring E is or ; L ₁ is selected from a bond; L ₂ is selected from -C(O)-; L ₃ is selected from a bond; L ₄ is selected from -NHC(O)NH-, -N(methyl)C(O)NH-, -N(cyclopropyl)C(O)NH-, -N(cyclopropyl)C(O)N(cyclopropyl)-, , wherein the "#" end is the end connected to ring B, and the "##" end is the end connected to ring E; L _5x and L _5y are independently selected from a bond; ^Ra is independently selected from halogen, methyl, C _3-5 cycloalkyl-(CH ₂ ) _w - at each occurrence; R ^b is independently selected from fluorine, chlorine, oxo, and methyl at each occurrence; R ^c is independently selected from hydrogen, fluorine, chlorine, oxo, methyl, ethyl, n-propyl, isopropyl, and n-butyl at each occurrence; R ^d is independently selected from optionally substituted C _1-3 alkyl and optionally substituted C _1-3 alkoxy at each occurrence; 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; R ^e is independently selected at each occurrence from fluorine, or optionally substituted C _1-3 alkyl (e.g., methyl, ethyl), C _3-5 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), C _3-5 cycloalkyl-(CH ₂ ) _w -; provided that when L ₄ is When , at least one (e.g., 1 or 2) of ^Ra or the substituents on ring E (or ^Re ) is _C3-5 cycloalkyl -( _CH2 ) _w- ; or, two ^Re (preferably, two adjacent ^Re ; further preferably, two adjacent ^Re located on different rings) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group (e.g., a 5-membered, 6-membered or 7-membered heterocyclic group), the 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 substituted or one or more substitutable sites of the substituted group are independently substituted by ^Re3 ; ^R1 and R ² The carbon rings formed together with the atoms to which they are attached are independently selected from , where the "~" end is connected to L _5x , and the "~~" end is connected to L _5y ; R ^f is selected from m is 2 or 3; q is 1, 2 or 3; n, o, p are each independently 0, 1, 2; w is 0, 1 or 2; R ^e3 is as defined in claim 1; provided that the following compounds are not included: 、 . The compound, stereoisomer, tautomer or pharmaceutically acceptable salt thereof as described in claim 1 or 2, wherein, provided that when _L4 is when at least one (e.g., one or two) of ^Ra or the substituents on ring E (or ^Re ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when neither Ra nor the substituents on ring E (or Re) are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, two ^Re (preferably, two ^Re located on different rings) are cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl- ^ethylene , cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl- ^ethylene , ) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 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 substituted or one or more substitutable positions of the substituted group are independently substituted by R ^e3 ; the R ^e3 is as defined for the compound of formula (I); preferably, the C _3-5 cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl; further preferably, it is cyclopropyl; provided that the following compounds are not included: 、 . The compound according to any one of claims 1 to 3, its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein, provided that at least one (e.g., one or two) of the substituents on ^Ra or ring E (or ^Re ) is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, when both the substituents on ^Ra and ring E (or ^Re ) are not cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene, the two Res ^are (Preferably, two ^Re located on different rings) together with the atoms to which they are attached form an optionally substituted 5-7 membered heterocyclic group, wherein the heterocyclic group (preferably a heterocycloalkyl group) contains 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 substituted or one or more substitutable positions of the substituted group are independently replaced by ^Re3 ; the ^Re3 is as defined for the compound of formula (I); preferably, the _C3-5 cycloalkyl group is selected from cyclopropyl, cyclobutyl and cyclopentyl; further preferably, it is cyclopropyl. The compound according to any one of claims 1 to 4, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is a compound represented by the following formula: Ring E selected from and ; ^Ra is independently selected at each occurrence from fluorine, methyl and _C3-5 cycloalkyl; m is 2 or 3; q is 2 or 3; ^Re is independently selected at each occurrence from fluorine, or an optionally substituted _C1-3 alkyl (e.g., methyl, ethyl), _C3-5 cycloalkyl; provided that at least one (e.g., one or two) of ^Ra or ^Re is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methylene, cyclopropyl-ethylene, cyclobutyl-methylene, cyclobutyl-ethylene, cyclopentyl-methylene or cyclopentyl-ethylene; or, two ^Re (preferably, two adjacent ^Re ; further preferably, two adjacent ^Re located on different rings) are selected from the group consisting of fluorine, methyl, and C3-5 cycloalkyl; ) together with the atoms to which they are attached 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; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substitutable positions of the substituted group are independently replaced by R ^e3 ; R ^e3 is independently selected from deuterium, halogen (e.g., fluorine, chlorine), hydroxyl, amino, oxirane, nitrile, -R ^e4 , -OR ^e4 , -S(O) ₂ R ^e4 , -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -S(O) ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )S(O) ₂ R ^e5 , -P(O)(R ^e4 )R ^e5 ; R ^e4 and R ^e5 are independently selected from hydrogen or C 1-3 alkyl (e.g., methyl, ethyl, propyl) or C _3-6 membered cycloalkyl (preferably 3-5 membered cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl) arbitrarily substituted by one or more (e.g., 2 or ₃ ) of hydrogen, deuterium, halogen (e.g., fluorine or chlorine), hydroxyl, amino, nitrile, oxo, or methoxy groups; preferably, the C _3-5 cycloalkyl is selected from cyclopropyl, cyclobutyl, and cyclopentyl; more preferably, it is cyclopropyl. The compound according to any one of claims 1 to 5, its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein for Hour, for 、 、 、 or ; preferably, for ; when for Hour, for 、 、 or . The compound according to any one of claims 1 to 6, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is a compound represented by the following formula: . The compound according to any one of claims 1 to 7, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is a compound represented by the following formula: 、 、 、 、 、 、 or ,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 bond, C _1-3 alkylene (e.g., methylene, ethylene, propylene; preferably methylene) or C _1-3 alkyl (e.g., methyl, ethyl, propyl; preferably methyl); or, L is combined with its adjacent R ₃ to form an optionally substituted 5-7 membered heterocyclic group, the heterocyclic group containing 1-3 (e.g., 1, 2 or 3) heteroatoms each independently selected from N, O or S, in which case ring G is absent; R ₃ is selected from H, F or methyl; R ₄ is selected from C _3-5 membered cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl; preferably cyclopropyl); Ring F is an optionally substituted 5-7 membered heterocyclic group, the 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 substituted or one or more substitutable positions of the substituted group are independently replaced by R ^e3 ; R ^e3 is independently selected from deuterium, halogen (e.g., fluorine, chlorine), oxo group, hydroxyl group, amino group, nitrile group, -R ^e4 , -OR ^e4 , -SO ₂ (R ^e4 ), -C(O)R ^e4 , -N(R ^e4 )(R ^e5 ), -SO ₂ N(R ^e4 )(R ^e5 ), -N(R ^e4 )SO ₂ (R ^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) arbitrarily substituted by hydrogen, halogen (e.g. fluorine or chlorine), hydroxyl, amino, nitrile, oxo, methoxy: C _1-3 alkyl (e.g. methyl, ethyl, propyl) or C _3-6 membered cycloalkyl (preferably 3-5 membered cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl). The compound according to any one of claims 1 to 8, its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein the compound is a compound represented by the following formula: 、 or . A compound, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: Compound structure and number Compound structure and number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, its stereoisomers, tautomers or pharmaceutically acceptable salts, optionally further comprising a pharmaceutically acceptable excipient. Use of the compound according to any one of claims 1 to 10, its stereoisomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 11 as a medicament or in the preparation of a medicament. The use as described in 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. The use as described in 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.