1,2,4-triazole compound and use thereof as APJ receptor agonist

Abstract

The present invention provides a compound represented by formula (I) or formula (II), or a pharmaceutically acceptable salt, prodrug, stereoisomer, stereoisomer mixture, tautomer, deuterated compound, hydrate or solvate thereof, and a use thereof. The compound has a good agonistic effect on APJ receptors, and can be used for treating and / or preventing diseases such as obesity, hypertension, pulmonary hypertension, and sarcopenia.

Description

1,2,4-triazole compounds and their use as apj receptor agonists TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to a class of APJ receptor agonists and application thereof. BACKGROUND

[0002] APJ (angiotensin II protein J receptor) is a class A GPCR (G Protein-Coupled Receptor), which can also be referred to as Apelin receptor. Apelin receptor has two endogenous ligands: Apelin and ELA. Apelin receptor and its endogenous ligands Apelin and ELA constitute the Apelin / APJ system. The coding gene APLN of Apelin encodes a 77-amino-acid precursor peptide, which can be cleaved by the endopeptidase family to leave the active C-terminal to form the active Apelin peptide. Apelin peptide has multiple length subtypes, and the most important subtypes include Apelin-36 of 36 amino acids, Apelin-17 of 17 amino acids, and Apelin-13 of 13 amino acids. The glutamine at the N-terminal of Apelin-13 is pyroglutamated to form Pyr-apelin-13, which is the most abundant Apelin peptide in circulation. Apelin / APJ system is widely distributed in heart, kidney, lung, brain, vascular system, muscle tissue, adipose tissue and other multiple tissues and organs. More and more research evidences show that Apelin / APJ system is involved in the regulation of various physiological and pathological processes, making it a new target for the treatment of various diseases, such as muscle-related diseases, aging-related symptoms, obesity, diabetes, osteoporosis, heart failure, myocardial infarction, arrhythmia, atherosclerosis and other cardiovascular diseases, and kidney diseases.

[0003] Sarcopenia generally refers to a syndrome of age-related decrease in muscle mass, muscle strength and / or physical function decline. Sarcopenia can cause physical dysfunction, increasing the risk of falls, disability and death in the elderly. GLP-1 drugs can also cause muscle loss, according to reports of clinical studies, GLP-1 drugs are accompanied by muscle loss while losing weight. The use of GLP-1 drugs in people over 50 years of age will increase the risk of sarcopenia. Apelin is an emerging target for muscle-related diseases. The LIFE-P cohort study found that an increase in Apelin content is positively correlated with an increase in exercise score. Skeletal muscle Apelin or Apelin receptor knockout mice have accelerated muscle aging, and Apelin peptide supplementation reverses age-related muscle loss. In three mouse models of muscular dystrophy, Apelin-13 peptide administration improved tissue regeneration and muscle strength.

[0004] Obesity has become one of the increasingly serious global problems affecting human health and aggravating social burden, and is often accompanied by the occurrence of diabetes, hypertension, hyperlipidemia and cardiovascular disease. Apelin is a beneficial adipokine with anti-insulin resistance properties, which is of great significance for improving insulin resistance and treating obesity and other related diseases. Apelin and its receptor are expressed in adipose tissue. As an adipokine, Apelin is considered a key regulator of lipid metabolism, and its expression is up-regulated in obesity. In mature adipocytes, Apelin can act on Apelin receptors through autocrine, inhibit preadipocyte lipogenesis, and reduce free fatty acid release through lipolysis to inhibit obesity formation. Transgenic mice overexpressing Apelin show resistance to diet-induced obesity. In contrast, Apelin-deficient mice have increased obesity, elevated plasma leptin levels and insulin resistance.

[0005] Diabetes mellitus is a major metabolic disorder disease threatening health in the world today, increasing the risk of many chronic diseases. The expression of Apelin in diabetic patients is higher than that in healthy controls, and the glycosylated hemoglobin level and serum Apelin level of type 2 diabetes patients are negatively correlated. Apelin can promote human cells to absorb excess glucose in the body, especially in the case of insufficient insulin secretion, and increasing the content of Apelin in the body helps to maintain blood glucose stability. Apelin is also involved in the regulation of insulin secretion and insulin resistance, and Apelin-13 peptide treatment can improve glucose tolerance and insulin sensitivity in insulin-resistant mice. In diabetic complications, Apelin shows a protective effect on the heart and blood vessels. It can increase glucose uptake in the heart, repair abnormal myocardial contractility caused by high glucose, and reduce the risk of atherosclerosis in heart blood vessels. In addition, Apelin can also reduce kidney enlargement and inflammation caused by diabetes. Therefore, the Apelin / APJ system is also expected to become a new target for the treatment of diabetes and its complications.

[0006] In addition to activating the G protein-dependent signaling pathway, the binding of Apelin to the Apelin receptor can also activate the β-arrestin pathway. The recruitment of β-arrestin protein can mediate receptor desensitization and endocytosis, and the endocytosed receptor is targeted for degradation or recycled to the cell surface. It is reported that the beneficial effects of Apelin are mainly due to the activation of the G protein-dependent signaling pathway, while the activation of the β-arrestin signaling pathway has a side effect of myocardial hypertrophy. Experiments have shown that the Apelin receptor can respond to mechanical stretch stimulation by activating the β-arrestin signaling pathway, inducing a myocardial hypertrophy phenotype on cardiomyocytes (including increasing the size of cardiomyocytes and inducing myocardial hypertrophy-related biomarkers). The myocardial hypertrophy phenotype caused by mechanical stretching can be blocked by knocking out β-arrestin, suggesting the key role of β-arrestin signaling in the side effects of myocardial hypertrophy.

[0007] In summary, the development of APJ receptor agonist drugs is helpful for the treatment of the above-mentioned diseases, and the G protein-biased APJ receptor agonist, which activates the G protein-dependent signaling pathway and avoids the recruitment of β-arrestin to avoid the side effects of β-arrestin, is an important direction for the development of the new generation of APJ receptor agonists (Apelin receptor agonists). SUMMARY

[0008] The present application includes providing a triazole-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, stereoisomer mixture, tautomer, deuterium, hydrate or solvate thereof.

[0009] Another object of the present application includes providing a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned triazol-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated form, hydrate or solvate thereof.

[0010] Another object of the present application includes providing the use of the above-mentioned triazol-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated form, hydrate or solvate thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases such as obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease and / or sarcopenia, or in the preparation of a medicament for preventing and / or treating diseases related to the APJ receptor.

[0011] Another object of the present application includes providing the use of the above-mentioned triazol-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated form, hydrate or solvate thereof, or the above-mentioned pharmaceutical composition in the preparation of an APJ receptor agonist.

[0012] To achieve the above-mentioned objects, the technical solutions adopted by the present application include:

[0013] In some embodiments, a triazol compound as shown in formula (I) or formula (II) or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated form, hydrate or solvate thereof is provided,

[0014] wherein:

[0015] R1 is C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C 2- C 10 alkenyl, C5-C 12 spirocyclic group, C5-C 12 heterospirocyclic group, C5-C 12 bridged cyclic group, C5-C 12 heterobridged cyclic group, or C5-C 15 heteroaryl; or the above-mentioned groups are substituted with one or more R 4a groups;

[0016] R2 is C 1- C 10 alkyl, C 3- C 10cycloalkyl, C 4- C 10 heterocycloalkyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the above groups are substituted by one or more R 4b substituents;

[0017] R3is C 3- C 10 cycloalkyl, C5-C 12 spirocyclyl, C5-C 12 bridged cyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the above groups are substituted by one or more R 4c substituents;

[0018] R a is hydrogen or C1-C4alkyl;

[0019] X is oxygen or nitrogen;

[0020] when X is oxygen, R b is absent; when X is nitrogen, R b is selected from C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the above groups are substituted by one or more halogen, cyano, nitro, oximino, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12Heterobridged cyclic groups, oxy subunits, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution;

[0021] R 4a R 4b R 4c Selected independently from C 1- C 10 Alkyl, C 2- C 10 alkenyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are affected by one or more halogens, cyano, nitro, oxonyl, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridged ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution;

[0022] Or, R 4aR 4b R 4c independently selected from hydrogen, halogen, cyano, nitro, oxyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, or -S(O)(NR7)R5R6;

[0023] or, when R1is C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, or C5-C 15 heteroaryl, two or more R 4a optionally together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or said collectively formed group is substituted with one or more halogen, C1-C6alkanoyl, C3-C6cycloalkanoyl, hydroxy, C1-C5alkoxy, C1-C5haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, diC1-C6alkylamino, diC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino, or oxyl; 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C6-C 10 aryl, or C5-C 15 heteroaryl; or said collectively formed group is substituted with one or more halogen, C1-C6alkanoyl, C3-C6cycloalkanoyl, hydroxy, C1-C5alkoxy, C1-C5haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, diC1-C6alkylamino, diC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino, or oxyl;

[0024] or, when R2is C3-C 10 cycloalkyl, C6-C 10 aryl, or C5-C 15 heteroaryl, two or more R 4b optionally together with the atoms to which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or said collectively formed group is substituted with one or more halogen, C1-C6alkanoyl, C3-C6cycloalkanoyl, hydroxy, C1-C5alkoxy, C1-C5haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, diC1-C6alkylamino, diC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino, or oxyl;

[0025] R5, R6, R7are independently selected from hydrogen, C1-C 10 alkyl, C3-C 10cycloalkyl, C4-C 10 heterocycloalkyl, C4-C 10 heterocyclyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the above mentioned groups are substituted by one or more halogen, cyano, nitro, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C4-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, oximino, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR 10 C(O)NR8R9, -NR 10 C(NH)NR8R9, -C(O)R8, -COOR8, -C(O)NR8R9, -SR8, -SO2R8, -SO2NR8R9, -S(O)(NR 10 )R8R9, C6-C 10 aryl or C5-C 15 heteroaryl; or the above mentioned groups are substituted by one or more halogen, C1-C6alkanoyl, C3-C6cycloalkanoyl, hydroxy, C1-C5alkoxy, C1-C5haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, bisC1-C6alkylamino, bisC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino or oximino;

[0026] Alternatively, R5, R6are optionally and together with the N atom to which they are commonly attached form a C4-C 10 heterocycloalkyl, C4-C 4- C 10 heterocyclyl, C5-C 12 heterospirocycloalkyl or C5-C 15 heteroaryl; or the above mentioned groups are substituted by one or more halogen, C1-C6alkanoyl, C3-C6cycloalkanoyl, hydroxy, C1-C5alkoxy, C1-C5haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, bisC1-C6alkylamino, bisC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino or oximino;

[0027] R8, R9, R 10 are independently selected from hydrogen, C 1- C 10 alkyl, C3- C 10 Cycloalkyl, C 4- C 10 Heterocycloalkyl, C 12 Spiroalkyl, C 12 Heterospiroalkyl, C 12 Bicycloalkyl, C 12 Heterobicycloalkyl, C 10 Aryl or C 15 Heteroaryl; or the aforementioned groups are substituted with one or more halogen, cyano, hydroxy, carboxy, amino, C 1- C 10 Alkyl, C 3- C 10 Cycloalkyl, C 4- C 10 Heterocycloalkyl, C 10 Cycloalkoxy, C 10 Heterocycloalkoxy, oximino, C 10 Aryl or C 15 Heteroaryl; or the aforementioned groups are substituted with one or more halogen, C

[0028] Alternatively, R8, R9optionally and the N atom to which they are both attached together form a C 4- C 10 Heterocycloalkyl, C 4- C 10 Heterocyclyl, C 12 Heterospiroalkyl or C 15 Heteroaryl; or the aforementioned groups are substituted with one or more halogen, C 3- C 10 Cycloalkyl, C 4- C 10 Heterocycloalkyl or C 15 Heteroaryl; or the aforementioned groups are substituted with one or more R 4a groups.

[0029] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is C5-C10heteroaryl (preferably C5-C6heteroaryl) substituted with one or more R 15 heteroaryl (preferably C5-C 10 heteroaryl); or the aforementioned group is substituted with one or more R 4a groups.

[0030] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is pyridyl; or the aforementioned group is substituted with one or more R 4a groups.

[0031] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is substituted pyridyl having the formula:

[0032] wherein the pyridyl is unsubstituted or substituted with 1 or 2 R 4a substituents, and the symbol drawn at the end of a bond indicates the point of attachment to the rest of the molecule.

[0033] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is substituted pyridyl having the formula:

[0034] wherein the pyridyl is unsubstituted or substituted with 1 or 2 R 4a substituents, and the symbol drawn at the end of a bond indicates the point of attachment to the rest of the molecule.

[0035] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is substituted pyridyl having the formula:

[0036] wherein the pyridyl is unsubstituted or substituted with 1 or 2 R 4a substituents, and the symbol drawn at the end of a bond indicates the point of attachment to the rest of the molecule.

[0037] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R 4a In each case, it is independently selected from hydrogen, halogen, cyano, C1-C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl groups, -OR5, -OC(O)R5, -NR5R6, -NR5C(O)R6;

[0038] Or when R 4a Selected from C1-C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 In the case of heterocyclic alkyl groups, the above groups are optionally replaced by one or more halogens, cyano groups, oxonides, or C. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl groups are substituted with -OR5, -NR5R6, -NR5C(O)R6, -C(O)R5, -COOR5, or -C(O)NR5R6.

[0039] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R1 is a pyridinyl group; or the pyridinyl group is surrounded by one to three R1 groups. 4a Replace; where R 4a In each case, it is independently selected from hydrogen, halogen, C1-C. 10 Alkyl, -OR5, -NR5R6, -NR5C(O)R6.

[0040] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R 4aindependently at each occurrence selected from hydrogen, halogen, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, isopropyl, cyclopropyl, cyclobutyl, 2,2-difluorocyclopropyl, methoxy, ethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropyloxy, cyclobutyloxy, amino, methylamino, dimethylamino, methylcarbamoyl, ethylcarbamoyl, 2-hydroxyethoxy, 2-hydroxy-2-methyl-propoxy, 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy, 2-methoxyethoxy, 2-(dimethylamino)ethoxy, 2-morpholinoethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, azetidinyl, oxetanyl, or 2,6-diazaspiro[3.3]heptan-2-yl.

[0041] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R1is pyridinyl; or the aforementioned pyridinyl is substituted with 1 to 2 R 4a substituents; wherein R 4a independently at each occurrence selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, or C1-C3 haloalkoxy.

[0042] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4a is C1-C3 alkyl or C1-C3 haloalkyl.

[0043] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4a is C1-C3 alkoxy or C1-C3 haloalkoxy.

[0044] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4a is C3-C6 cycloalkoxy.

[0045] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R2is C1-C 10 alkyl, C 3- C 10 alkyl, C4- C 10 heterocycloalkyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the aforementioned groups are substituted by one or more R 4b groups.

[0046] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is C6-C 10 aryl or C5-C 15 heteroaryl (preferably C5-C 10 heteroaryl); or the aforementioned groups are substituted by one or more R 4b groups.

[0047] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is C6aryl or C6heteroaryl; or the aforementioned groups are substituted by one or more R 4b groups.

[0048] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is

[0049] R 4b as defined in any one of the technical solutions herein, and the symbol drawn at one end of a bond indicates the point of attachment to the rest of the molecule.

[0050] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4b is independently selected at each occurrence from hydrogen, halogen, C1-C3alkyl, C3-C5cycloalkyl, C4-C6heterocycloalkyl, -OR5, -NR5R6, -NR5C(O)R6, -COOR5, -C(O)NR5R6.

[0051] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is C1-C 10 alkyl; or the aforementioned groups are substituted by one or more R 4b groups.

[0052] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R 4b In each case, it is independently selected from hydrogen, halogen, oxygen subunit, C6-C. 10 Aryl or C5-C 15 Mixed aromatics;

[0053] Or when R 4b Selected from C6-C 10 Aryl or C5-C 15 In the case of heteroaryl groups, the above groups are optionally converted by one or more halogens, cyano groups, nitro groups, oxonyl groups, C6 groups, etc. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridged ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution.

[0054] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R 4b In each case, C6-C are selected independently. 10 Aryl or C5-C 15 Heteroaryl; or the above groups are surrounded by one or more halogens, cyano groups, C1-C3 alkyl groups, C 3- C5 cycloalkyl, C 4- C6 heterocyclic alkyl, -OR5, -NR5R6, -NR5C(O)R6, -COOR5, -C(O)NR5R6 substitution.

[0055] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R5, R6are optionally and independently selected from hydrogen, C 1- C3alkyl, C 3- C6cycloalkyl, C 4- C6heterocycloalkyl; or the aforementioned groups are substituted with one or more halogen, cyano, C 1- C3alkyl, C 3- C6cycloalkyl, C 4- C6heterocycloalkyl, oximino, C1-C3alkoxy, C1-C3haloalkoxy, C1-C6alkanoyloxy, C3-C6cycloalkanoyloxy, amino, C1-C6alkylamino, C1-C6haloalkylamino, bisC1-C6alkylamino, bisC1-C6haloalkylamino, C1-C6alkanoylamino, C3-C6cycloalkanoylamino, or oximino; or R5, R6optionally and together with the N atom to which they are both attached form a C 4- C6heterocycloalkyl, C5-C 12 heterospirocycloalkyl, or C5-C 15 heteroaryl; or the aforementioned groups are substituted with one or more halogen, C1-C5alkoxy, C1-C3haloalkoxy, amino, C1-C3alkylamino, bisC1-C3alkylamino, C3-C6cycloalkanoylamino, or oximino.

[0056] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is C6-C 10 aryl or C5-C 15 heteroaryl; or the aforementioned groups are substituted with one or more R 4c groups.

[0057] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is C6aryl or C5-C6heteroaryl (preferably aryl); or the aforementioned groups are substituted with one or more R 4c groups (preferably R 4c groups are 1 to 3 in number).

[0058] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4c is independently selected from C 1- C 10 alkyl, C 3-C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or the aforementioned groups are substituted with one or more halogen, cyano, nitro, oximino, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 aryl or C5-C 15 heteroaryl; or the aforementioned groups are substituted with one or more halogen, cyano, nitro, oximino, C

[0059] or R 4c is independently selected from hydrogen, halogen, cyano, nitro, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, or -S(O)(NR7)R5R6.

[0060] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4c is present in an amount of 1 to 3; wherein 0 or 1 R 4c is C6-C 10 aryl or C5-C 15 heteroaryl; or the aforementioned C6-C10 aryl or C6-C 15 heteroaryl is substituted with one or more halogen, cyano, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C5-C 12 spirocyclic, C5-C 12 heterospirocyclic, C5-C 12 bridged cyclic, C5-C 12 heterobridged cyclic, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, or C5-C 15 heteroaryl; additionally 0 to 3 R 4c are independently selected from hydrogen, halogen, cyano, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C1-C5 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, di-C1-C3 alkylamino, C3-C6 cycloalkylcarboxamido.

[0061] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4c is 2; wherein 1 R 4c is C6-C 10 aryl or C6-C 15 heteroaryl, or the aforementioned C6-C 10 aryl or C6-C 15 heteroaryl is substituted with one or more halogen, cyano, C 1- C 10 alkyl, C 3- C 10 cycloalkyl, C 4- C 10 heterocycloalkyl, C5-C 12 spirocyclic, C5-C 12 heterospirocyclic, C5-C 12 bridged cyclic, C5-C 12Hybrid bridged ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6 or C5-C 15 heteroaryl substitution; another R 4c Selected from hydrogen, halogen, cyano, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C1-C5 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, bisC1-C3 alkylamino, C3-C6 cycloalkanoylamino.

[0062] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvation thereof, wherein R a X is hydrogen, R is oxygen. b It does not exist.

[0063] In some embodiments, a triazole compound of formula (I') or a pharmaceutically acceptable salt thereof, a prodrug, a stereoisomer, a mixture of stereoisomers, a tautomer, a deuterated derivative, a hydrate thereof, or a solvate thereof is provided.

[0064] in:

[0065] R1 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C2-C 10 Alkenyl or C5-C except furanyl 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C2-C 10 Alkenyl or C5-C except furanyl 15 Heteroaryl groups are substituted with one or more R groups. 4a Group substitution;

[0066] R2 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 4b substituted;

[0067] R3is C3-C 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 4c substituted;

[0068] R a is hydrogen or C1-C4alkyl;

[0069] R 4a , R 4b , R 4c are independently selected from C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, C3-C 10 cycloalkenyl, C4-C 10 heterocycloalkyl, C4-C 10 heterocyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, C3-C 10 cycloalkenyl, C4-C 10 heterocycloalkyl, C4-C 10 heterocyclyl, C6-C 10 aryl or C5-C 15 heteroaryl; or said C1-C4alkyl, C1-C2haloalkyl, C2-C3alkenyl, C3-C4cycloalkyl, C4-C5heterocycloalkyl, C6-C5aryl, or C5-C5heteroaryl is substituted with one or more R 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12Bridge ring base, C5-C 12 Hybrid bridged ring group, -O(CH2) j R5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -(CH2) q C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution;

[0070] Or, R 4a R 4b R 4c It is independently selected from hydrogen, halogen, cyano, nitro, oxonyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6 or -S(O)(NR7)R5R6;

[0071] R5, R6, and R7 are independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, nitro groups, or C groups. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12heterocyclyl, oximino, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR 10 C(O)NR8R9, -NR 10 C(O)NR8R9, -NR 10 C(O)NR8R9, -NR 10 C(O)NR8R9, -NR 15 C(O)NR8R9, -NR

[0072] R8, R9, R 10 are independently selected from hydrogen, C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl or C5-C 15 heteroaryl; or said C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl or C5-C 15 heteroaryl is substituted by one or more halogen, cyano, hydroxy, carboxyl, amino, C1-C6alkylamino, C1-C6haloalkylamino, bis-C1-C6alkylamino, bis-C1-C6haloalkylamino, C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C3-C 10 cycloalkoxy, C4-C 10 heterocycloalkoxy, oximino, C6-C 10 aryl or C5-C 15 heteroaryl is substituted by one or more halogen, cyano, hydroxy, carboxyl, amino, C1-C6alkylamino, C1-C6haloalkylamino, bis-C1-C6alkylamino, bis-C1-C6haloalkylamino, C1-C

[0073] j, q are each independently selected from 0, 1, 2, 3 or 4.

[0074] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is C5-C6heteroaryl containing 1 nitrogen atom (preferably pyridinyl); or said C5-C6heteroaryl is substituted with 1 to 2 R 4a substituents; wherein R 4a are independently selected from hydrogen, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkoxy, or C1-C3haloalkoxy.

[0075] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is

[0076] wherein the symbol indicates the point of attachment to the remainder of the molecule when drawn at the end of a bond.

[0077] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is C6-C8aryl or C6-C8heteroaryl; or said C6-C8aryl or C6-C8heteroaryl is substituted with one or more R 4b groups.

[0078] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is

[0079] wherein R 4b is as defined in any one of the technical solutions herein, and the symbol indicates the point of attachment to the remainder of the molecule when drawn at the end of a bond; preferably, R 4b is hydrogen or -OR5, and R5is unsubstituted C1-C6alkyl or C1-C6alkyl substituted with halogen.

[0080] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is C6-C 10 aryl or C5-C 10 heteroaryl; or said C6-C 10 aryl or C5-C 10 heteroaryl is substituted with one or more R 4c groups.

[0081] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is C6-C8aryl or C5-C6heteroaryl (preferably C6aryl); or said C6-C8aryl or C5-C6heteroaryl is substituted with one or more R 4c groups (preferably R 4cthe number of which is 1 to 3.

[0082] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is

[0083] wherein, R 4c R3is as defined in any of the technical solutions herein. 11 are independently selected from hydrogen, halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, or C1-C3haloalkoxy, and the symbol indicates the point of attachment to the rest of the molecule when drawn at the end of a bond.

[0084] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4c are independently selected from hydrogen, C 1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C 2- C4alkenyl, C 3- C6cycloalkyl, C4-C6cycloalkenyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C6-C 10 aryl, or C5-C 10 heteroaryl; or the C 1- C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C 2- C4alkenyl, C 3- C6cycloalkyl, C4-C6cycloalkenyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C6-C 10 aryl, or C5-C 10 heteroaryl substituted with one or more halogen, cyano, oximino, C 1- C6alkyl, C 3- C6cycloalkyl, C 4- C 10 heterocycloalkyl, -OR5, -NR5R6, C6-C 10 aryl, or C5-C 10 heteroaryl;

[0085] or R 4cindependently selected from hydrogen, halogen, cyano, nitro, -OR5, or -NR5R6;

[0086] R5, R6are independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C 3- C6cycloalkyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C6-C 10 aryl, or C5-C 10 heteroaryl; or said C1-C6alkyl, C1-C6haloalkyl, C 3- C6cycloalkyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C6-C 10 aryl, or C5-C 10 heteroaryl is substituted with one or more halogen, C1-C6alkyl, C 3- C6cycloalkyl, C 4- C 10 heterocycloalkyl, C 4- C 10 heterocyclyl, C6-C 10 aryl, -OR8, -NR8R9;

[0087] R8, R9are independently selected from hydrogen, C1-C6alkyl, or C3-C6cycloalkyl.

[0088] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 4c is independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C3alkoxy, C 2- C4alkenyl, C 3- C6cycloalkyl, C4-C6cycloalkenyl, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl, pyrimidoimidazolyl, pyrimidopyrazolyl, or indolyl; or said R 4c is optionally substituted with one or more halogen, cyano, oxido, C 1- C6alkyl, C 3-C6cycloalkyl, -OR5, -NR5R6, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl substituted;

[0089] or R 4c is independently selected from hydrogen, halogen, cyano, nitro, -OR5, or -NR5R6;

[0090] R5, R6are independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, phenyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl; or said optional group of R5, R6is optionally substituted with one or more halogen, C1-C6alkyl, C 3- C6cycloalkyl, -OR8, -NR8R9, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl substituted;

[0091] R8, R9are independently selected from hydrogen, C1-C6alkyl, or C3-C6cycloalkyl.

[0092] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4c is selected from halogen, -OR5, -NR5R6, C 1- C6alkyl, C2-C4alkenyl, C1-C6haloalkyl, C 3- C6cycloalkyl, or the following ring groups: said optional group of R 4c is optionally substituted with one or more halogen, cyano, or C 1- C6alkyl;

[0093] Y is each independently selected from NR 10 or O;

[0094] R5, R6, R 10 are independently selected from hydrogen, amino, C1-C6alkyl, C1-C6haloalkyl, bis C1-C3alkylamino, C3-C6cycloalkyl, C 4- C 10heteroaryl; wherein said C1-C6alkyl is optionally substituted with one or more C3-C6cycloalkyl, C3-C6heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, heteroaryl, halogen, cyano, oxo, hydroxy, or C1-C6alkoxy; 10 heteroaryl; wherein said C1-C6alkyl is optionally substituted with one or more C3-C6cycloalkyl, C3-C6heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, heteroaryl, halogen, cyano, oxo, hydroxy, or C1-C6alkoxy; 4- C 10 heteroaryl; wherein said C1-C6alkyl is optionally substituted with one or more C3-C6cycloalkyl, C3-C6heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, heteroaryl, halogen, cyano, oxo, hydroxy, or C1-C6alkoxy; 10 heteroaryl; wherein said C1-C6alkyl is optionally substituted with one or more C3-C6cycloalkyl, C3-C6heterocycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C6-C10aryl, heteroaryl, halogen, cyano, oxo, hydroxy, or C1-C6alkoxy;

[0095] each of m, n, n1is independently selected from 0, 1, 2, 3, or 4.

[0096] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R5, R6, R 10 is independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl; wherein said C1-C6alkyl is optionally substituted with one or more C3-C6cycloalkyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl.

[0097] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein the triazole compound of Formula (I’) has a structure according to Formula (I’-1) or Formula (I’-2):

[0098] wherein, R a , R 4a , R 4b , R 4c are each independently as defined in any of the technical solutions herein.

[0099] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein in Formula (I’-1) or Formula (I’-2), R 4c is selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, or the following ring group: said ring group is optionally substituted with one or more halogen, cyano, or C1-C6alkyl.

[0100] In some embodiments, there is provided a compound, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, stereoisomer, solvate, or hydrate thereof, optionally selected from any one of the following compounds:

[0101] In some embodiments, there is provided a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable potassium salt or a sodium salt.

[0102] In some embodiments, there is provided a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable potassium salt having a structure according to Formula (II):

[0103] wherein R1, R2, R3are each independently defined in any one of the technical solutions herein.

[0104] In some embodiments, there is provided a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein the pharmaceutically acceptable potassium salt has a structure according to Formula (II-1) or Formula (II-2):

[0105] wherein R 4a , R 4b , R 4c are each independently defined in any one of the technical solutions herein.

[0106] In some embodiments, there is provided a pharmaceutical composition (also referred to herein as “a first pharmaceutical composition”) comprising a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

[0107] In some embodiments, another pharmaceutical composition (also referred to herein as a“second pharmaceutical composition”) is provided, which comprises a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, or a pharmaceutical composition described above (i.e., the first pharmaceutical composition described above), and another drug that agonizes GLP-1 receptor (i.e., glucagon-like peptide-1 receptor).

[0108] In some embodiments, the drug that agonizes GLP-1 receptor described herein is tirzepatide.

[0109] In some embodiments, use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first pharmaceutical composition and the second pharmaceutical composition described above) as a medicament (i.e., for therapy) is provided.

[0110] In some embodiments, use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first pharmaceutical composition and the second pharmaceutical composition described above) in the manufacture of an APJ receptor agonist is provided.

[0111] In some embodiments, use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first pharmaceutical composition and the second pharmaceutical composition described above) in the manufacture of a medicament for the prevention and / or treatment of obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia, or for the prevention and / or treatment of a disease associated with APJ receptor is provided.

[0112] In some embodiments, a method for the prevention and / or treatment of obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia, or for the prevention and / or treatment of a disease associated with APJ receptor is provided, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first pharmaceutical composition and the second pharmaceutical composition described above).

[0113] In some embodiments, the disease associated with APJ receptor described herein is obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia.

[0114] In some embodiments, the compounds described herein are G protein-biased APJ receptor agonists.

[0115] In some embodiments, the compounds described herein have little, even no or almost no activation effect on the β-arrestin signaling pathway.

[0116] The beneficial technical effects achieved are:

[0117] (1) The compounds of the present application have good activity in activating APJ receptors.

[0118] (2) The compounds of the present application can effectively agonize APJ receptors and have high bias towards G protein signaling pathways, which helps to achieve better efficacy and safety.

[0119] (3) The compounds of the present application have weak activation effect on the β-arrestin signaling pathway under the condition of effectively agonizing APJ receptors, effectively avoiding the side effect of myocardial hypertrophy caused by the activation of the β-arrestin signaling pathway, and significantly improving the safety of the drug.

[0120] (4) The compounds of the present application have good pharmacokinetic properties compared with the compounds disclosed in the prior art, such as good Cmax, AUC, bioavailability and other parameters.

[0121] (5) The compounds of the present application have significant weight loss effect, and can significantly reduce the body weight of mice, reduce the fat weight of mice, reduce the fat / body weight ratio and increase the lean body weight / body weight ratio in a DIO mouse model.

[0122] Terms:

[0123] Unless otherwise specified, all terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0124] The term "C1-C 10"Alkyl" refers to a saturated branched or straight monovalent hydrocarbon group derived from a parent alkane containing 1 to 10 carbon atoms by removing a hydrogen atom from a single carbon atom. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl (such as prop-1-yl and prop-2-yl), butyl (such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-methyl-prop-2-yl, tert-butyl), and similar groups. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, while in other embodiments, the alkyl group contains 1 to 4 carbon atoms. In other embodiments, the alkyl group contains 1 or 2 carbon atoms. Branched alkyl groups contain at least 3 carbon atoms and typically contain 3 to 7 carbon atoms, or in some embodiments, 3 to 6 carbon atoms. Alkyl groups having 1 to 6 carbon atoms may be referred to as C1-C6 alkyl groups; alkyl groups having 1 to 4 carbon atoms may be referred to as C1-C4 alkyl groups.

[0125] The term "C1-C" 10 "Halogenated alkyl" refers to C1-C 10 A group obtained by substituting an alkyl group with one or more halogens. Typical alkyl halogens include, but are not limited to, trifluoromethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and similar groups. Alkyl halogens having 1 to 6 carbon atoms are called C1-C6 alkyl halogens; alkyl halogens having 1 to 3 carbon atoms are called C1-C3 alkyl halogens.

[0126] The term "C3-C" 10 "Cycloalkyl" refers to a saturated cycloalkyl group derived from a parent monocyclic or fused-ring cycloalkanes containing 3 to 10 carbon atoms by removing a hydrogen atom from a single carbon atom. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and their analogues. Cycloalkyl groups can be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having 3 to 10 ring members can be referred to as C3-C. 10 Cycloalkyl; cycloalkyl groups having 4 to 7 ring members can be called C4-C 10 Cycloalkyl group. In some embodiments, the cycloalkyl group may be C3-C6. 10 Cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4-C6 cycloalkyl.

[0127] The term "C4-C" 10 "Cycloalkenyl" refers to a non-aromatic monocyclic or bicyclic carbocyclic ring containing at least one double bond (e.g., one, two, or three double bonds). Typical cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0128] Term "C" 3- C 10 "Cycloalkoxy" refers to -OR, where R represents C3-C as defined in this paper.10 Cycloalkyl groups. Typical cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and similar groups. Cycloalkoxy groups having 3 to 6 carbon atoms can be called C3-C6 cycloalkoxy groups.

[0129] The term "C4-C" 10 "Heterocyclic alkyl" refers to alkyl groups formed at C4-C6. 10 In cycloalkyl groups, heterocyclic alkyl groups are derived by replacing one or more carbon atoms with heteroatoms. Typical heteroatoms include oxygen, nitrogen, and sulfur. Typical heterocyclic alkyl groups include, but are not limited to, oxoheterobutylalkyl, tetrahydrofuranyl, tetrahydropyranyl, dioxohexacycloalkyl, azaheterobutylalkyl, tetrahydropyrroleyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and similar groups. In some embodiments, the heterocyclic alkyl group comprises 3 to 9 carbon atoms and 1 to 2 heteroatoms; while in other embodiments, the heterocyclic alkyl group comprises 4 to 6 carbon atoms and 1 to 2 heteroatoms.

[0130] The term "C4-C" 10 "Heterocyclic group" refers to a group formed at C4-C6. 10 In cycloalkyl groups, a group derived by replacing one or more single bonds with double bonds has at least one saturated or unsaturated but non-aromatic ring. Typical heterocyclic groups include 4,5-dihydrooxazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydroquinoline-4-yl, 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-b]pyridin-7-yl and similar groups.

[0131] The term "C4-C" 10 "Heterocyclic alkoxy" refers to -OR, where R represents C4-C as defined in this paper. 10 Heterocyclic alkyl groups. Typical heterocyclic alkoxy groups include, but are not limited to, oxetane-3-yloxy, (tetrahydrofuran-2-yl)oxy, (tetrahydrofuran-3-yl)oxy, piperidin-3-yloxy, piperidin-4-yloxy, (tetrahydro-2H-pyran-3-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, and similar groups. Cycloalkoxy groups with a total of 4 to 6 carbon atoms and heteroatoms can be called C64-alkyl groups. 4- C6 heterocyclic alkoxy group.

[0132] The term "C2-C" 10"Alkenyl" refers to an unsaturated branched or straight chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a parent alkene containing 2 to 10 carbon atoms. The group can be in either the Z or E (cis or trans) form around the double bond. Typical alkenyl groups include, but are not limited to, ethenyl, propenyl groups such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1 -yl (allyl), and prop-2-en-2-yl; butenyl groups such as but-1 -en-1 -yl, but-1 -en-2-yl, 2-methyl-prop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-1 -yl, but-2-en-2-yl, but-1,3-dien-1 -yl, and but-1,3-dien-2-yl; and the like. In certain embodiments, alkenyl groups have 2 to 10 carbon atoms. In certain embodiments, alkenyl groups have 2 to 6 carbon atoms, and in other embodiments, 2 to 4 carbon atoms.

[0133] The term "C5-C 12 "Spirocyclyl" refers to a spirocyclic group derived by the removal of one hydrogen atom from a parent spirocycle containing 5 to 12 carbon atoms; wherein the above "parent spirocycle" refers to an alicyclic hydrocarbon formed by sharing one carbon atom between two monocyclic or fused ring cycloalkanes. Typical spirocyclyl groups include, but are not limited to, spiro[2.3]hexanyl groups such as spiro[2.3]hexan-1 -yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl; spiro[3.3]heptanyl groups such as spiro[3.3]heptan-1 -yl, spiro[3.3]heptan-2-yl; spiro[3.5]nonanyl groups such as spiro[3.5]nonan-1 -yl, spiro[3.5]nonan-2-yl, spiro[3.5]nonan-5-yl, spiro[3.5]nonanyl-6-yl, spiro[3.5]nonan-7-yl; and the like. In certain embodiments, spirocyclyl groups have 5 to 12 carbon atoms; while in other embodiments, spirocyclyl groups contain 7 to 11 carbon atoms.

[0134] The term "C5-C 12 "Heterospirocyclyl" refers to a heterospirocyclic group derived by replacing one or more carbon atoms in a C5-C 12 Spirocyclyl with a heteroatom. Wherein, typical heteroatoms include oxygen, nitrogen, and sulfur. Typical heterospirocyclyl groups include, but are not limited to, 2,6-diazaspiro[3.3]heptanyl, 1 -azaspiro[4.4]octanyl, 2-azaspiro[4.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, and the like. In certain embodiments, heterospirocyclyl groups have 4 to 11 carbon atoms and 1 heteroatom; while in other embodiments, heterospirocyclyl groups contain 3 to 11 carbon atoms and 2 to 3 heteroatoms.

[0135] The term "C5-C 12A "bridged ring group" refers to a bridged ring group derived from a parent bridged ring containing 5 to 12 carbon atoms by removing a hydrogen atom from a single carbon atom; wherein the aforementioned "parent bridged ring" refers to an alicyclic hydrocarbon formed by two monocyclic or fused-ring cycloalkanes sharing 3 or more carbon atoms. Typical bridged ring groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and similar groups. In some embodiments, the bridged ring group has 5 to 12 carbon atoms; while in other embodiments, the bridged ring group has 7 to 10 carbon atoms.

[0136] The term "C5-C" 12 "Mixed bridge ring base" refers to the base in C5-C 12 In bridged cyclic groups, heterobridged cyclic groups are derived by replacing one or more carbon atoms with heteroatoms. Typical heteroatoms include oxygen, nitrogen, and sulfur. Typical heterobridged cyclic groups include, but are not limited to, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, and similar groups. In some embodiments, the heterobridged cyclic group has 4 to 11 carbon atoms and 1 to 2 heteroatoms; while in other embodiments, the heterobridged cyclic group has 5 to 11 carbon atoms and 1 to 3 heteroatoms.

[0137] The term "C5-C" 15"Heteroaryl" refers to a monovalent heteroaromatic group derived by removal of one hydrogen atom from a 5- to 15-membered parent heteroaromatic ring system. Heteroaryl groups typically include one or more heteroatoms, for example 1, 2, 3, or 4, selected from oxygen, nitrogen, or sulfur, with the remaining atoms being carbon. In certain embodiments, a heteroaryl group is a 5- to 15-membered aromatic ring, monocyclic, bicyclic, and tricyclic, including 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a monocyclic heteroaryl group can include 5, 6, 7, or 8 ring members, and can include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom, wherein the heteroatoms are independently selected from oxygen, nitrogen, or sulfur. In a bicyclic heteroaryl ring group, both rings are aromatic, and at least one ring must include a heteroatom, but it is not necessary that both rings include a heteroatom. In a tricyclic heteroaryl group, all three rings are aromatic, and at least one ring includes at least one heteroatom. Examples of heteroaryl groups include, but are not limited to, groups derived from pyrrole, furan, thiophene, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, cinnoline, indazole, indole, benzofuran, benzothiophene, benzopyrazole, benzimidazole, benzopyrrole, pyrimidoimidazole, pyrimidopyrazole, isoindole, quinoline, isoquinoline, naphthridine, 2H-benzo[D][l,2,3]triazole, phtalazine, pteridine, purine, pyrrolizine, quinazoline, quinoxaline, acridine, carbazole, indenocarbazole, phenanthroline, phenarsenazole, phenoxathine, and the like. In certain embodiments, a heteroaryl group can be a 5- to 15-membered heteroaryl group, referred to as C5-C 15 heteroaryl; in certain embodiments, a heteroaryl group can be a 5- to 10-membered heteroaryl group, referred to as C5-C 10 heteroaryl.

[0138] The term "C6-C 10 aryl" refers to a monovalent aromatic hydrocarbon group derived by removal of one hydrogen atom from a 6- to 10-membered parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, such as benzene. Aryl also encompasses bicyclic carbocyclic ring systems in which each ring is aromatic, such as naphthalene. Aryl groups can thus include fused ring systems in which the rings are carbocyclic aromatic rings. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups can be referred to as C6-C l0 aryl. If one or more carbocyclic aromatic rings are fused to an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, as defined herein, rather than an aryl group.

[0139] The term "halogen" refers to a fluorine, chlorine, bromine, or iodine radical.

[0140] The term "oxa" refers to an =0 group. For example, when the 4-position of a cyclohexyl group is substituted with an oxa group, the 4-oxacyclohexyl group results. For another example, when the 6-position of a piperidin-2-yl group is substituted with an oxa group, the 6-oxapiperidin-2-yl group results.

[0141] The term "C1-C5alkanoyl" refers to the group -C(O)R, wherein R represents hydrogen or C1-C5alkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, isopropylcarbonyl, and the like.

[0142] The term "C3-C6cycloalkanoyl" refers to the group -C(O)R, wherein R represents C3-C6cycloalkyl as defined herein. Representative examples include, but are not limited to, cyclopropylcarbonyl, cyclobutylcarbonyl, and the like.

[0143] The term "C1-C5alkoxy" refers to the group -OR, wherein R represents C1-C5alkyl as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propyloxy, butyloxy, cyclohexyloxy, and the like. Typical alkoxy groups contain 1 to 5 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms in the R group. Alkoxy groups containing 1 to 5 carbon atoms can be referred to as C1-C5alkoxy, and alkoxy groups containing 1 to 3 carbon atoms can be referred to as C1-C3alkoxy.

[0144] The term "C1-C5haloalkoxy" refers to a C1-C5alkoxy group substituted with one or more halogen. Representative examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, monofluoroethoxy, 1,2-difluoroethoxy, 2,2-difluoroethoxy, 2-chloro-l-fluoroethoxy, and the like.

[0145] The term "C1-C6alkanoyloxy" refers to the group -OR, wherein R represents C1-C6alkanoyl as defined herein. Representative examples include, but are not limited to, formyloxy, acetyloxy, isopropylcarbonyloxy, and the like.

[0146] The term "C3-C6cycloalkanoyloxy" refers to the group -OR, wherein R represents C3-C6cycloalkanoyl as defined herein. Representative examples include, but are not limited to, cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, and the like.

[0147] The term "amino" refers to the -NH2group.

[0148] The term "C1-C6alkyl" refers to a straight or branched carbon chain having one to six carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl. Typical alkyl groups will have 1 to 3 carbon atoms, 1 to 2 carbon atoms, or 1 carbon atom and can be referred to as C1-C3alkyl, C1-C2alkyl, or C1-C1alkyl, respectively.

[0149] The term "C1-C6haloalkyl" refers to a C1-C6alkyl group as defined herein substituted by one or more halogen atoms. Representative examples include, but are not limited to, (2,2-difluoroethyl), (2,2,2-trifluoroethyl), (2,2,2-trifluoroethyl), (2,2-difluoropropyl), (2,3-difluoropropyl), and the like.

[0150] The term "di-C1-C6alkylamino" refers to the group -NR N1 R N2 wherein R N1 and R N2 each independently represent a C1-C6alkyl group as defined herein. Representative examples include, but are not limited to, dimethylamino, ethyl(methyl)amino, isobutyl(methyl)amino, isobutyl(ethyl)amino, and the like.

[0151] The term "di-C1-C6haloalkylamino" refers to a di-C1-C6alkylamino group as defined herein substituted by one or more halogen atoms. Representative examples include, but are not limited to, (2-fluoropropyl)(methyl)amino, (2,2-difluoroethyl)(methyl)amino, (2,2,2-trifluoroethyl)(methyl)amino, (2,2-difluoropropyl)(2-fluoroethyl)amino, and the like.

[0152] The term "C1-C6alkanoylamino" refers to the group -NHR, wherein R represents a C1-C6alkanoyl group as defined herein. Representative examples include, but are not limited to, formanilino, acetylamino, isopropylamino, and the like.

[0153] The term "C3-C6cycloalkanoylamino" refers to the group -NHR, wherein R represents a C3-C6cycloalkanoyl group as defined herein. Representative examples include, but are not limited to, cyclopropanoylamino, cyclobutanoylamino, and the like.

[0154] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "C6-C 10 aryl or C5-C 15 heteroaryl optionally substituted by one or more halogen" means that the halogen can or can not be present, and this description includes instances in which the C6-C10 aryl or C5-C 15 heteroaryl is not substituted with halogen. 10 aryl or C5-C 15 heteroaryl is not substituted with halogen.

[0155] The term "substituted" means that one or more of the hydrogen atoms present in the given structure are optionally replaced with a particular substituent. Unless otherwise indicated, one substituent group can be replaced with a substituent at each substitutable position of the group. When more than one position in the given structure can be substituted with one or more substituents selected from a particular group, the substituents can be the same or different at each position.

[0156] The term "pharmaceutically acceptable salt" means a salt that is within the scope of sound medical judgment for use with humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., Wiley- VCH, 2002. Pharmaceutically acceptable salts of the compounds of this application include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable, nontoxic acid salts are specifically formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or from bases such as ammonia, cyclic amines, and organic bases. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. Other pharmaceutically acceptable salts include pharmaceutically acceptable metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium, calcium, or magnesium salts.

[0157] The term "isomer" refers to compounds that have the same molecular formula but differ in the connectivity or order of their atoms or in the spatial arrangement of their atoms and are referred to as "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers." Stereoisomers that are mirror images of one another are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or they can be designated by the direction which the molecule rotates a plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers). Chiral compounds can exist as individual enantiomers or as mixtures of enantiomers. Mixtures of enantiomers in equal proportions are called "racemic mixtures."

[0158] The term "tautomer" refers to a particular compound structure that exists in an interchangeable form and has a change in the position of a hydrogen atom and an electron. Thus, two structures can be in equilibrium by the movement of a pi electron and an atom, usually H. For example, an enol and a ketone are tautomers because they can be rapidly interconverted by treatment with an acid or a base.

[0159] The term "treatment" refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism or other predisposing circumstances), i.e., prophylactic treatment. Treatment can also be continued after symptoms have resolved, for example, to delay their recurrence.

[0160] The term "prevention" refers to preventing the disease, disorder, or condition from developing in a human or animal that can be predisposed to the disease, disorder, and / or condition, but has not yet been diagnosed as having the disease, disorder, and / or condition; and / or inhibiting the disease, disorder, or condition, i.e., arresting its development. BRIEF DESCRIPTION OF DRAWINGS

[0161] Figure 1 is a graph of the body weight change of mice after two weeks of continuous administration in Experimental Example 4.

[0162] Figure 2 is a graph of the percentage body weight change of mice after two weeks of continuous administration in Experimental Example 4.

[0163] Figure 3 is a graph of the fat weight in the body composition of mice after two weeks of continuous administration in Experimental Example 4.

[0164] Figure 4 is a graph of fat / weight ratio and lean body weight / weight ratio of mice after two weeks of continuous administration in Experimental Example 4. DETAILED DESCRIPTION

[0165] The compounds of the present application can be prepared from readily available starting materials and reagents by employing standard synthetic procedures and steps. It will be appreciated that, unless otherwise indicated, typically or preferably, reaction conditions such as reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc. are those commonly used as a starting point in that reaction, although they can be varied as is understood by the skilled artisan. Optimum reaction conditions can vary depending on the particular reactants or solvent used, but such optimum reaction conditions can nevertheless be determined by one skilled in the art by routine optimisation procedures. Additionally, it can be necessary to protect certain functional groups, as is well understood in the art, in order to prevent undesirable side reactions. Suitable protecting groups, and conditions for protecting and deprotecting these groups, are well known in the art.

[0166] For the preparation of the compounds of the present application as defined above, the following detailed preparation methods are provided. These compounds can be synthesized by those skilled in the art of organic synthesis using known or commercially available starting materials and reagents.

[0167] The following abbreviations are used to designate various reagents, solvents, units, instruments, or detection methods: DMF N,N-dimethylformamide Pd(PPh3)4 palladium tetraphenylphosphine tetrakis °C degrees Celsius h hour LCMS liquid chromatography mass spectrometer TLC thin layer chromatography Pd(dba)2 palladium bis(acetonitrile) dichloride BINAP 1,1'-binaphthalene-2,2'-diphenylphosphine Pd-PEPPSI palladium-PEPPSI TM- IPent Dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) Pd(dppf)Cl2 (l,l'-Bis(diphenylphosphino) ferrocene)dichloropalladium Pd2(dba)3.CHCl3 Tris(dibenzylideneacetone)dipalladium-chloroform adduct BrettPhos 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl- 11 '-biphenyl Xantphos-G4-Pd Methanesulfonic acid (4,5-bisdiphenylphosphino-9,9- dimethoxyxanthene)(2'-methylamino-l,l'-biphenyl-2-yl)palladium(II) sSPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-3'-sodium sulfonate- 1,1'-biphenyl)(2'-amino-l,l'-biphenyl-2-yl)palladium(II) PdCl2(dtbpf) [l,l'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Me4-t-BuXphos 2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl TBAF Tetra-n-butylammonium fluoride MPLC Medium pressure preparative chromatography Ruphos-Pd-G4 Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri- isopropyl-l,l'-biphenyl)(2'-amino-l,l'-biphenyl-2-yl)palladium(II) X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium Xantphos 4,5-Bisdiphenylphosphino-9,9-dimethoxyxanthene DIEA N,N-Diisopropylethylamine Ruphos 2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl Xantphos-G3-Pd Methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphino- xanthene)(2'-amino-l,l'-biphenyl-2-yl)palladium(II)

[0168] For the preparation of the compounds of the application as defined above, the following detailed preparation methods apply. These compounds can be synthesized by a person skilled in the art of organic synthesis, using known or commercially available starting materials and reagents.

[0169] The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). The determination of NMR uses a Bruker Avance III 400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). The determination of LC-MS uses an Agilent LCMS1260-6120 liquid chromatograph-mass spectrometer or an ACQUITY QDA liquid chromatograph-mass spectrometer of Waters Corporation.

[0170] Thin layer chromatography (TLC) uses Yantai Xinuo thin layer chromatography GF254 silica gel plate, and the specification of TLC used is 0.2mm-0.25mm. Medium pressure preparative column chromatography separation uses a sepaBean Machine rapid liquid phase preparative chromatograph of Changzhou Santai Technology Co., Ltd. Normal phase column chromatography uses a Biotage silica gel column of Changzhou Santai Technology Co., Ltd., 40-63μm. Reverse phase column chromatography uses an Agela Technologies reverse phase C18 chromatographic column, 20-35μm.

[0171] Synthesis of compound 1 of example 1

[0172] Synthesis of intermediate 1c in the first step

[0173] In a three-necked flask, the starting material 1a (1.00g, 3.53mmol) was dissolved in dioxane (15mL) and water (5mL). The starting material 1b (611mg, 3.53mmol) and cesium carbonate (2.30g, 7.06mmol) were added, and the nitrogen atmosphere was replaced and maintained. Pd(PPh3)4 (204mg, 176μmol) was added, and the reaction was carried out at 100℃ for 18h. After LCMS showed that the reaction was complete, water (20mL) was added to the reaction system, and extracted with ethyl acetate (10mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product of intermediate 1c (1.4g). MS-ESI Theoretical value [M+H] + : 250.1; Found: 250.1.

[0174] Synthesis of intermediate 1e in the second step

[0175] In a three-necked flask, the starting material 1d (10.0 g, 65.3 mmol) was dissolved in dichloromethane (10 mL), then 2,6-dimethylpyridine (30.0 mL, 258 mmol) was added, and the nitrogen atmosphere was maintained. After cooling to 0 °C, sulfuric oxide (11.26 g, 97.9 mmol) was added dropwise slowly. After the addition was completed, the reaction was continued at 25 °C for 2 h, and TLC showed that the reaction was complete. The filtrate was obtained by filtration, and concentrated to give the crude intermediate 1e (7.90 g).

[0176] Step 3. Synthesis of intermediate 1f

[0177] In a three-necked flask, the crude intermediate 1e (8.60 g, 44 mmol) was dissolved in acetonitrile (18 mL), and tert-butyl sulfonamide (6.3 g, 46 mmol) was added, and the nitrogen atmosphere was maintained. After the addition of cesium carbonate (18.6 g, 57 mmol) in portions, the reaction was carried out at 25 °C for 16 h, and TLC showed that the reaction was complete. Filtration was performed, and the obtained filtrate was concentrated and subjected to silica gel column chromatography (dichloromethane:methanol = 99:1-94:6, v / v) to give the intermediate 1f (7.30 g, 22.0 mmol, yield 49.9%).

[0178] Step 4. Synthesis of intermediate 1g

[0179] In a three-necked flask, the intermediate 1f (9.11 g, 27.4 mmol) and the starting material 5-methylnicotinic hydrazide (4.35 g, 28.8 mmol) were dissolved in acetonitrile (100 mL), and the nitrogen atmosphere was maintained. Silver nitrate (10.2 g, 60.1 mmol) was added, and the reaction was carried out at 25 °C for 2 h, and TLC showed that the reaction was complete. The obtained reaction system was concentrated and subjected to silica gel column chromatography (dichloromethane:methanol = 99:1-94:6, v / v) to give the intermediate 1g (7.00 g, 15.6 mmol, yield 56.9%). 1 H NMR (400 MHz, DMSO-d6) 10.68 (br. s, 1H), 9.09 (br. s, 1H), 8.91-8.53 (m, 3H), 8.14-7.97 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.76-6.67 (m, 2H), 3.75-3.72 (m, 6H), 2.35 (s, 3H), 1.26-1.21 (m, 9H).

[0180] Step 5. Synthesis of intermediate 1h

[0181] In a three-necked flask, intermediate 1g (7 g, 15.57 mmol) was dissolved in dioxane (35 mL) and purged with nitrogen and kept under nitrogen atmosphere. After the addition of trifluoroacetic acid (5.78 mL, 77.86 mmol), it was heated to 100 °C for 18 h. LCMS showed the reaction was complete. The filtrate was obtained by filtration and concentrated to give intermediate 1h crude (15.0 g). MS-ESI [M+H] calc’d for C12H9F3N2O, 232.1; found, 232.2. + : 432.2; found: 432.6.

[0182] Step 6 Synthesis of intermediate 1i

[0183] In a three-necked flask, intermediate 1h (15.0 g, 34.8 mmol) was dissolved in trifluoroacetic acid (75 mL) and anisole (11.3 g, 104 mmol) was added. It was purged with nitrogen and kept under nitrogen atmosphere. It was heated to 100 °C for 18 h. LCMS showed the reaction was complete. After the removal of trifluoroacetic acid by concentration, the concentrate was added to ice water and the pH was adjusted to 8-9 with 10% aqueous sodium bicarbonate solution (40 mL). It was filtered and washed with water (50 mL), petroleum ether (50 mL) and methyl tert-butyl ether (50 mL) respectively. The resulting filter cake was dried to give intermediate 1i crude (5 g, 16.1 mmol, 46.3% yield). MS-ESI [M+H] calc’d for C12H9F3N2O, 232.1; found, 232.2. + : 312.1; found: 312.2.

[0184] Step 7 Synthesis of intermediate 1j

[0185] In a three-necked flask, intermediate 1i crude (5 g, 16.1 mmol) was dissolved in dibromomethane (200 mL) and benzyltriethylammonium bromide (13.1 g, 48.2 mmol), sodium nitrite (22.2 g, 321 mmol) and 2,2-dichloroacetic acid (4.14 g, 32.1 mmol) were added. It was purged with nitrogen and kept under nitrogen atmosphere and reacted at 25 °C for 2 h. LCMS showed the reaction was complete. The filtrate was obtained by filtration and concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:1, v / v) to give intermediate 1j (1.82 g, 4.85 mmol, 30.2% yield). MS-ESI [M+H] calc’d for C19H19BrF3N2O, 375.0; found, 375.1. + : 312.1; found: 312.2. 1 H NMR (400 MHz, DMSO-d6): δ 8.49-8.42 (m, 1H), 8.26-8.18 (m, 1H), 7.68-7.63 (m, 1H), 7.52-7.60 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H), 3.72 (s, 6H), 2.26 (s, 3H).

[0186] Eighth Step Synthesis of Compound 1

[0187] In a three-neck flask, intermediate 1j (150 mg, 400 μmol), intermediate 1c (149 mg, 600 μmol), sodium tert-butoxide (38.4 mg, 400 μmol), and Pd(dba)2(46.0 mg, 80.0 μmol) and BINAP (74.7 mg, 120 μmol) were dissolved in dioxane (10 mL). After being purged with nitrogen and kept under nitrogen atmosphere, it was heated to 120 °C for 2 h. LCMS showed the reaction was complete. The filtrate was filtered, concentrated and purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 40*200mm 7μm; mobile phase: [water (0.1% FA) - acetonitrile]; elution gradient: 18% - 58% over 15 min) to give compound 1 (50.0 mg, 92 μmol, 23% yield). MS-ESI calc. for [M+H] + : 544.2; found: 544.2. 1 H NMR: (400 MHz, DMSO-d6): δ 13.67 (s, 1H), 8.84-8.74 (m, 3H), 8.51 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.93-7.86 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H), 6.81-6.77 (m, 2H), 3.57 (s, 6H), 2.32 (s, 3H), 2.22 (s, 3H). 13 C NMR: (100 MHz, DMSO-d6): δ 160.11, 157.98, 156.08, 152.28, 152.20, 151.07, 146.61, 144.36, 138.00, 135.18, 133.64, 132.68, 130.36, 130.03, 129.43, 127.64, 124.99, 121.48, 109.13, 105.10, 56.42, 17.87, 15.20.

[0188] Example 2 Synthesis of Compound 2

[0189] First Step Synthesis of Intermediate 2b

[0190] In a dry single-necked flask, starting material 2a (10.00 g, 66.16 mmol) was dissolved in methanol (200 mL), followed by the sequential addition of cesium carbonate (64.67 g, 198.48 mmol) and hydrazine hydrochloride (9.07 g, 132.32 mmol). After the addition was complete, the reaction was carried out at 70 °C for 5 h, and TLC showed that the reaction was complete. After cooling to room temperature, the mixture was filtered, washed with methanol (20 mL × 3), and the filtrate and washings were combined, concentrated, and purified by silica gel column chromatography to give intermediate 2b (7.1 g, 47.01 mmol, yield 71.1%). 1 H NMR (400MHz, DMSO-d6) δ9.90(s,1H),8.76(d,J=1.9Hz,1H),8.53(d,J=1.5Hz,1H),7.97(d,J=0.6Hz,1H),4.55(s,2H),2.34(s,3H).

[0191] The synthesis of intermediate 1e in the second step

[0192] In a dry three-necked flask, starting material 1d (1.00 g, 6.53 mmol) was dissolved in dichloromethane (10 mL) and water (10 mL). Sodium bicarbonate (1.37 g, 16.32 mmol) was added, and the mixture was cooled to 0 °C. Phosgene (0.9 g, 7.84 mmol) was added, and the mixture was kept at 0 °C for 10 min. The temperature was then raised to room temperature, and the reaction was continued for 1 h. TLC showed that the reaction was complete. Water (25 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was slurried with petroleum ether (50 mL), filtered, and used to give intermediate 1e (1.00 g, 5.12 mmol, yield 78.46%). MS-ESI theoretical value [M+H] + : 196.0; Measured value: 196.3.

[0193] The third step involves the synthesis of intermediate 2c.

[0194] In a dry three-necked flask, the starting material 3-methylbenzenesulfonamide (0.35 g, 2.04 mmol) was dissolved in acetonitrile (25 mL), and intermediate 1e (0.42 g, 2.04 mmol) was added in portions. After the addition was complete, the reaction solution was cooled to 10 °C, cesium carbonate (0.86 g, 2.65 mmol) was added, and the reaction was carried out at 10 °C for 10 min. The mixture was then brought to room temperature and reacted for another 22 h. LC-MS showed that the reaction was complete. The resulting reaction solution was poured into water (25 mL), the pH was adjusted to 7 with citric acid, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give intermediate 2c (0.68 g, 1.86 mmol, yield 91.1%). MS-ESI theoretical value [M+H] +: 367.1 ; found: 367.0.

[0195] Synthesis of intermediate 2d in the fourth step

[0196] In a dry flask, intermediate 2c (0.68 g, 1.86 mmol) was dissolved in acetonitrile (25 mL). After the reaction solution was cooled to 0 °C, cesium carbonate (0.79 g, 2.42 mmol) was added and stirred for 10 min, intermediate 2b (0.28 g, 1.86 mmol) and silver nitrate (0.63 g, 3.72 mmol) were added. After the addition, it was warmed to room temperature and reacted for 2 h, TLC showed that the reaction was complete. The reaction solution was filtered, concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give intermediate 2d (0.40 g, 0.83 mmol, yield 44.44 %). MS-ESI [M+H] calc’d for C26H21FN4O4, 483.1; found: 483.2. + : 484.2; found: 484.2.

[0197] Synthesis of compound 2 in the fifth step

[0198] In a dry flask, intermediate 2d (0.39 g, 0.81 mmol) was dissolved in dioxane (10 mL), and methane sulfonic acid (0.23 g, 2.43 mmol) was added dropwise. After the addition, it was warmed to 100 °C and reacted for 2 h, TLC showed that the reaction was complete. Water (40 mL) was added, and the pH was adjusted to 7 with aqueous sodium carbonate solution. It was extracted with dichloromethane (50 mL x 3), and the organic phase was combined and washed with saturated brine (50 mL x 2), concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 2 (141.7 mg, 0.30 mmol, yield 37.62 %). MS-ESI [M+H] calc’d for C26H21FN4O4, 483.1; found: 483.2. + : 466.1; found: 466.2. 1 HNMR (400 MHz, DMSO-d6): δ 13.49 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.63-7.55 (m, 3H), 7.53-7.33 (m, 3H), 6.82 (d, J = 8.5 Hz, 2H), 3.62 (s, 6H), 2.37 (s, 3H), 2.23 (s, 3H).

[0199] Synthesis of compound 3 in Example 3

[0200] Synthesis of intermediate 3a in the first step

[0201] Compound 3-fluorobenzene-l-sulfonamide (1.00 g, 5.71 mmol), intermediate le (1.11 g, 5.71 mmol) were added into acetonitrile (30 mL). After the addition of cesium carbonate (2.23 g, 6.85 mmol), the reaction was carried out at 25 °C for 16 h. After TLC showed the reaction was complete, the pH was adjusted to 7 with aqueous citric acid solution, water (40 mL) and ethyl acetate (40 mL) were added, and filtered. The resulting filter cake was dried under vacuum to give intermediate 3a (1.50 g, 4.05 mmol, 70.9% yield).

[0202] Second Step, Synthesis of Intermediate 3b

[0203] Intermediate 3a (1.5 g, 4.05 mmol) was dissolved in acetonitrile (40 mL), and after cooling to 0 °C, 5-methylnicotinohydrazide (0.67 g, 4.46 mmol), silver nitrate (1.38 g, 8.10 mmol), and cesium carbonate (1.32 g, 4.05 mmol) were added sequentially. After addition, the reaction was continued at room temperature for 2 h. After TLC showed the reaction was complete, dichloromethane (20 mL) and methanol (20 mL) were added. After complete dissolution, the resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give intermediate 3b (0.50 g, 1.03 mmol, 25.3% yield). MS-ESI [M+H] calc’d for C21H18FN5O3, 488.1; found, 488.2. +

[0204] Third Step, Synthesis of Compound 3

[0205] Intermediate 3b (0.50 g, 1.03 mmol) was dissolved in 1,4-dioxane (15 mL), and methane sulfonic acid (0.30 g, 3.09 mmol) was added slowly. After addition, the reaction was heated to 100 °C for 3 h. After TLC showed the reaction was complete, the methane sulfonic acid was quenched with aqueous sodium bicarbonate solution, and concentrated. In the residue, ethyl acetate / petroleum ether (66:33, 20 mL) was added to slurry, filtered, and the resulting filter cake was purified by silica gel column chromatography (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 3 (0.20 g, 0.43 mmol, 41.5% yield). MS-ESI [M+H] calc’d for C21H17FN4O3, 470.1; found, 470.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H), 8.50 (s, 1H), 8.18 (t, J = 14.0 Hz, 1H), 7.70 - 7.35 (m, 6H), 6.83 (d, J = 8.8 Hz, 2H), 3.64 (d, J = 6.4 Hz, 6H), 2.32 (d, J = 9.2 Hz, 3H).​​

[0206] Synthesis of compound 4 of example 4

[0207] Synthesis of intermediate 4a in the first step

[0208] Compound 3-chlorobenzene-1-sulfonamide (1.00 g, 5.22 mmol) was dissolved in acetonitrile (20 mL), and intermediate 1e (1.12 g, 5.74 mmol) was added. After cooling to 10 °C, cesium carbonate (2.55 g, 7.83 mmol) was slowly added, and the mixture was warmed to 30 °C and stirred for 16 h. After the reaction was completed as indicated by TLC, the mixture was filtered and washed with dichloromethane. The filtrate was concentrated to give crude intermediate 4a (1.20 g, 3.10 mmol, 59.4% yield), which was used directly in the next step.

[0209] Synthesis of intermediate 4b in the second step

[0210] The crude intermediate 4a (1.20 g, 3.10 mmol) was dissolved in acetonitrile (20 mL), and 5-methylnicotinic hydrazide (0.56 g, 3.72 mmol), silver nitrate (1.05 g, 6.20 mmol), and cesium carbonate (1.01 g, 3.10 mmol) were added sequentially. After the addition was complete, the mixture was slowly warmed to 25 °C and stirred for 1 h. After the reaction was completed as indicated by TLC, the mixture was dissolved in methanol and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-92:8, v / v) to give intermediate 4b (0.60 g, 1.19 mmol, 38.4% yield).

[0211] Synthesis of compound 4 in the third step

[0212] Intermediate 4b (0.60 g, 1.19 mmol) was dissolved in 1,4-dioxane (10 mL), and methane sulfonic acid (0.34 g, 3.57 mmol) was slowly added. After the addition was complete, the mixture was heated to 100 °C and stirred for 3 h. After the reaction was completed as indicated by TLC, the methane sulfonic acid was quenched with aqueous sodium bicarbonate solution, and the mixture was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 4 (0.20 g, 0.41 mmol, 34.5% yield). MS-ESI [M+H] calc’d for C19H15N5O4S: 486.1; found: 486.0. + 1 ​H NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.79 (t, J = 2.0 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.69 - 7.63 (m, 1H), 7.59 (t, J = 8.0 Hz, 2H), 7.51 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.64 (s, 6H), 2.23 (s, 3H).

[0213] Synthesis of compound 5 of example 5

[0214] Synthesis of intermediate 5a in the first step

[0215] Compound 3-bromobenzene-1-sulfonamide (5.00 g, 21.18 mmol), intermediate 1e (4.14 g, 21.18 mmol) were dissolved in acetonitrile (20 mL). After cooling to 10 °C, cesium carbonate (10.35 g, 31.77 mmol) was added slowly. After the addition was completed, the reaction was continued at room temperature for 16 h. After TLC showed that the reaction was complete, the pH was adjusted to 7-8 with aqueous citric acid solution, and the resulting filter cake was dried under vacuum to obtain crude intermediate 5a (9.00 g, 20.87 mmol, yield 98.5%), which was directly used in the next step.

[0216] Synthesis of intermediate 5b in the second step

[0217] Intermediate 5a (9.00 g, 20.87 mmol) was dissolved in acetonitrile (200 mL), and after cooling to 0 °C, 5-methylnicotinohydrazide (3.47 g, 22.96 mmol), silver nitrate (7.09 g, 41.74 mmol), and cesium carbonate (6.80 g, 20.87 mmol) were added sequentially. After the addition was completed, the reaction was continued at room temperature for 2 h. After TLC showed that the reaction was complete, methanol (50 mL) was added, and after concentration, purification was performed by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to obtain intermediate 5b (8.00 g, 14.61 mmol, yield 69.9%). MS-ESI [M+H] Theoretical: 550.1; Found: 550.1. +

[0218] Synthesis of compound 5 in the third step

[0219] ​Intermediate 5b (8.00 g, 14.61 mmol) was dissolved in 1,4-dioxane (200 mL), and methane sulfonic acid (4.21 g, 43.83 mmol) was added slowly. After addition, the temperature was raised to 100 °C for 3 h. TLC showed the reaction was complete, and the pH was adjusted to about 7 with aqueous sodium bicarbonate solution, and concentrated. The resulting residue was dissolved in dichloromethane / methanol mixture (10:90, 200 mL), and filtered. The resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-96:4, v / v) to give compound 5 (6.35 g, 11.97 mmol, 81.9% yield). MS-ESI [M+H] calculated for C26H21N5O4: 530.0; found: 530.0. + 1 H NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.93 (t, J = 1.6 Hz, 1H), 7.77 (t, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.51 (td, J = 8.0, 3.2 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.64 (s, 6H), 2.23 (s, 3H).

[0220] Synthesis of compound 6

[0221] Compound 5 (0.20 g, 0.38 mmol) and 1,4-dioxane (30 mL) were added into a dry single-neck flask. After stirring and dissolving, potassium tert-butoxide (85 mg, 0.76 mmol), aniline (71 mg, 0.76 mmol), and Pd-PEPPSI TM -IPent (15 mg, 0.019 mmol) were added in sequence, and the nitrogen atmosphere was replaced and maintained. The reaction was heated to reflux for 12 h. After TLC showed the reaction was complete, it was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 6 (0.15 g, 0.27 mmol, 73.3% yield). MS-ESI [M+H] calculated for C28H24N6O4: 543.2; found: 543.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 8.56 - 8.39 (m, 2H), 8.17 (d, J = 1.9 Hz, 1H), 7.58 (s, 1H), 7.47 (dd, J = 9.7, 7.3 Hz, 2H), 7.35 (t, J = 7.9 Hz, 1H), 7.25 (t, J = 7.9 Hz, 2H), 7.17 (dd, J = 13.4, 4.8 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H), 3.57 (d, J = 5.9 Hz, 6H), 2.23 (s, 3H).

[0222] Synthesis of compound 7

[0223] In a dry single neck flask, compound 5 (0.20 g, 0.38 mmol) and 1,4-dioxane (20 mL) were added. After stirring to dissolve, potassium tert-butoxide (85 mg, 0.76 mmol), 1-methyl-1H-pyrazol-4-amine (74 mg, 0.76 mmol) and Pd-PEPPSI TM -IPent (15 mg, 0.019 mmol) were added successively, replaced by nitrogen and kept nitrogen atmosphere, heated to reflux for 6 h. After TLC showed that the reaction was completed, it was filtered, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to obtain compound 7 (70 mg, 0.13 mmol, yield 33.7%). MS-ESI [M+H] Theoretical value: 547.2; Found: 547.2. + : 547.2; Found: 547.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 1.5 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 7.81 (s, 1H), 7.59 (d, J = 12.3 Hz, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 6H), 2.23 (s, 3H).

[0224] Synthesis of compound 8

[0225] In a dry single neck flask was added compound 5 (0.30 g, 0.57 mmol) and 1,4-dioxane (20 mL). After stirring to dissolve, potassium tert-butoxide (130 mg, 1.14 mmol), 4-amino-1-methylpiperidine (130 mg, 1.14 mmol) and Pd-PEPPSI TM -IPent (23 mg, 0.028 mmol), nitrogen was replaced and nitrogen atmosphere was maintained, heated to reflux for 8 h. TLC showed the reaction was completed, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v), compound 8 (100 mg, 0.18 mmol, 31.4% yield) was obtained. MS-ESI [M+H]+calcd for C32H32N7O2: 564.2; found: 564.2. + : 547.2; found: 547.2. 1 H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 8.26 (s, 1H), 7.64 (s, 1H), 7.45 (t, J = 8.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.81 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 3.63 (s, 6H), 3.54 (s, 1H), 3.34 (s, 2H), 2.91 (t, J = 11.1 Hz, 2H), 2.71 (s, 3H), 2.27 (s, 3H), 2.16 (d, J = 11.7 Hz, 2H), 1.67 (d, J = 11.6 Hz, 2H).

[0226] Example 9 Synthesis of compound 9

[0227] In a dry single neck flask was added compound 5 (0.20 g, 0.38 mmol) and 1,4-dioxane (20 mL). After stirring to dissolve, potassium tert-butoxide (85 mg, 0.76 mmol), 1-methyl-1H-pyrazol-3-amine (74 mg, 0.76 mmol) and Pd-PEPPSI TM -IPent (23 mg, 0.028 mmol), nitrogen was replaced and nitrogen atmosphere was maintained, heated to reflux for 8 h. TLC showed the reaction was completed, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v), compound 8 (100 mg, 0.18 mmol, 31.4% yield) was obtained. MS-ESI [M+H]+calcd for C32H32N7O2: 564.2; found: 564.2. + : 547.2; found: 547.2. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.28 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H), 5.76 (d, J = 2.8 Hz, 1H), 3.73 (s, 3H), 3.58 (s, 6H), 2.23 (s, 3H).

[0228] Synthesis of compound 10 of example 10

[0229] Synthesis of intermediate 10a of first step

[0230] In a dry single neck flask, compound 5 (0.2 g, 0.38 mmol) and 1,4-dioxane (20 mL) were added. After stirring to dissolve, potassium tert-butoxide (85 mg, 0.76 mmol), benzophenone imine (140 mg, 0.76 mmol) and Pd-PEPPSI TM -IPent (15 mg, 0.019 mmol), nitrogen was replaced and kept nitrogen atmosphere, heated to reflux for 8 h. After TLC showed the reaction was completed, concentrated, purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1, v / v), to obtain intermediate 10a (0.14 g, 0.22 mmol, yield 58.9%).

[0231] Synthesis of compound 10 of second step

[0232] Intermediate 10a (0.14 g, 0.22 mmol) was dissolved in methanol (20 mL), hydroxylamine hydrochloride (76 mg, 1.1 mmol) was added, stirred at room temperature for 2 h. After TLC showed the reaction was completed, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v), to obtain compound 10 (48 mg, 0.10 mmol, yield 46.4%). + MS-ESI [M+H] : 467.1; found: 467.2. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.46 (d, J = 1.4 Hz, 1H), 8.17 (d, J = 1.8 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.96 (t, J = 1.9 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.68 (dd, J = 8.0, 1.4 Hz, 1H), 5.41 (s, 2H), 3.63 (s, 6H), 2.23 (s, 3H).

[0233] Synthesis of compound 11

[0234] In a dry single neck flask, compound 5 (0.2 g, 0.38 mmol) and 1,4-dioxane (20 mL) were added. After stirring to dissolve, potassium tert-butoxide (85 mg, 0.76 mmol), tert-butyl 2-(methylamino)ethylcarbamate (130 mg, 0.76 mmol) and Pd-PEPPSI TM -IPent (15 mg, 0.019 mmol), nitrogen was replaced and nitrogen atmosphere was maintained, heated to reflux reaction for 8 h. After TLC showed that the reaction was completed, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v), compound 11 (130 mg, 0.24 mmol, yield 62.3%) was obtained. MS-ESI [M+H] Theoretical value: 550.2; Found: 550.2. + : 550.2; Found: 550.2. 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.01 (t, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.2, 1.4 Hz, 1H), 7.63 (s, 1H), 7.47 (dt, J = 13.8, 8.3 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 3.80 (dd, J = 9.1, 6.7 Hz, 2H), 3.60 (s, 6H), 3.47 (dd, J = 9.0, 6.9 Hz, 2H), 2.78 (s, 3H), 2.24 (s, 3H).

[0235] Synthesis of compound 12

[0236] In a dry single neck flask was added compound 5 (0.5 g, 0.94 mmol) and 1,4-dioxane (30 mL). After stirring to dissolve, potassium tert-butoxide (210 mg, 1.88 mmol), trifluoroethylamine (190 mg, 1.88 mmol) and Pd-PEPPSI™-IPent (37 mg, 0.047 mmol) were added sequentially, purged with nitrogen and kept under nitrogen atmosphere, heated to reflux for 8 h. After TLC showed the reaction was complete, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 12 (92 mg, 0.16 mmol, 17.8% yield). MS-ESI [M+H] calc’d for C26H21FN4O4: 549.2; found: 549.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 8.2, 2.0 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.61 (t, J = 6.9 Hz, 1H), 4.06 - 3.87 (m, 2H), 3.60 (s, 6H), 2.23 (s, 3H).

[0237] Example 13 Synthesis of compound 13

[0238] In a dry single neck flask was added compound 5 (0.30 g, 0.57 mmol) and 1,4-dioxane (20 mL). After stirring to dissolve, potassium tert-butoxide (130 mg, 1.14 mmol), 3-oxetanamine (83 mg, 1.14 mmol) and Pd-PEPPSI TM -IPent (23 mg, 0.028 mmol) were added sequentially, purged with nitrogen and kept under nitrogen atmosphere, heated to reflux for 8 h. After TLC showed the reaction was complete, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 13 (110 mg, 0.21 mmol, 37.2% yield). MS-ESI [M+H] calc’d for C26H21FN4O4: 549.2; found: 549.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.46 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 6.5 Hz, 1H), 6.61 (dd, J = 8.0, 1.8 Hz, 1H), 4.83 (t, J = 6.5 Hz, 2H), 4.60 - 4.48 (m, 1H), 4.39 (t, J = 6.0 Hz, 2H), 3.61 (s, 6H), 2.23 (s, 3H).

[0239] Synthesis of compound 14

[0240] In a dry single neck flask, compound 5 (0.30 g, 0.57 mmol) and 1,4-dioxane (20 mL) were added. After stirring to dissolve, potassium tert-butoxide (130 mg, 1.14 mmol), (S)-3-aminotetrahydrofuran (99 mg, 1.14 mmol) and Pd-PEPPSI TM -IPent (23 mg, 0.028 mmol) were added successively, replaced by nitrogen and kept nitrogen atmosphere, heated to reflux and stirred for 8 h. After TLC showed the reaction was completed, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v), compound 14 (100 mg, 0.19 mmol, 33.0% yield) was obtained. MS-ESI [M+H]+calcd: 537.2; found: 537.2. + 1 ​H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.21 (d, J = 6.3 Hz, 1H), 3.97 (d, J = 3.4 Hz, 1H), 3.89 - 3.84 (m, 1H), 3.80 (t, J = 7.6 Hz, 1H), 3.73 (dt, J = 13.5, 6.8 Hz, 1H), 3.61 (s, 6H), 3.49 (dd, J = 8.7, 3.5 Hz, 1H), 2.21 (d, J = 8.9 Hz, 3H), 2.19 - 2.11 (m, 1H), 1.73 (dd, J = 16.5, 12.4 Hz, 1H).

[0241] Synthesis of compound 15

[0242] Synthesis of intermediate 15b

[0243] Compound 15a (1.00 g, 4.24 mmol) was dissolved in 1,4-dioxane (20 mL), and potassium cyclopropyltrifluoroborate (2.51 g, 16.96 mmol), Pd(dppf)Cl2(0.31 g, 0.42 mmol), potassium carbonate (1.76 g, 12.72 mmol) and water (4 mL) were added successively. After replacing nitrogen, the reaction was carried out at 110 °C for 8 h, and the reaction progress was monitored by TLC and LCMS. After the reaction was completed, it was cooled to room temperature, diluted with water and dichloromethane (20 mL) was added, extracted, separated, and the aqueous phase was further extracted with dichloromethane (20 mL x 3). The combined organic phase was dried, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 90:10-70:30, v / v) to give intermediate 15b (0.72 g, 3.65 mmol, 86.2% yield). MS-ESI Calcd for [M+NH4] + : 215.1, found: 215.2.

[0244] Synthesis of intermediate 15c

[0245] Intermediate 15b (611.9 mg. 3.10 mmol) was dissolved in acetonitrile (10 mL), intermediate 1e (0.55 g, 2.82 mmol) was added and cooled to 0 °C, cesium carbonate (1.19 g, 3.67 mmol) was added portionwise. After addition, the reaction was allowed to proceed at room temperature overnight, the progress of the reaction was monitored by TLC. After completion of the reaction, it was concentrated, dichloromethane (20 mL) and water (30 mL) were added, the mixture was extracted, the layers were separated, the aqueous phase was further extracted with dichloromethane (20 mL x 3). The combined organic phases were dried, concentrated to give crude intermediate 15c which was used directly in the next step without purification. MS-ESI [M+H] calc’d for C26H28N6O4, 493.2, found 493.2. + : 393.1, found 393.2.

[0246] Third Step: Synthesis of intermediate 15d

[0247] Intermediate 15c (1.00 g, 2.55 mmol) was dissolved in acetonitrile (20 mL). After cooling to 0 °C, 5-methylnicotinohydrazide (385.5 mg, 2.55 mmol), cesium carbonate (1.66 g, 5.10 mmol) and silver nitrate (866.5 mg, 5.10 mmol) were added sequentially. After addition, the mixture was stirred for 10 minutes, then allowed to warm to room temperature and the reaction was allowed to proceed, the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was filtered, the resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 15d (1.10 g, 2.16 mmol, 84.7% yield). MS-ESI [M+H] calc’d for C30H30N8O4, 510.2, found 510.2. + : 393.1, found 393.2.

[0248] Fourth Step: Synthesis of compound 15

[0249] Intermediate 15d (1.10 g, 2.16 mmol) was dissolved in dioxane (10 mL), methane sulfonic acid (0.62 g, 6.48 mmol) was added dropwise slowly. After addition, the mixture was allowed to warm to 110 °C and the reaction was allowed to proceed for 8 hours, the progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, it was cooled to room temperature, water (20 mL) and dichloromethane (20 mL) were added and the mixture was extracted, the layers were separated. The aqueous phase was further extracted with dichloromethane (20 mL x 2). The combined organic phases were collected, dried, concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 15 (0.47 mg, 0.96 mmol, 44.3% yield). MS-ESI [M+H] calc’d for C30H30N8O4, 492.2, found 492.1. + : 393.1, found 393.2. 1H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.39 (t, J = 7.7 Hz, 1H), 7.25 (dt, J = 7.9, 1.4 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 3.62 (s, 6H), 2.28 (s, 3H), 1.99 (tt, J = 8.3, 5.0 Hz, 1H), 1.09 - 0.92 (m, 2H), 0.79 - 0.64 (m, 2H).

[0250] Synthesis of compound 16

[0251] Compound 5 (1.00 g, 1.89 mmol) was dissolved in 1,4-dioxane (5 mL), then (cyclohex-1-en-1-yl)boronic acid (476.1 mg, 3.78 mmol), Pd(dppf)Cl2(0.14 g, 0.19 mmol), potassium carbonate (0.78 g, 5.67 mmol) and water (2 mL) were added successively. After replacing nitrogen, the reaction was refluxed at 110 °C for 8 h, and the reaction progress was monitored by TLC and LCMS. After the reaction was completed, it was cooled to room temperature, water (20 mL) and dichloromethane (20 mL) were added for extraction, and the aqueous phase was continuously extracted with dichloromethane (20 mL x 3). The combined organic phase was dried, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 16 (564 mg, 1.06 mmol, 56.3% yield). MS-ESI Calcd for [M+H] C28H28N4O4: 532.2, found: 532.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.63 - 7.54 (m, 3H), 7.48 (dt, J = 11.4, 8.1 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 6.23 (s, 1H), 3.60 (s, 6H), 2.37 (s, 2H), 2.22 (s, 5H), 1.78 - 1.70 (m, 2H), 1.65 - 1.55 (m, 2H).

[0252] Synthesis of compound 17

[0253] Synthesis of intermediate 17a ​

[0254] Compound 5 (500.0 mg, 0.94 mmol) was dissolved in 1,4-dioxane (10 mL), and (4-(Boc-amino)cyclohex-1-en-1-yl)boronic acid pinacol ester (334.3 mg, 1.03 mmol), Pd(dppf)Cl2(34.4 mg, 0.05 mmol), potassium carbonate (390.0 mg, 2.82 mmol) and water (2 mL) were added successively. After replacing nitrogen, the reaction was carried out at 110 °C for 8 h, and the reaction progress was monitored by TLC and LCMS. After the reaction was completed, it was cooled to room temperature, water (20 mL) and dichloromethane (20 mL) were added, and the mixture was extracted and separated. The aqueous phase was further extracted with dichloromethane (20 mL x 3). The combined organic phase was dried, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 17a (332.1 mg, 0.51 mmol, 54.8% yield). MS-ESI [M+H] calc’d for C26H32N4O4: 467.2, found: 467.2. +

[0255] Second Step: Synthesis of Compound 17

[0256] Intermediate 17a (240.0 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL). After cooling to 0 °C, hydrogen chloride ethyl acetate solution (4.0 M, 3 mL) was added dropwise slowly. After the reaction was completed at this temperature, it was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 17 (110.0 mg, 0.20 mmol, 54.2% yield). MS-ESI [M+H] calc’d for C21H22N4O2: 347.2, found: 347.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.45 (q, J = 8.1, 7.6 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 6.10 (s, 1H), 3.61 (s, 6H), 3.49 - 3.21 (m, 4H), 2.35 - 2.25 (m, 1H), 2.20 (s, 3H), 2.16 - 2.07 (m, 1H), 1.83 - 1.71 (m, 1H), 1.17 (t, J = 7.3 Hz, 1H).

[0257] Example 18: Synthesis of Compound 18

[0258] First Step: Synthesis of Intermediate 18a​​

[0259] Intermediate 1c (1.00 g, 5.12 mmol) was dissolved in acetonitrile (10 mL), then 1e (1.30 g, 5.22 mmol) was added, cooled to 0 °C, and cesium carbonate (2.17 g, 6.66 mmol) was added portionwise. After addition, it was warmed to room temperature and reacted overnight. After TLC showed the reaction was complete, it was concentrated, and the resulting residue was dissolved in dichloromethane (20 mL). Water (30 mL) was added, extracted, and the aqueous phase was extracted with dichloromethane (20 mL x 3). The combined organic phase was dried, concentrated, and the crude product of intermediate 18a was used directly in the next step without purification. MS-ESI [M+H] calc’d for C26H32N4O6, 445.1, found 445.0. +

[0260] Second Step: Synthesis of Intermediate 18b

[0261] The crude product of intermediate 18b (500.0 mg, 1.12 mmol) was dissolved in acetonitrile (10 mL). After cooling to 0 °C, 2-(morpholin-4-yl)acetic hydrazide (214.0 mg, 1.34 mmol), cesium carbonate (474.4 mg, 1.46 mmol), and silver nitrate (380.5 mg, 2.24 mmol) were added sequentially. After stirring for 10 min, it was warmed to room temperature and reacted further, with the reaction progress monitored by TLC and LCMS. After the reaction was complete, it was filtered, the resulting filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 18b (387.0 mg, 0.68 mmol, 60.4% yield). MS-ESI [M+H] calc’d for C32H42N8O6, 570.2, found 570.1. +

[0262] Third Step: Synthesis of Compound 18

[0263] After intermediate 18b (300 mg, 0.53 mmol) was dissolved in dioxane (5 mL), methane sulfonic acid (153 mg, 1.59 mmol) was added dropwise slowly. After addition, it was warmed to 110 °C and reacted for 8 h, with the reaction progress monitored by TLC and LCMS. After the reaction was complete, it was cooled to room temperature, water (10 mL) and dichloromethane (10 mL) were added, extracted, and the aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phase was dried, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 18 (103 mg, 0.19 mmol, 35.5% yield). MS-ESI [M+H] calc’d for C32H36N8O6, 552.2, found 552.2. + 1 ​​​H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 8.79 (s, 2H), 8.74 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 3.62 (s, 6H), 3.39 (s, 5H), 3.27 (s, 4H), 2.12 (s, 4H).

[0264] Synthesis of compound 19

[0265] Synthesis of intermediate 19a

[0266] Into a single-neck flask was added compound 3-(trifluoromethyl)benzene-1- sulfonamide (1.00 g, 4.44 mmol) and intermediate 1e (0.87 g, 4.44 mmol) and acetonitrile (30 mL). Cesium carbonate (1.59 g, 4.88 mmol) was added and the reaction was allowed to proceed at 25 °C for 16 h. After TLC showed the reaction was complete, the pH was adjusted to about 7 with aqueous citric acid solution, water (40 mL) and ethyl acetate (40 mL) were added, the resulting mixture was filtered and the resulting filter cake was dried under vacuum to give crude intermediate 19a (1.60 g, 3.81 mmol, 85.7% yield).

[0267] Synthesis of intermediate 19b

[0268] Intermediate 19a (1.60 g, 3.81 mmol) was dissolved in acetonitrile (40 mL) and then 5-methylnicotinohydrazide (0.63 g, 4.19 mmol), silver nitrate (1.29 g, 7.59 mmol) and cesium carbonate (2.48 g, 7.61 mmol) were added at 0 °C. After addition, the temperature was slowly increased to 25 °C and the reaction was allowed to proceed for 2 h. After TLC showed the reaction was complete, dichloromethane (20 mL) and methanol (20 mL) were added, the resulting mixture was filtered and the resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give intermediate 19b (0.50 g, 0.93 mmol, 24.4% yield).

[0269] Synthesis of compound 19

[0270] Intermediate 19b (0.15 g, 0.28 mmol) was dissolved in 1,4-dioxane (10 mL), and then methanesulfonic acid (81.0 mg, 0.84 mmol) was added slowly. After addition, the reaction was heated to 100 °C for 3 h. TLC showed that the reaction was complete, and then the reaction was quenched with aqueous sodium bicarbonate solution. The mixture was concentrated, and then the residue was slurried with ethyl acetate / petroleum ether (66:33, 20 mL). The resulting filter cake was purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 19 (96.2 mg, 0.19 mmol, 66.2% yield). MS-ESI [M+H] calculated for C26H22N5O5S, 520.1 found, 520.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 8.47 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 9.6 Hz, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.51 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 3.59 (d, J = 11.8 Hz, 6H), 2.23 (s, 3H).

[0271] Synthesis of compound 20

[0272] First step: Synthesis of intermediate 20a

[0273] Compound 3-(propan-2-yl)benzene-1-sulfonamide (1.00 g, 5.02 mmol) and intermediate 1e (0.98 g, 5.02 mmol) were added to acetonitrile (30 mL). After the addition of cesium carbonate (1.96 g, 6.02 mmol), the reaction was stirred at 25 °C for 16 h. After TLC showed that the reaction was complete, the pH was adjusted to about 7 with aqueous citric acid solution, and then water (40 mL) and ethyl acetate (40 mL) were added. The resulting filter cake was dried under vacuum to give crude intermediate 20a (1.00 g, 2.53 mmol, 50.5% yield).

[0274] Second step: Synthesis of intermediate 20b

[0275] ​Intermediate 20a (1.00 g, 2.53 mmol) was dissolved in acetonitrile (30 mL). After cooling to 0 °C, 5-methylnicotinic hydrazide (0.42 g, 2.78 mmol), silver nitrate (0.86 g, 5.06 mmol) and cesium carbonate (1.65 g, 5.06 mmol) were added. After addition, the reaction was continued at room temperature for 2 h. After TLC showed the reaction was complete, dichloromethane (20 mL) and methanol (20 mL) were added and filtered. The resulting filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-90:10, v / v) to give intermediate 20b (0.60 g, 1.18 mmol, 46.3% yield).

[0276] Step 3. Synthesis of compound 20

[0277] Intermediate 20b (0.60 g, 1.18 mmol) was dissolved in 1,4-dioxane (15 mL) and then methanesulfonic acid (0.34 g, 3.54 mmol) was added slowly. After addition, the reaction was continued at 100 °C for 3 h. After TLC showed the reaction was complete, it was concentrated. The resulting residue was slurried with ethyl acetate / petroleum ether (66:33, 20 mL). The resulting filter cake was purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 20 (97.2 mg, 0.20 mmol, 16.8% yield). MS-ESI [M+H] calc’d for C26H25N7O4: 494.2, found: 494.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.66 (s, 1H), 7.58 (d, J = 6.8 Hz, 2H), 7.50 (t, J = 8.4 Hz, 1H), 7.45 (d, J = 5.5 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.61 (s, 6H), 2.99 - 2.93 (m, 1H), 2.31 (s, 3H), 1.21 (d, J = 6.8 Hz, 6H).

[0278] Example 21. Synthesis of compound 21

[0279] ​Compound 5 (0.15 g, 0.28 mmol), sodium tert-butoxide (54 mg, 0.56 mmol) and Pd-PEPPSI™-IPent (22 mg, 0.028 mmol) were dissolved in 1,4-dioxane (5 mL). The nitrogen was replaced and kept nitrogen atmosphere, and heated to 110 °C for 6 h. After LCMS showed the reaction was complete, methanol (20 mL) and dichloromethane (20 mL) were added, and filtered. The resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-92:8, v / v) to give compound 21 (30.1 mg, 0.07 mmol, 23.6%). MS-ESI calculated for [M+H] C28H25N4O4, 452.1 found: 452.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.64 - 7.44 (m, 5H), 6.82 (d, J = 8.4 Hz, 2H), 3.62 (s, 6H), 2.23 (s, 3H).

[0280] Example 22 Synthesis of compound 22

[0281] Compound 5 (0.10 g, 0.19 mmol), Pd2(dba)3.CHCl3(20 mg, 0.019 mmol), BrettPhos (0.015 g, 0.028 mmol) and sodium tert-butoxide (37 mg, 0.38 mmol) were dissolved in 1,4-dioxane (5 mL). The nitrogen was replaced and kept nitrogen atmosphere, and cyclopropylamine (11 mg, 0.19 mmol) was added and heated to 80 °C for 8 h. After TLC showed the reaction was complete, dichloromethane / methanol (66:33, 20 mL) was added, and filtered. The resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 22 (36.5 mg, 0.07 mmol, yield 38.2%). MS-ESI calculated for [M+H] C28H27N4O4, 507.2 found: 507.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 1.9 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.86 - 6.77 (m, 3H), 6.45 (s, 1H), 3.61 (s, 6H), 2.32 - 2.28 (m, 1H), 2.23 (s, 3H), 0.74 - 0.64 (m, 2H), 0.38 - 0.31 (m, 2H).

[0282] Synthesis of compound 23

[0283] In a single neck flask, compound 5 (200 mg, 0.38 mmol), 2,2-difluoroethan-1-amine (62 mg, 0.76 mmol), potassium tert-butoxide (85 mg, 0.76 mmol) and Pd-PEPPSI™-IPent (30 mg, 0.038 mmol) were added successively. Nitrogen was purged and kept the atmosphere, 1,4-dioxane (10 mL) was added and heated to 110 °C for 6 h. TLC showed the reaction was complete, dichloromethane / methanol (66:33, 20 mL) was added. The resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 23 (28.6 mg, 0.05 mmol, 14.3% yield). MS-ESI calc. for [M+H] + : 531.2, found: 531.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 1.9 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.86 - 6.77 (m, 3H), 6.45 (s, 1H), 3.61 (s, 6H), 2.32 - 2.28 (m, 1H), 2.23 (s, 3H), 0.74 - 0.64 (m, 2H), 0.38 - 0.31 (m, 2H).

[0284] Synthesis of compound 24

[0285] Compound 5 (300 mg, 0.57 mmol), Xantphos-G4-Pd (55 mg, 0.057 mmol), sodium tert-butoxide (110 mg, 1.14 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen atmosphere, methyl(2-(morpholin-4-yl)ethyl)amine (98.64 mg, 0.68 mmol) was added and the reaction was continued at 110 °C for 8 h. TLC showed the reaction was complete, dichloromethane / methanol (66:33, 20 mL) was added. The resulting mixture was filtered, the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 24 (68.9 mg, 0.17 mmol, 20.5% yield). MS-ESI [M+H] calc’d for C32H35N7O4: 594.2, found: 594.3. + 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 9.2 Hz, 3H), 3.57 (d, J = 16.7 Hz, 6H), 3.52 (dd, J = 9.8, 5.6 Hz, 4H), 3.44 (d, J = 27.2 Hz, 2H), 2.93 (s, 3H), 2.36 (d, J = 23.6 Hz, 6H), 2.23 (s, 3H).

[0286] Synthesis of compound 25

[0287] Synthesis of intermediate 25b

[0288] Compound 24a (0.30 g, 2.56 mmol) and intermediate 1c (0.51 g, 2.05 mmol) were added into acetonitrile (5 mL). After cooling to 10 °C, cesium carbonate (1.67 g, 5.13 mmol) was added and the reaction was continued at 25 °C for 16 h. TLC showed the reaction was complete, the pH was adjusted to 7-8 with citric acid and the mixture was filtered. The resulting filter cake was dried under vacuum to give crude intermediate 25b (0.20 g, 0.55 mmol, 21.3% yield) which was used directly in the next step.

[0289] Synthesis of intermediate 25c

[0290] ​The crude intermediate 25b (0.15 g, 0.41 mmol) was dissolved in acetonitrile (10 mL) and cooled to 0 °C. Cesium carbonate (0.20 g, 0.61 mmol), 5-methylnicotinic hydrazide (62 mg, 0.41 mmol) and silver nitrate (0.10 g, 0.61 mmol) were added successively. After addition, the temperature was raised to 25 °C and the reaction was stirred for 2 h. TLC showed that the reaction was complete. Methanol (10 mL) was added and the mixture was filtered. The filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-92:8, v / v) to give intermediate 25c (0.15 g, 0.31 mmol, 75.8% yield).

[0291] Synthesis of compound 25

[0292] Intermediate 25c (0.15 g, 0.31 mmol) was dissolved in 1,4-dioxane (10 mL) and then methanesulfonic acid (89 mg, 0.93 mmol) was added slowly. After addition, the temperature was raised to 100 °C and the reaction was stirred for 3 h. TLC showed that the reaction was complete. After quenching with aqueous sodium bicarbonate solution, the reaction mixture was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-97:3, v / v) to give compound 25 (6.9 mg, 0.01 mmol, 4.8% yield). MS-ESI [M+H] calculated: 466.2, found: 466.1. + 1 H NMR (400 MHz, CDC13) δ 11.64 - 11.51 (m, 1H), 9.31 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.70 (s, 1H), 8.61 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 4.02 (s, 2H), 3.73 (s, 2H), 3.28 (s, 3H), 2.62 (s, 3H), 2.45 (s, 3H).

[0293] Synthesis of compound 26

[0294] ​In a dry single neck flask, compound 5 (0.4 g, 0.75 mmol) and 1,4-dioxane (20 mL) were added. After stirring to dissolve, cesium carbonate (0.49 g, 1.5 mmol), 3-aminopyridine (0.14 g, 1.5 mmol) and sSPhos Pd G2 (62 mg, 0.075 mmol) were added in turn, replaced by nitrogen and kept in nitrogen atmosphere and heated to reflux reaction for 12 h. After TLC showed that the reaction was completed, water (20 mL) was added, and extracted with dichloromethane (30 mL x 3). The organic phase was combined and concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v) to obtain compound 26 (82 mg, 0.15 mmol, yield 20.0%). MS-ESI [M+H] Theoretical value: 544.2, Actual value: 544.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 8.17 (s, 1H), 8.10 (d, J = 4.1 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J = 8.5 Hz, 3H), 7.40 (t, J = 7.9 Hz, 1H), 7.23 (dd, J = 14.2, 8.0 Hz, 3H), 6.79 (d, J = 8.5 Hz, 2H), 3.59 (s, 6H), 2.23 (s, 3H).

[0295] Synthesis of compound 27 of example 27

[0296] Synthesis of intermediate 27b of first step

[0297] Compound 27a (2.00 g, 19.21 mmol) was dissolved in methanol (20 mL), and cesium carbonate (6.26 g, 19.21 mmol) and hydrazine hydrochloride (1.97 g, 28.75 mmol) were added in turn. After adding, heated to 70°C for 4 h. After TLC showed that the reaction was complete, filtered and washed with methanol. The filtrate and washing liquid were combined, concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:1, v / v) to obtain intermediate 27b (1.00 g, 9.61 mmol, yield 50%). 1 H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 3.99 (s, 2H), 3.89 (s, 2H), 3.42 (s, 3H).

[0298] Synthesis of intermediate 27c of second step

[0299] ​Intermediate 18a (1.88 g, 4.23 mmol) was dissolved in acetonitrile (20 mL) and after stirring at 0 °C for 5 min, intermediate 27b (0.53 g, 5.08 mmol), silver nitrate (0.86 g, 5.06 mmol) and cesium carbonate (2.07 g, 6.35 mmol) were added sequentially. After the addition, the reaction was continued at 0 °C for 10 min and then was allowed to warm to room temperature and stirred for 2 h. After TLC showed that the reaction was complete, methanol (50 mL) was added, filtered and washed with methanol. The resulting filter cake was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give intermediate 27c (0.55 g, 1.07 mmol, 25.27% yield). MS-ESI [M+H] calculated for C23H19FN6O4: 515.2, found: 515.1. +

[0300] Third step Synthesis of compound 27

[0301] Intermediate 27c (0.55 g, 1.07 mmol) was dissolved in dioxane (10 mL) and methane sulfonic acid (0.51 g, 5.35 mmol) was added slowly. After the addition, the reaction was allowed to warm to 100 °C and stirred for 3 h. After TLC showed that the starting material was consumed, the pH was adjusted to 7 with aqueous sodium bicarbonate solution, water (20 mL) was added and extracted with dichloromethane (100 mL x 3). The combined organic phase was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 27 (17 mg, 0.034 mmol, 3.2% yield). MS-ESI [M+H] calculated for C23H19FN6O4: 497.2, found: 497.2. + 1 H NMR (400 MHz, CDC13) δ 9.02 (s, 1H), 8.70 (s, 2H), 8.58 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 2H), 4.19 (s, 2H), 3.60 (s, 6H), 3.19 (s, 3H), 2.40 (s, 3H).

[0302] Example 28 Synthesis of compound 28

[0303] First step Synthesis of intermediate 28b

[0304] ​​Compound 28a (2.00 g, 28.12 mmol) was dissolved in dichloromethane (25 mL) and water (25 mL), sodium bicarbonate (2.83 g, 33.74 mmol) was added and cooled to 0 °C. After stirring for 10 min, thiophosgene (4.85 g, 42.18 mmol) was added and the reaction was continued for 10 min. The temperature was raised to room temperature and the reaction was continued for 1 h. The reaction was monitored by TLC and upon completion, the reaction was added to water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic layers were combined, concentrated and the residue was slurried with petroleum ether (100 mL) and filtered. The obtained filter cake was dried to obtain intermediate 28b (2.81 g, 24.86 mmol, 88.3% yield).

[0305] Second Step: Synthesis of intermediate 28c

[0306] Intermediate 28b (0.50 g, 4.42 mmol) and intermediate 1c (1.10 g, 4.41 mmol) were dissolved in acetonitrile (50 mL) and cooled to 0 °C. After stirring for 5 min, cesium carbonate (2.16 g, 6.63 mmol) was added slowly. After addition, the temperature was raised to room temperature and the reaction was continued for 16 h. Upon completion of the reaction by TLC, it was filtered and washed with methanol. The filtrate and washings were combined, concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to obtain intermediate 28c (1.43 g, 3.95 mmol, 89.3% yield).

[0307] Third Step: Synthesis of intermediate 28d

[0308] Intermediate 28c (1.43 g, 3.95 mmol) was dissolved in acetonitrile (20 mL) and cooled to 0 °C. After stirring for 5 min, 5-methylnicotinohydrazide (0.72 g, 4.76 mmol), silver nitrate (0.81 g, 4.77 mmol) and cesium carbonate (1.93 g, 5.92 mmol) were added sequentially. After addition, the temperature was raised to room temperature after 10 min at 0 °C and the reaction was continued for 2 h. Upon completion of the reaction by TLC, methanol (50 mL) was added, filtered and washed with methanol. The obtained filter cake was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to obtain intermediate 28d (0.61 g, 1.27 mmol, 32.2% yield).

[0309] Fourth Step: Synthesis of compound 28

[0310] Intermediate 28d (0.61 g, 1.27 mmol) was dissolved in 1,4-dioxane (10 mL) and methanesulfonic acid (0.61 g, 6.35 mmol) was added slowly. After addition, the temperature was raised to 100 °C for 3 h. TLC showed the reaction was complete, the pH was adjusted to 7 with aqueous sodium bicarbonate solution, water (50 mL) was added, and extracted with dichloromethane (100 mL x 3). The organic phase was combined, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 28 (47 mg, 0.10 mmol, 8.0% yield). MS-ESI [M+H] calc’d for C19H17N7O3: 402.2, found: 402.2. + 1 H NMR (400 MHz, CDCl3) δ 11.27 (s, 1H), 9.00 (s, 1H), 8.58 (s, 3H), 8.54-8.42 (m, 2H), 8.01 (d, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.53 (t, J = 7.8 Hz, 1H), 4.52-4.35 (m, 1H), 2.94-2.75 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 2.10 (dd, J = 17.3, 8.4 Hz, 2H), 1.79 (q, J = 10.2 Hz, 1H), 1.58 (dd, J = 18.9, 8.6 Hz, 1H).

[0311] Synthesis of compound 29

[0312] Synthesis of intermediate 29b

[0313] Compound 29a (0.70 g, 4.09 mmol) was dissolved in acetonitrile (25 mL), after adding intermediate 1e (0.80 g, 4.10 mmol) in portions, the temperature was raised to 10 °C and cesium carbonate (1.73 g, 5.31 mmol) was added. After addition, the reaction was continued at 10 °C for 10 min, the temperature was raised to room temperature and the reaction was continued for 22 h. After LCMS showed the reaction was complete, the reaction was poured into water (10 mL), the pH was adjusted to 7 with aqueous citric acid solution, and extracted with dichloromethane (10 mL x 3). The organic phase was combined and washed with saturated brine (10 mL x 3), concentrated to give intermediate 29b crude (1.00 g, 2.73 mmol, 66.8% yield). MS-ESI [M+H] calc’d for C19H17N7O3: 402.2, found: 402.2. +

[0314] Synthesis of intermediate 29c

[0315] ​​The crude intermediate 29b (1.00 g, 2.73 mmol) was dissolved in acetonitrile (10 mL), cooled to 0 °C, and then cesium carbonate (1.16 g, 3.56 mmol) was added. After stirring for 10 min, 5-methylnicotinohydrazide (0.41 g, 2.71 mmol) and silver nitrate (0.93 g, 5.47 mmol) were added. After the addition was completed, the reaction was allowed to warm to room temperature and stirred for 1 h. After the reaction was completed as indicated by LCMS, the reaction was filtered, and the resulting filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-95:5, v / v) to give intermediate 29c (0.31 g, 0.64 mmol, 23.5% yield). MS-ESI [M+H] calculated for C21H19N6O3, 484.2, found 484.2. +

[0316] Step 3. Synthesis of compound 29

[0317] Intermediate 29c (0.31 g, 0.64 mmol) was dissolved in 1,4-dioxane (5 mL), and methanesulfonic acid (0.18 g, 1.87 mmol) was added dropwise. After the addition was completed, the reaction was allowed to warm to 100 °C and stirred for 2 h. After the reaction was completed as indicated by LCMS, water (10 mL) was added and the pH was adjusted to 7 with aqueous sodium carbonate solution. The organic phase was extracted with dichloromethane (10 mL x 3), the combined organic phases were washed with saturated brine (10 mL x 2), concentrated, and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 29 (60.3 mg, 0.13 mmol, 20.2% yield). MS-ESI [M+H] calculated for C21H19N6O3, 466.2, found 466.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.46 (dd, J = 2.1, 0.9 Hz, 1H), 8.16 (dd, J = 2.1, 0.7 Hz, 1H), 7.97 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (td, J = 2.1, 0.8 Hz, 1H), 7.53 - 7.39 (m, 2H), 7.35 - 7.27 (m, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.63 (s, 6H), 2.41 (s, 3H), 2.23 (d, J = 0.8 Hz, 3H).

[0318] Example 30. Synthesis of compound 30

[0319] Step 1. Synthesis of intermediate 30b

[0320] ​​Compound 30a (0.96 g, 5.61 mmol) was dissolved in acetonitrile (10 mL), and intermediate 1e (1.00 g, 5.12 mmol) was added. The reaction was cooled to 0 °C, and cesium carbonate (2.17 g, 6.66 mmol) was added portionwise. After the addition was completed, the reaction was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete. The reaction was filtered, and the resulting filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 30b (1.59 g, 4.34 mmol, 84.7% yield). MS-ESI [M+H] calc’d for C26H28N4O4, 367.1, found 367.2. + : 367.1, found 367.2.

[0321] Second Step: Synthesis of intermediate 30c

[0322] Intermediate 30b (2.00 g, 5.46 mmol) and 5-methylnicotinohydrazide (0.83 g, 5.40 mmol) were dissolved in acetonitrile (20 mL). Silver nitrate (1.85 g, 10.89 mmol) and cesium carbonate (3.56 g, 10.93 mmol) were added sequentially at room temperature and the reaction was continued for 1 h. TLC monitoring showed that the reaction was complete. The reaction was filtered, and the filtrate was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 30c (1.83 g, 3.78 mmol, 69.4% yield). MS-ESI [M+H] calc’d for C28H30N6O4, 484.2, found 484.2. + : 484.2, found 484.2.

[0323] Third Step: Synthesis of compound 30

[0324] Intermediate 30c (1.00 g, 2.07 mmol) was dissolved in 1,4-dioxane (10 mL), and methanesulfonic acid (0.60 g, 6.24 mmol) was added dropwise slowly. After the addition was completed, the reaction was heated to 110 °C for 8 h. TLC monitoring showed that the reaction was complete. The reaction was cooled to room temperature, and water (20 mL) was added. The pH was adjusted to neutral with saturated aqueous sodium bicarbonate solution. Dichloromethane (20 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (20 mL x 5). The organic phases were combined, dried, concentrated, and purified by column chromatography on silica gel (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 30 (170 mg, 0.37 mmol, 17.7% yield). MS-ESI [M+H] calc’d for C28H30N6O4, 466.1, found 466.2. + : 484.2, found 484.2. 1H NMR (400MHz, DMSO-d6) δ13.48(s,1H),8.45(s,1H),8.16(d,J=2.1Hz,1H),7.66(d,J=8.2Hz,2H),7.57(s,1H) ,7.49(t,J=8.5Hz,1H),7.32(d,J=8.0Hz,2H),6.81(d,J=8.6Hz,2H),3.63(s,6H),2.35(s,3H),2.23(s,3H).

[0325] Example 31 Synthesis of Compound 31

[0326] Synthesis of intermediate 31b in the first step

[0327] Compound 31a (20.00 g, 116.14 mmol) was dissolved in 180 mL of 30% sulfuric acid aqueous solution. The solution was cooled to 0 °C, and an aqueous solution of sodium nitrite (10.42 g, 151.01 mmol, dissolved in 20 mL of water) was added dropwise. After the addition was complete, the reaction was continued at 0 °C for 0.5 h, then heated to 100 °C and continued for another 0.5 h. After LC-MS showed that the reaction was complete, the solution was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 31b (11.00 g, 63.5 mmol, yield 54.7%). MS-ESI theoretical value [M+NH4] + : 191.1, measured value: 191.3.

[0328] The second step involves the synthesis of intermediate 31c.

[0329] Intermediate 31b (0.90 g, 5.20 mmol), cesium carbonate (4.24 g, 13.01 mmol), tetrabutylammonium iodide (1.92 g, 5.20 mmol), and acetonitrile (10 mL) were added to a three-necked flask. After cooling to 0 °C, bromocyclopentane (0.93 g, 6.24 mmol) was slowly added. After the addition was complete, the temperature was raised to 60 °C and the reaction was continued for 8 h. LC-MS showed that the reaction was complete. The reaction solution was poured into water (10 mL), and the pH was adjusted to 7 with citric acid aqueous solution. Extraction was performed with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give intermediate 31c (0.28 g, 1.16 mmol, yield 22.3%). MS-ESI theoretical value [M+NH4] + : 259.1, measured value: 259.2.

[0330] Synthesis of intermediate 31d in the third step

[0331] Intermediate 31c (0.28 g, 1.16 mmol) was dissolved in acetonitrile (5 mL). After cooling to 0 °C, cesium carbonate (0.49 g, 1.50 mmol) and intermediate 1e (0.24 g, 1.23 mmol) were added. After the reaction was carried out for 0.5 h, it was allowed to warm to room temperature and continue to react for 22 h. LCMS showed that the reaction was complete, the reaction solution was poured into water (10 mL), and the pH was adjusted to 7 with an aqueous citric acid solution. Extraction was performed with dichloromethane (10 mL x 5), the organic phases were combined, washed with saturated brine (10 mL x 2), and concentrated to obtain the crude intermediate 31d (0.50 g, 1.15 mmol, 98.7% yield).

[0332] Synthesis of intermediate 31e in the fourth step

[0333] The crude intermediate 31d (0.50 g, 1.15 mmol) was dissolved in acetonitrile (10 mL). After cooling to 0 °C, cesium carbonate (0.49 g, 1.50 mmol) was added, stirring was continued for 10 min, 5-methylnicotinohydrazide (0.17 g, 1.12 mmol) and silver nitrate (0.39 g, 2.30 mmol) were added. After the addition was completed, it was allowed to warm to room temperature and continue to react for 1 h. After LCMS showed that the reaction was complete, it was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to obtain intermediate 31e (0.25 g, 0.45 mmol, 39.4% yield).

[0334] Synthesis of compound 31 in the fifth step

[0335] After intermediate 31e (0.25 g, 0.45 mmol) was dissolved in 1,4-dioxane (5 mL), methane sulfonic acid (0.13 g, 1.35 mmol) was added dropwise. After the addition was completed, it was allowed to warm to 100 °C and continue to react for 2 h. LCMS showed that the reaction was complete, water (10 mL) was added and the pH was adjusted to 7 with an aqueous sodium carbonate solution. Extraction was performed with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 2), and concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to obtain compound 31 (68.0 mg, 0.13 mmol, 28.1% yield). MS-ESI [M+H] Theoretical value: 536.2, Found: 536.2. + 1 ​H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.51 - 8.40 (m, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.58 (q, J = 1.8 Hz, 1H), 7.46 (dt, J = 30.0, 8.2 Hz, 2H), 7.32 - 7.21 (m, 2H), 7.08 (ddd, J = 8.1, 2.6, 1.0 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 4.93 - 4.79 (m, 1H), 3.62 (s, 6H), 2.23 (s, 3H), 1.90 (dd, J = 11.7, 6.0 Hz, 2H), 1.78 - 1.53 (m, 6H).

[0336] Synthesis of compound 32

[0337] Synthesis of intermediate 32b in the first step

[0338] After compound 32a (0.50 g, 2.67 mmol) was dissolved in acetonitrile (10 mL), intermediate 1e (0.55 g, 2.82 mmol) was added in portions. After addition, it was cooled to 10 °C, cesium carbonate (1.13 g, 3.47 mmol) was added and reacted at 10 °C for 10 min. It was continued to react at room temperature for 22 h. LCMS showed that the reaction was complete, the reaction solution was poured into water (10 mL), and the pH was adjusted to 7 with aqueous citric acid solution. It was extracted with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 3), and concentrated to give the crude intermediate 32b (0.94 g, 2.46 mmol, yield 92.0 %). MS-ESI [M+H] calculated for C26H26N6O4: 483.2, found: 483.2. +

[0339] Synthesis of intermediate 32c in the second step

[0340] After the crude intermediate 32b (0.94 g, 2.46 mmol) was dissolved in acetonitrile (10 mL), it was cooled to 0 °C, and cesium carbonate (1.04 g, 3.19 mmol) was added. After 10 min of reaction, 5-methylnicotinohydrazide (0.37 g, 2.45 mmol) and silver nitrate (0.84 g, 4.94 mmol) were added. After addition, it was continued to react at room temperature for 1 h. LCMS showed that the reaction was complete, it was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give intermediate 32c (0.79 g, 1.53 mmol, yield 64.3 %). MS-ESI [M+H] calculated for C28H28N8O4: 500.2, found: 500.2. + ​​

[0341] Step 3. Synthesis of compound 32

[0342] After intermediate 32c (0.79 g, 1.53 mmol) was dissolved in 1,4-dioxane (10 mL), methane sulfonic acid (0.44 g, 4.58 mmol) was added dropwise. After the addition was completed, the temperature was increased to 100 °C for 2 h. LCMS showed that the reaction was complete, water (30 mL) was added, and the pH was adjusted to 7 with aqueous sodium carbonate solution. Extraction was performed with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 2), concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 99:1-95:5, v / v) to give compound 32 (300.0 mg, 0.62 mmol, 40.7% yield). MS-ESI [M+H] calculated: 482.1, found: 482.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.48 (dt, J = 16.8, 8.3 Hz, 2H), 7.33 (dd, J = 4.5, 2.3 Hz, 2H), 7.13 (dd, J = 8.2, 2.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 3.80 (s, 3H), 3.62 (s, 6H), 2.23 (s, 3H).

[0343] Example 33. Synthesis of compound 33

[0344] Compound 5 (0.10 g, 0.19 mmol), imidazole (32.0 mg, 0.47 mmol), potassium phosphate (0.12 g, 0.57 mmol), N1,N2-di(furan-2-ylmethyl)oxal diamide (40.0 mg, 0.16 mmol) and cuprous oxide (20.0 mg, 0.13 mmol) were dissolved in dimethyl sulfoxide (3 mL). The nitrogen atmosphere was replaced and heated to 120 °C for 36 h. LCMS showed that the reaction was complete, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give compound 33 (12.9 mg, 0.02 mmol, 13.2% yield). MS-ESI [M+H] calculated: 518.2, found: 518.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.35 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.85 (t, J = 7.7 Hz, 2H), 7.76 - 7.65 (m, 2H), 7.57 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.17 (s, 1H), 6.81 (d, J = 8.6 Hz, 2H), 3.58 (s, 6H), 2.22 (s, 3H).

[0345] Synthesis of compound 34

[0346] Compound 5 (0.10 g, 0.19 mmol), potassium vinyltrifluoroborate (76.0 mg, 0.57 mmol), cesium carbonate (0.15 g, 0.46 mmol) and PdCl2(dtbpf) (12.0 mg, 0.018 mmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The nitrogen atmosphere was replaced and heated to 120 °C for 12 h. LCMS showed the reaction was complete, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give compound 34 (25.7 mg, 0.054 mmol, 28.5% yield). MS-ESI [M+H] calculated for C26H21FN4O4: 478.2, found: 478.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.58 (d, J = 2.2 Hz, 1H), 7.57 - 7.45 (m, 2H), 6.91 - 6.74 (m, 3H), 5.94 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H), 3.61 (s, 6H), 2.23 (s, 3H).

[0347] Synthesis of compound 35

[0348] Synthesis of intermediate 35b

[0349] ​Dissolve compound 35a (0.50 g, 3.16 mmol) in acetonitrile (10 mL), add intermediate 1e (0.65 g, 3.33 mmol) portionwise. After addition, cool to 10 °C, add cesium carbonate (1.34 g, 4.11 mmol). After 10 min at 10 °C, warm to room temperature and continue to react for 22 h. LCMS shows the reaction is complete, pour the reaction into water (10 mL), adjust the pH to 7 with aqueous citric acid. Extract with dichloromethane (10 mL x 3), combine the organic phases, wash with saturated brine (10 mL x 3), concentrate to give intermediate 35b crude (0.94 g, 2.65 mmol, 84.1% yield). MS-ESI [M+H] calc’d for C26H30N4O4, 454.2, found 454.3. + : 454.2, found 454.3.

[0350] Second Step, synthesis of intermediate 35c

[0351] Dissolve intermediate 35b (0.70 g, 1.98 mmol) in acetonitrile (10 mL), cool to 0 °C, add cesium carbonate (0.84 g, 2.58 mmol). After 10 min, add 5-methylnicotinohydrazide (0.30 g, 1.98 mmol) and silver nitrate (0.67 g, 3.94 mmol). After addition, warm to room temperature and continue to react for 1 h. LCMS shows the reaction is complete, filter the reaction, concentrate, purify by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give intermediate 35c (0.28 g, 0.60 mmol, 30.1% yield). MS-ESI [M+H] calc’d for C30H30N6O4, 534.2, found 534.3. + : 534.2, found 534.3.

[0352] Third Step, synthesis of compound 35

[0353] Dissolve intermediate 35c (0.28 g, 0.60 mmol) in 1,4-dioxane (10 mL), add methanesulfonic acid (0.17 g, 1.77 mmol) dropwise. After addition, warm to 100 °C and continue to react for 2 h. LCMS shows the reaction is complete, add water (10 mL), adjust the pH to 7 with aqueous sodium carbonate. Extract with dichloromethane (10 mL x 3), combine the organic phases, wash with saturated brine (10 mL x 2), concentrate, purify by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 35 (44.0 mg, 0.097 mmol, 15.6% yield). MS-ESI [M+H] calc’d for C30H30N6O4, 534.2, found 534.3. + : 534.2, found 534.3. 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 8.94 (dd, J = 2.4, 0.9 Hz, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.53 - 8.43 (m, 1H), 8.22 - 8.07 (m, 2H), 7.64 - 7.55 (m, 2H), 7.51 (t, J = 8.5 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 3.62 (s, 6H), 2.23 (s, 3H).

[0354] Synthesis of compound 36

[0355] Compound 5 (0.10 g, 0.19 mmol), (6-(trifluoromethyl)pyridin-3-yl)boronic acid (0.11 g, 0.58 mmol), cesium carbonate (0.15 g, 0.46 mmol) and PdCl2(dtbpf) (12.0 mg, 0.018 mmol) were dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL). The nitrogen atmosphere was replaced and warmed to 120 °C for 12 h. LCMS showed the reaction was complete, the reaction was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to give compound 36 (67.1 mg, 0.11 mmol, 59.7% yield). MS-ESI [M+H] calc’d for + : 597.1, found: 597.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 9.15 (d, J = 2.3 Hz, 1H), 8.44 (dd, J = 11.6, 2.4 Hz, 2H), 8.26 (t, J = 1.8 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H), 8.06 (dd, J = 12.0, 7.9 Hz, 2H), 7.86 (dt, J = 7.9, 1.4 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.49 (t, J = 8.5 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 3.58 (s, 6H), 2.22 (s, 3H).

[0356] Synthesis of compound 37

[0357] Synthesis of intermediate 37a

[0358] Compound 5 (0.40 g, 0.75 mmol), potassium hydroxide (0.13 g, 2.32 mmol), Me4-t-BuXphos (18.0 mg, 0.037 mmol) and Pd2(dba)3(8.6 mg, 0.009 mmol) were dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). The nitrogen atmosphere was replaced and maintained, and the temperature was raised to 120 °C for 12 h. LCMS showed the reaction was complete, and the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-80:20, v / v) to give intermediate 37a (324.5 mg, 0.69 mmol, 92.0% yield). MS-ESI [M+H] calculated for C26H28N4O4, 468.1 found, 468.2. +

[0359] Second Step Synthesis of Compound 37

[0360] Intermediate 37a (50.0 mg, 0.11 mmol), 4-(2-bromoethyl)morpholine (23.0 mg, 0.12 mmol) and cesium carbonate (90.0 mg, 0.28 mmol) were dissolved in acetonitrile (2 mL). The reaction was carried out at 20 °C for 12 h. LCMS showed the reaction was complete, and the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-80:20, v / v) to give compound 37 (7.9 mg, 0.014 mmol, 12.7% yield). MS-ESI [M+H] calculated for C30H36N6O4, 581.2 found, 581.2. + 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.59 - 8.28 (m, 1H), 8.19 (d, J = 2.1 Hz, 1H), 7.59 (t, J = 2.3 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.82 (ddd, J = 8.0, 2.6, 1.0 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 4.42 (t, J = 6.7 Hz, 2H), 3.62 (s, 6H), 3.56 (t, J = 4.6 Hz, 4H), 2.83 (t, J = 6.6 Hz, 2H), 2.45 (t, J = 4.7 Hz, 4H), 2.25 (s, 3H).

[0361] Example 38 Synthesis of Compound 38

[0362] First Step Synthesis of Intermediate 38b ​​

[0363] Compound 38a (1.00 g, 9.89 mmol) was dissolved in a mixture of dichloromethane (10 mL) and water (10 mL), and sodium bicarbonate solid (2.08 g, 24.76 mmol) was added. After cooling to 0 °C, phosgene (1.59 g, 13.83 mmol) was added. The reaction was carried out at 0 °C for 10 min, then at room temperature for 1 h. LC-MS showed that the reaction was complete, and the reaction solution was poured into water (25 mL). The solution was extracted with dichloromethane (25 mL × 3), the organic phases were combined, dried, and concentrated to give intermediate 38b (1.20 g, 8.37 mmol, yield 84.8%). 1 H NMR (400MHz, CDCl3) δ4.02–3.78(m,3H),3.55(ddd,J=11.6,7.9,3.2Hz,2H),2.07–1.90(m,2H),1.89–1.67(m,2H).

[0364] The second step involves the synthesis of intermediate 38c.

[0365] Intermediate 1c (0.73 g, 2.93 mmol) was dissolved in acetonitrile (10 mL), and intermediate 38b (0.40 g, 2.79 mmol) was added in portions, followed by cooling to 10 °C. Cesium carbonate (1.36 g, 4.17 mmol) was added, and the reaction was allowed to proceed for 10 min, then brought to room temperature and continued for 22 h. LC-MS showed the reaction was complete. The reaction mixture was poured into water (10 mL), and the pH was adjusted to 7 with citric acid. Extraction was performed with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), and concentrated to obtain crude intermediate 38c (0.82 g, 2.09 mmol, yield 74.8%). MS-ESI theoretical value [M+H] + 393.1, measured value: 393.2.

[0366] The third step involves the synthesis of intermediate 38d.

[0367] Intermediate 38c (0.82 g, 2.09 mmol) was dissolved in acetonitrile (10 mL) and cooled to 0 °C. Cesium carbonate (0.89 g, 2.73 mmol) was added, and after reacting for 10 min, 5-methylnicotinamide (0.32 g, 2.12 mmol) and silver nitrate (0.71 g, 4.18 mmol) were added. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for another 1 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give intermediate 38d (0.43 g, 0.84 mmol, yield 40.4%). MS-ESI theoretical value [M+H] + : 510.2, measured value: 510.1.

[0368] Fourth Step Synthesis of compound 38

[0369] Intermediate 38d (0.43 g, 0.84 mmol) was dissolved in 1,4-dioxane (10 mL), and methane sulfonic acid (0.24 g, 2.50 mmol) was added dropwise. After the addition was completed, the temperature was raised to 100 °C for 2 h. After LCMS showed the reaction was completed, water (10 mL) was added, and the pH was adjusted to 7 with aqueous sodium carbonate solution. The organic phase was extracted with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 2), concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 38 (4.5 mg, 0.009 mmol, 1.1% yield). MS-ESI [M+H] calculated for C26H22F3N7O4: 492.2, found: 492.1. + 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.81 (s, 2H), 8.63 (d, J = 2.1 Hz, 1H), 8.57 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 7.9 Hz, 1H), 8.11 - 7.98 (m, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.02 (p, J = 6.4, 5.7 Hz, 2H), 3.84 (dd, J = 11.6, 4.5 Hz, 2H), 3.23 (t, J = 11.8 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.99 (s, 1H), 1.79 - 1.60 (m, 2H).

[0370] Example 39 Synthesis of compound 39

[0371] First Step Synthesis of intermediate 39b

[0372] ​Compound 39a (1.50 g, 17.21 mmol) was dissolved in a mixed solvent of dichloromethane (10 mL) and water (10 mL), and sodium bicarbonate (3.61 g, 42.97 mmol) was added. After cooling to 0 °C, thiophosgene (2.77 g, 24.09 mmol) was added dropwise. After addition, the reaction was continued for 10 min at room temperature for 1 h. LCMS showed that the reaction was complete, and the reaction solution was poured into water (25 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 3), and concentrated. The obtained residue was slurried with petroleum ether (50 mL), and filtered. The filter cake was dried to obtain intermediate 39b (2.00 g, 15.48 mmol, 89.9% yield). 1 H NMR (400 MHz, DMSO-d6) δ 3.75 (tt, J = 8.1, 4.8 Hz, 6H), 1.84 - 1.50 (m, 4H), 0.94 (t, J = 7.4 Hz, 1H).

[0373] Synthesis of intermediate 39c

[0374] Intermediate 1c (0.41 g, 1.64 mmol) was dissolved in acetonitrile (10 mL), and intermediate 39b (0.20 g, 1.55 mmol) was added in portions. After addition, cesium carbonate (0.76 g, 2.33 mmol) was added at 10 °C. After 10 min, the reaction was continued at room temperature for 22 h. LCMS showed that the reaction was complete, and the reaction solution was poured into water (10 mL), and the pH was adjusted to 7 with an aqueous citric acid solution. Extraction was performed with dichloromethane (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL x 3), concentrated to obtain intermediate 39c crude (0.35 g, 0.92 mmol, 59.7% yield). MS-ESI [M+H] Theoretical: 379.1, Found: 379.1. +

[0375] Synthesis of intermediate 39d

[0376] Intermediate 39c (0.35 g, 0.92 mmol) was dissolved in acetonitrile (5 mL), and cesium carbonate (0.39 g, 1.20 mmol) was added after cooling to 0 °C. After 10 min, 5-methylnicotinoylhydrazine (0.14 g, 0.93 mmol) and silver nitrate (0.31 g, 1.82 mmol) were added. After addition, the reaction was continued at room temperature for 1 h. LCMS showed that the reaction was complete, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to obtain intermediate 39d (0.20 g, 0.40 mmol, 43.6% yield). MS-ESI [M+H] Theoretical: 379.1, Found: 379.1. + ​: 496.2, found: 496.2.

[0377] Step 4 Synthesis of compound 39

[0378] Intermediate 39d (0.20 g, 0.40 mmol) was dissolved in 1,4-dioxane (5 mL), and methane sulfonic acid (0.12 g, 1.25 mmol) was added dropwise. After the addition was completed, the reaction was heated to 100 °C for 2 h. LCMS showed that the reaction was complete, water (10 mL) was added, and the pH was adjusted to 7 with aqueous sodium carbonate solution. Extraction was performed with dichloromethane (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 2), concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-95:5, v / v) to give compound 39 (6.6 mg, 0.01 mmol, 3.4% yield). MS-ESI Theoretical value [M+H] + : 478.2, found: 478.2. 1 H NMR (400 MHz, CDCl3) δ 11.26 (s, 1H), 9.04 (s, 1H), 8.74-8.42 (m, 5H), 8.04 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H), 7.59 (t, J = 7.8 Hz, 1H), 3.77 (s, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 2.19 (s, 2H), 1.73 (s, 2H), 1.27 (d, J = 12.3 Hz, 6H).

[0379] Example 40 Synthesis of compound 40

[0380] In a 100 mL three-necked flask, compound 5 (200 mg, 0.37 mmol), 1,4-dioxane (10 mL), water (2 mL), cyclopenten-1-ylboronic acid (85 mg, 0.76 mmol), potassium carbonate (315 mg, 2.28 mmol), and Pd(dppf)Cl2(28 mg, 0.038 mmol) were added successively. The nitrogen atmosphere was replaced and protected, and the reaction was heated to 100 °C for 4 h. After the reaction was complete, as indicated by LCMS and TLC monitoring, the reaction solution was concentrated. Water (10 mL) was added to the resulting residue, and extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 40 (120 mg, 0.23 mmol, 62.2% yield). MS-ESI Theoretical value [M+H] + : 518.2, found: 518.2. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.46 (d, J = 1.2 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.66 - 7.56 (m, 3H), 7.53 - 7.45 (m, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.39 (t, J = 2.0 Hz, 1H), 3.59 (s, 6H), 2.71 - 2.62 (m, 2H), 2.56-2.51 (m, 2H), 2.22 (s, 3H), 2.03 - 1.95 (m, 2H).

[0381] Synthesis of compound 41

[0382] In a 100 mL single necked flask, compound 40 (120 mg, 0.23 mmol) was dissolved in methanol (30 mL), and palladium on carbon (60 mg) was added. After hydrogen replacement, it was heated to 60 °C for 8 h. LCMS and TLC monitoring showed that the reaction was complete, the reaction was filtered with diatomite. The filtrate was concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 41 (27 mg, 0.052 mmol, 22.6% yield). MS-ESI [M+H] calculated: 520.2, found: 520.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.46 (d, J = 1.0 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H), 7.71 - 7.38 (m, 6H), 6.81 (d, J = 4.9 Hz, 2H), 3.60 (s, 6H), 3.07 - 2.99 (m, 1H), 2.22 (s, 3H), 2.03 - 1.51 (m, 8H).

[0383] Synthesis of compound 42

[0384] ​In a 100 mL flask, compound 5 (200 mg, 0.38 mmol), 1,4-dioxane (10 mL), water (2 mL), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (130 mg, 0.57 mmol), potassium carbonate (157.56 mg, 1.14 mmol) and Pd(PPh3)4(44 mg, 0.038 mmol) were added successively. After nitrogen replacement and keeping nitrogen atmosphere, the reaction was heated to 100 °C for 4 h. After LCMS and TLC monitoring showed the reaction was completed, the reaction was concentrated. Water (100 mL) was added to the residue, which was extracted with ethyl acetate (30 mL x 3) and dichloromethane (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate and concentrated. Purification was performed by silica gel column chromatography (dichloromethane:methanol = 5:1, v / v) to give compound 42 (183 mg, 0.33 mmol, 86.8% yield). MS-ESI [M+H] calculated for C28H28N4O5: 547.2, found: 547.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.10 (d, J = 10.6 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.49 - 7.34 (m, 4H), 6.78 (d, J = 8.5 Hz, 2H), 6.16 (s, 1H), 3.59 (s, 6H), 3.04 (d, J = 3.3 Hz, 2H), 2.59 (t, J = 5.6 Hz, 2H), 2.29 (s, 3H), 2.18 (s, 2H), 1.89 (s, 3H).

[0385] Example 43 Synthesis of compound 43

[0386] In a 100 mL flask, compound 42 (180 mg, 0.33 mmol), methanol (30 mL) and palladium on carbon (90 mg) were added successively. After hydrogen replacement, the reaction was heated to 60 °C for 8 h. After LCMS and TLC monitoring showed the reaction was completed, the reaction was filtered with celite. The filtrate was concentrated and purified by C18-silica gel column chromatography, eluted with base method (ammonium bicarbonate-water-acetonitrile system, acetonitrile content 0-50%) first, then eluted with acid method (trifluoroacetic acid-water-acetonitrile system, acetonitrile content 0-50%) to give compound 43 (55 mg, 0.1 mmol, 30.3% yield). MS-ESI [M+H] calculated for C29H30N4O5: 549.2, found: 549.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 1.4 Hz, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.56 (s, 1H), 7.53 - 7.43 (m, 3H), 6.81 (d, J = 8.6 Hz, 2H), 3.60 (s, 6H), 3.52 - 3.49 (m, 1H), 3.15 - 2.85 (m, 4H), 2.81 (s, 3H), 2.22 (s, 3H), 2.05 - 1.97 (m, 2H), 1.95 - 1.81 (m, 2H).

[0387] Synthesis of compound 44

[0388] In a 100 mL single necked flask, intermediate 37a (100 mg, 0.21 mmol), anhydrous DMF (10 mL), N-(3-chloropropyl)piperidine hydrochloride (51 mg, 0.26 mmol) and cesium carbonate (270 mg, 0.84 mmoL) were added successively. The reaction was heated to 40 °C for 16 h. After LCMS and TLC monitoring showed the reaction was complete, it was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 5:1, v / v) to give compound 44 (31 mg, 0.05 mmol, 23.8% yield). MS-ESI [M+H] calc’d for C30H37C12N4O2: 593.2, found: 593.2. + 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.29 (s, 1H), 7.59 (s, 1H), 7.49 - 7.30 (m, 4H), 7.02 (d, J = 6.1 Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 3.60 (s, 6H), 3.40 - 3.30 (m, 2H), 3.25 - 3.07 (m, 4H), 2.40 - 2.31 (m, 2H), 2.29 (s, 3H), 2.05 - 1.85 (m, 4H), 1.80 - 1.12 (m, 4H).

[0389] Synthesis of compound 45

[0390] ​In a 100 mL single necked flask, was added intermediate 37a (100 mg, 0.21 mmol), anhydrous DMF (10 mL), cesium carbonate (205 mg, 0.63 mmol) and iodoethane (33 mg, 0.21 mmol) successively. The reaction was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LCMS and TLC, it was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 45 (21 mg, 0.04 mmol, 19.0% yield). MS-ESI calculated for [M+H] C26H26N5O4, 496.2 found, 496.2. + 1 HNMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.46 (d, J = 0.6 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.61 - 7.27 (m, 5H), 7.10 (s, 1H), 6.82 (d, J = 0.7 Hz, 2H), 4.12 - 3.98 (m, 2H), 3.62 (s, 6H), 2.22 (s, 3H), 1.38 - 1.29 (m, 3H).

[0391] Synthesis of compound 46

[0392] In a 100 mL single necked flask, was added intermediate 37a (100 mg, 0.21 mmol), anhydrous DMF (10 mL), cesium carbonate (205 mg, 0.63 mmol) and iodoethane (33 mg, 0.21 mmol) successively. The reaction was stirred at 25 °C for 16 h. After the reaction was completed as monitored by LCMS and TLC, it was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 45 (21 mg, 0.04 mmol, 19.0% yield). MS-ESI calculated for [M+H] C26H26N5O4, 496.2 found, 496.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.15 (s, 1H), 7.53 (s, 1H), 7.47 (t, J = 8.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.32 - 7.23 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.69 - 4.57 (m, 1H), 3.62 (s, 6H), 2.21 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H).

[0393] Synthesis of compound 47

[0394] ​​In a 100 mL single necked flask, was added successively intermediate 37a (80 mg, 0.17 mmol), R-carboxylate (28 mg, 0.27 mmol), TBAF (1 M, 0.32 mL) and anhydrous DMF (4 mL). The reaction was heated to 140 °C for 1 h. TLC and LCMS monitoring showed the reaction was complete, concentrated, purified by normal phase column (dichloromethane: methanol = 10:1, v / v) to give compound 46 (13 mg, 0.025 mmol, 14.7% yield). MS-ESI calculated for [M+H]: 526.2, found: 526.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.94 (d, J = 4.8 Hz, 1H), 4.02 - 3.92 (m, 1H), 3.90 - 3.77 (m, 2H), 3.63 (s, 6H), 2.22 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H).

[0395] Synthesis of compound 48

[0396] In a 100 mL single necked flask, was added successively intermediate 37a (80 mg, 0.17 mmol), R-carboxylate (28 mg, 0.27 mmol), TBAF (1 M, 0.32 mL) and anhydrous DMF (4 mL). The reaction was heated to 140 °C for 1 h. TLC and LCMS monitoring showed the reaction was complete, concentrated, purified by normal phase column (dichloromethane: methanol = 10:1, v / v) to give compound 46 (13 mg, 0.025 mmol, 14.7% yield). MS-ESI calculated for [M+H]: 526.2, found: 526.2. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.11 (dd, J = 8.2, 2.6 Hz, 1H), 7.03 (s, 1H), 6.82 (d, J = 8.6 Hz, 2H), 4.94 (d, J = 4.7 Hz, 1H), 3.96 (s, 1H), 3.84 (p, J = 4.1 Hz, 2H), 3.63 (s, 6H), 2.23 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H).

[0397] Example 49 Synthesis of compound 49

[0398] In a 100 mL three-necked flask, was added sequentially intermediate 37a (145 mg, 0.31 mmol), (iodomethyl)cyclopropane (56 mg, 0.31 mmol), potassium carbonate (64 mg, 0.46 mmol) and anhydrous DMF (4 mL). The reaction was heated to 40 °C for 4 h. TLC and LCMS monitoring showed the reaction was complete. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was combined, washed with saturated brine (20 mL), concentrated and purified by normal phase column (dichloromethane:methanol = 20:1, v / v) to give compound 49 (24 mg, 0.05 mmol, 16.1% yield). MS-ESI calc. for [M+H] + : 522.2, found: 522.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.49 (d, J = 2.1, 0.8 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.42 (t, J = 8.5 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.95 - 6.92 (m, 1H), 6.89 - 6.86 (m, 1H), 6.84 - 6.79 (m, 1H), 6.70 (s, 1H), 6.68 (s, 1H), 4.20 (d, J = 7.2 Hz, 2H), 3.63 (s, 6H), 2.25 (s, 3H), 1.48 - 1.32 (m, 1H), 0.61 - 0.55 (m, 2H), 0.49 - 0.43 (m, 2H).

[0399] Example 50 Synthesis of compound 50

[0400] In a 100 mL single necked flask, intermediate 37a (100 mg, 0.21 mmol), anhydrous DMF (10 mL), cesium carbonate (205 mg, 0.63 mmol) and 2-methoxybromoethane (44 mg, 0.32 mmol) were added successively. The reaction was stirred at 25 °C for 16 h. LCMS and TLC monitoring showed the reaction was complete. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 50 (20 mg, 0.038 mmol, 18.1% yield). MS-ESI calculated for [M+H]: 526.2, found: 526.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.47 (s, 1H), 8.17 (s, 1H), 7.61 - 7.31 (m, 5H), 7.14 (d, J = 6.5 Hz, 1H), 6.82 (d, J = 7.9 Hz, 2H), 4.19 - 4.08 (m, 2H), 3.71 - 3.66 (m, 2H), 3.63 (s, 6H), 3.31 (s, 3H), 2.23 (s, 3H).

[0401] Example 51 Synthesis of compound 51

[0402] In a 100 mL sealed tube, intermediate 37a (20 mg, 0.04 mmol), (S)-5- (bromomethyl)-2-pyrrolidinone (9 mg, 0.05 mmol), cesium carbonate (42 mg, 0.13 mmol) and super dry acetonitrile (1 mL) were added successively. The reaction was heated to 70 °C for 4 h. LCMS monitoring showed the reaction was complete. The reaction mixture was filtered, washed with ethyl acetate, the resulting filtrate was concentrated and purified by reverse phase MPLC (acetonitrile: water (5% NH4HCO3) = 0:100 - 30:70, v / v), lyophilized to give compound 51 (4 mg, 0.007 mmol, 17.5% yield). MS-ESI calculated for [M+H]: 565.2, found: 565.3. + 1 ​​H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.90 (s, 1H), 7.58 (s, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.17 - 7.08 (m, 1H), 6.82 (d, J = 8.6 Hz, 2H), 4.03 - 3.96 (m, 1H), 3.94 - 3.87 (m, 2H), 3.63 (d, J = 3.1 Hz, 6H), 2.31 - 2.24 (m, 1H), 2.23 (s, 3H), 2.21 - 2.09 (m, 2H), 1.93 - 1.78 (m, 1H).

[0403] Synthesis of compound 52

[0404] In a 10 mL single necked flask, was added sequentially intermediate 37a (100 mg, 0.21 mmol), 4-chloro-2-fluorobenzyl bromide (48 mg, 0.21 mmol), cesium carbonate (205 mg, 0.63 mmol) and DMF (1 mL). The reaction was stirred at 25 °C for 4 h. TLC and LCMS monitoring showed the reaction was complete. The reaction mixture was concentrated and purified by normal phase column (dichloromethane:methanol = 20:1, v / v) to give compound 52 (5 mg, 0.01 mmol, 4.8% yield). MS-ESI calc. for [M+H] C32H25ClF2N4O4: 610.1, found: 610.1. + 1 H NMR (400 MHz, CD3OD) δ 8.44 - 8.33 (m, 1H), 8.20 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.45 - 7.34 (m, 2H), 7.31 - 7.22 (m, 2H), 7.11 (t, J = 7.9 Hz, 1H), 6.97 - 6.93 (m, 1H), 6.92 (t, J = 2.1 Hz, 1H), 6.86 - 6.78 (m, 1H), 6.58 (d, J = 8.6 Hz, 2H), 5.57 (s, 2H), 3.65 (s, 6H), 2.25 (s, 3H).

[0405] Synthesis of compound 53

[0406] Synthesis of intermediate 53a

[0407] ​In a 250 mL single-neck flask, compound 5 (2.50 g, 4.71 mmol), bis(pinacolato)diboron (3.59 g, 14.13 mmol), potassium acetate (1.39 g, 14.13 mmol), Pd(dppf)Cl2(340 mg, 0.47 mmol) and dimethyl sulfoxide (60 mL) were added successively. After nitrogen replacement and keeping the nitrogen atmosphere, it was heated to 120 °C for 6 h. LCMS and TLC monitoring showed that the reaction was complete. Water (500 mL) was added and extracted with ethyl acetate (100 mL x 3). The organic phase was combined, washed with saturated aqueous sodium chloride solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to give intermediate 53a (2.12 g, 3.67 mmol, 77.9% yield). MS-ESI [M+H] calculated for C26H25FN4O2, 478.2, found 478.2. + : 535.2, found 535.2.

[0408] Second Step: Synthesis of compound 53

[0409] Intermediate 53a (100 mg, 0.17 mmol) and acetonitrile (6 mL) were added to a 100 mL dry three-neck flask, followed by the addition of piperidine (19 mg, 0.22 mmol), copper acetate (40 mg, 0.22 mmol) and triethylamine (34 mg, 0.34 mmol) successively. After addition, it was slowly warmed to 80 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete. Dichloromethane (50 mL) was added, the reaction solution was washed with water, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound 53 (28 mg, 0.05 mmol, 29% yield). MS-ESI [M+H] calculated for C28H27FN4O2, 515.2, found 515.2. + : 535.2, found 535.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.16 (s, 1H), 7.55 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.05 (dd, J = 8.1, 2.0 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 3.62 (s, 6H), 3.17 (d, J = 5.1 Hz, 4H), 2.22 (s, 3H), 1.69 - 1.49 (m, 6H).

[0410] Example 54: Synthesis of compound 54

[0411] Intermediate 53a (100 mg, 0.17 mmol) and acetonitrile (6 mL) were added into a 100 mL dry three-necked flask, then morpholine (19 mg, 0.22 mmol), copper acetate (40 mg, 0.22 mmol) and triethylamine (34 mg, 0.34 mmol) were added in turn. After addition, the temperature was slowly increased to 80 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete. After the reaction was completed, dichloromethane (50 mL) was added, and the reaction solution was washed with water, and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound 54 (20 mg, 0.04 mmol, 21.5% yield). MS-ESI [M+H] calculated for C28H25FN4O4: 537.2, found: 537.2. + : 537.2, found: 537.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.57 (s, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 5.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.58 (d, J = 8.5 Hz, 2H), 3.78 - 3.72 (m, 4H), 3.51 (s, 6H), 3.12 - 3.04 (m, 4H), 2.28 (s, 3H).

[0412] Synthesis of compound 55

[0413] Compound 5 (500 mg, 0.94 mmol), N-methylhomopiperazine (120 mg, 1.03 mmol), Ruphos-Pd-G4 (80 mg, 0.09 mmol) and anhydrous DMF (15 mL) were added into a 100 mL dry three-necked flask. After addition, nitrogen was replaced and a nitrogen atmosphere was maintained, and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 1.41 mL) was added. After addition, the temperature was slowly increased to 110 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete, and the reaction solution was concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound 55 (110 mg, 0.20 mmol, 21% yield). MS-ESI [M+H] calculated for C32H37FN4O4: 564.2, found: 564.2. + : 537.2, found: 537.2. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.95 (d, J = 7.7 Hz, 1H), 6.83 (dd, J = 13.9, 5.4 Hz, 3H), 3.61 (s, 6H), 3.58 - 3.54 (m, 2H), 3.44 (t, J = 6.1 Hz, 3H), 2.76 - 2.66 (m, 2H), 2.62 - 2.54 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 1.99 - 1.87 (m, 2H).

[0414] Synthesis of compound 56

[0415] Intermediate 53a (420 mg, 0.73 mmol) was added into a 50 mL dry flask, then 3- fluoropyridine hydrochloride (123 mg, 1.10 mmol), BINAP (56 mg, 0.09 mmol), cesium carbonate (714 mg, 2.09 mmol), palladium acetate (34 mg, 0.15 mmol) and anhydrous 1,4-dioxane (10 mL) were added in turn. The nitrogen atmosphere was replaced and kept, and the temperature was raised to 110 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete. 1,4-Dioxane (10 mL) was added to the reaction solution, filtered and washed with 1,4-dioxane (5 mL x 2). The filtrate and washing liquid were combined and concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound 56 (85 mg, 0.16 mmol, 22% yield). MS-ESI [M+H] calculated: 525.2, found: 525.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.15 (s, 1H), 7.55 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.30 (s, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.1 Hz, 1H), 5.22 - 4.80 (m, 1H), 4.19 (s, 2H), 3.93 (s, 1H), 3.86 (s, 1H), 3.62 (s, 6H), 2.22 (s, 3H).

[0416] Synthesis of compound 57

[0417] ​Compound 5 (113 mg, 0.21 mmol) was added to a 100 mL dry flask, followed by 3-hydroxyindole hydrochloride (35 mg, 0.32 mmol), Ruphos-Pd-G4 (17 mg, 0.02 mmol) and anhydrous DMF (5 mL) in turn. Nitrogen was replaced for three times and kept nitrogen atmosphere, then slowly injected lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 0.32 mL). After addition, slowly warmed to 110 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete, the reaction solution was concentrated, purified by normal phase column (dichloromethane:methanol = 8:1, v / v) to give compound 57 (50 mg, 0.10 mmol, 48% yield). MS-ESI [M+H] calculated for C28H23FN4O4: 523.2, found: 523.2. + : 523.2, found: 523.2. 1 H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.57 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.87 - 6.77 (m, 3H), 6.56 (d, J = 7.5 Hz, 1H), 5.66 (d, J = 6.6 Hz, 1H), 4.58 (dd, J = 11.2, 4.9 Hz, 1H), 4.10 (t, J = 7.3 Hz, 2H), 3.62 (s, 6H), 3.52 (dd, J = 7.6, 5.0 Hz, 2H), 2.22 (s, 3H).

[0418] Synthesis of compound 58

[0419] Compound 5 (225 mg, 0.39 mmol) was added to a 100 mL dry flask, followed by N,N-dimethylpiperidin-4-amine (76 mg, 0.59 mmol), Ruphos-Pd-G4 (34 mg, 0.04 mmol) and anhydrous DMF (5 mL) in turn. Nitrogen was replaced for three times and kept nitrogen atmosphere, then slowly injected lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 0.59 mL). After addition, slowly warmed to 110 °C for 6 h. TLC and LCMS monitoring showed that the reaction was complete, the reaction solution was concentrated, purified by normal phase column (dichloromethane:methanol = 10:1, v / v) to give compound 58 (100 mg, 0.17 mmol, 44% yield). MS-ESI [M+H] calculated for C29H27FN4O4: 578.2, found: 578.2. + : 523.2, found: 523.2. 1H NMR (400 MHz, DMSO-d6) δ 12.82 - 12.10 (m, 1H), 8.40 (s, 1H), 8.14 (s, 1H), 7.53 (s, 1H), 7.47 (t, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.81 (d, J = 8.6 Hz, 2H), 3.80 (d, J = 12.5 Hz, 2H), 3.61 (s, 6H), 2.89 (s, 1H), 2.71 (t, J = 12.1 Hz, 2H), 2.50 - 2.48 (m, 6H), 2.21 (s, 3H), 2.03 (d, J = 11.5 Hz, 2H), 1.62 (dd, J = 20.6, 11.7 Hz, 2H).

[0420] Synthesis of compound 59

[0421] Synthesis of intermediate 59a

[0422] In a 100 mL single necked flask, intermediate 37a (450 mg, 0.96 mmol), 1-tert- butyloxycarbonyl-4-iodomethylpiperidine (468 mg, 1.44 mmol), cesium carbonate (938 mg, 2.88 mmol) and DMF (5 mL) were added successively. The reaction mixture was heated to 80 °C for 8 h. LCMS monitoring showed the reaction was completed. The reaction mixture was concentrated and purified by normal phase MPLC (dichloromethane:methanol = 20:1, v / v) to give intermediate 59a (290 mg, 0.44 mmol, 45.8% yield). MS-ESI [M+H] calc’d for C26H34IN5O6, 665.3, found 665.3. + : 565.2, found: 565.2.

[0423] Synthesis of compound 59

[0424] In a 100 mL single necked flask, intermediate 59a (290 mg, 0.44 mmol) was dissolved in methanol (3 mL), hydrogen chloride in 1,4-dioxane (4 M, 3 mL) was added. The reaction mixture was stirred at room temperature for 1 h. TLC monitoring showed the reaction was completed. The reaction mixture was concentrated and purified by reverse phase MPLC (0.5% ammonium bicarbonate in water: acetonitrile = 100-50%) and lyophilized to give compound 59 (60 mg, 0.11 mmol, 25.0% yield). MS-ESI [M+H] calc’d for C21H25IN5O5, 565.2, found 565.2. + : 565.2, found: 565.2. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.33 - 7.27 (m, 2H), 7.01 - 6.92 (m, 1H), 6.79 (d, J = 8.5 Hz, 2H), 3.87 (d, J = 6.3 Hz, 2H), 3.63 (s, 6H), 2.96 - 2.80 (m, 2H), 2.53 - 2.52 (m, 2H), 2.18 (s, 3H), 1.97 - 1.84 (m, 3H), 1.53 - 1.41 (m, 2H).

[0425] Synthesis of compound 60

[0426] After intermediate 53a (0.2 g, 0.35 mmol) was dissolved in 1,4-dioxane / water mixed solvent (66:33, 20 mL), potassium carbonate (97 mg, 0.7 mmol), 5-bromo-2-methyl-2H-indazole (150 mg, 0.71 mmol) and sSPhos Pd G2 (29 mg, 0.035 mmol) were added successively, replaced by nitrogen and kept in nitrogen atmosphere, heated to 120 °C for 3 h. TLC showed that the reaction was completed, water (20 mL) was added, and extracted with dichloromethane (30 mL x 3). The organic phase was combined, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v) to give compound 60 (52 mg, 0.089 mmol, 25.8% yield). MS-ESI [M+H] Theoretical value: 582.2, Found: 582.2. + 1 H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.46 (s, 2H), 8.20 - 8.09 (m, 2H), 8.03 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 9.4 Hz, 2H), 7.67 - 7.55 (m, 3H), 7.50 (t, J = 8.5 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 4.21 (s, 3H), 3.57 (s, 6H), 2.22 (s, 3H).

[0427] Synthesis of compound 61

[0428] Step 1. Synthesis of intermediate 61b

[0429] ​Compound 61a (2.00 g, 12.0 mmol) was dissolved in methanol (20 mL), hydrazine hydrate (972 mg, 15.6 mmol, 80%) was added, and the reaction was continued at 25 °C for 18 h, and then concentrated. The residue was slurried with ethyl acetate (2 mL) and n-hexane (20 mL), concentrated, and dried to give intermediate 61b (1.93 g, 11.5 mmol, 96.2% yield). MS-ESI [M+H] calc’d for C17H22N4O4, 168.2, found 168.2. + : 168.2, found 168.2.

[0430] Second Step: Synthesis of Intermediate 5a

[0431] 3-Bromobenzene-1-sulfonamide (2.00 g, 8.5 mmol) and intermediate 1e (1.80 g, 9.0 mmol) were dissolved in acetonitrile (20 mL), and cesium carbonate (3.60 g, 11.0 mmol) was added. The reaction was replaced with nitrogen and kept under nitrogen atmosphere, and reacted at room temperature for 19 h. LCMS monitoring showed about 90% product of the reaction, and the resulting reaction was directly used for the next step. MS-ESI [M+H] calc’d for C26H26N4O4S, 431.0, found 431.0. + : 431.0, found 431.0.

[0432] Third Step: Synthesis of Intermediate 61c

[0433] The reaction solution from the second step was cooled to 0 °C, and intermediate 61b (1.53 g, 9.2 mmol) and silver nitrate (2.9 g, 17.0 mmol) were added slowly in portions. After the addition was completed, the reaction was continued for 1 h, filtered through celite, and the resulting filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-94:6, v / v) to give intermediate 61c (4.2 g, 7.44 mmol, 87.5% yield for two steps). MS-ESI [M+H] calc’d for C28H30N4O6S, 564.0, found 564.0. + : 564.0, found 564.0.

[0434] Fourth Step: Synthesis of Intermediate 61d

[0435] Methanesulfonic acid (1.2 g, 12.7 mmol) was added slowly dropwise to a solution of intermediate 61c (2.0 g, 3.5 mmol) in 1,4-dioxane (20 mL), and the reaction was continued at 90 °C for 5 h. After cooling to room temperature, water was added, and the pH was adjusted to about 7 by dropwise addition of aqueous sodium bicarbonate solution. The resulting filter cake was dried under vacuum to give intermediate 61d (1.6 g, 2.9 mmol, 83.7% yield). MS-ESI [M+H] calc’d for C28H30N4O6S, 546.1, found 546.1. + : 546.1, found 546.1.

[0436] Step 5. Synthesis of compound 61

[0437] To a solution of intermediate 61d (300 mg, 0.55 mmol) in acetonitrile (10 mL) was added compound 5-methyl-2-(tributylstannyl)pyrimidine (316.1 mg, 0.83 mmol), X-Phos (79 mg, 0.17 mmol) and Pd2(dba)3(50 mg, 0.06 mmol), after addition, the reaction was heated to 120 °C and reacted under microwave for 1 h. Ethyl acetate (20 mL) and water (20 mL) were added, the mixture was extracted, separated, the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-94:6, v / v) to give compound 61 (60 mg, 0.11 mmol, 19.5% yield). MS-ESI [M+H] calculated: 560.2, found: 560.1. + 1 H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 8.86 - 8.71 (m, 3H), 8.51 (d, J = 7.9 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.82 - 7.75 (m, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.39 (t, J = 8.5 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.5 Hz, 2H), 3.52 (s, 6H), 3.06 (s, 3H), 2.34 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.03, 159.32, 157.16, 155.05, 145.71, 143.68, 141.63, 139.48, 137.15, 130.21, 129.45, 129.17, 128.55, 126.82, 124.16, 114.63, 111.98, 110.86, 103.95, 55.37, 51.75, 14.39.

[0438] Example 62. Synthesis of compound 62

[0439] First Step. Synthesis of intermediate 62b

[0440] ​Compound 62a (1.00 g, 4.13 mmol), benzyl mercaptan (564 mg, 4.55 mmol), Pd2(dba)3(378 mg, 0.413 mmol), Xantphos (478 mg, 0.827 mmol) and DIEA (1.61 g, 12.4 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction was heated to 70 °C for 2 h. The resulting filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to give intermediate 62b (600 mg, 2.10 mmol, 50.9% yield). MS-ESI [M+H] calc’d for C26H28N2O2S, 287, found 287. + : 287, found 287.

[0441] Second Step: Synthesis of intermediate 62c

[0442] Intermediate 62b (600 mg, 2.10 mmol) and N-chlorosuccinimide (843 mg, 6.31 mmol) were dissolved in acetonitrile / water mixed solvent (90:10, 6 mL) and reacted at room temperature for 2 h. The resulting filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1, v / v) to give intermediate 62c (300 mg, 1.15 mmol, 54.5% yield). MS-ESI [M+H] calc’d for C19H20N2O2S, 263, found 263. + : 263, found 263.

[0443] Third Step: Synthesis of intermediate 62d

[0444] Intermediate 1i (800 mg, 2.57 mmol) was dissolved in tetrahydrofuran (16 mL), and potassium bis(trimethylsilyl)amide (1 M, 3.86 mL, 3.86 mmol) was added, and stirred at room temperature for 10 min. A tetrahydrofuran solution of intermediate 62c (952 mg, 3.66 mmol, dissolved in 2 mL of tetrahydrofuran) was added, and the reaction was continued at room temperature for 1 h. Water (5 mL) was added, and extracted with ethyl acetate (20 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol = 98:2-92:8, v / v) to give intermediate 62d (380 mg, 0.71 mmol, 27.6% yield). MS-ESI [M+H] calc’d for C34H40N4O2S, 536.0, found 536.0. + : 263, found 263.

[0445] Fourth Step: Synthesis of compound 62

[0446] Intermediate 62d (300 mg, 0.56 mmol), 5-methyl-2-(tributylstannyl)pyrimidine (430 mg, 1.12 mmol), X-Phos (80 mg, 0.168 mmol) and Pd2(dba)3(51 mg, 0.056 mmol) were dissolved in acetonitrile (10 mL), heated to 120 °C and reacted under microwave for 1 h. The reaction was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v) and high pressure preparative liquid chromatography (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 10%-90% over 15 min) to give compound 62 (12 mg, 0.02 mmol, 3.9% yield). MS-ESI [M+H] calc’d for C26H22N7O4: 550, found: 550. + 1 H NMR (400 MHz, DMSO-d6) δ 13.84 (s, 1H), 8.72 (s, 2H), 8.49 (d, J = 20.5 Hz, 2H), 8.19 (dd, J = 8.8, 1.5 Hz, 2H), 7.60 (s, 1H), 7.51 (s, 1H), 6.84 (d, J = 8.6 Hz, 2H), 3.65 (d, J = 10.8 Hz, 6H), 2.30 (s, 3H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 158.13, 156.39, 144.57, 140.40, 135.39, 133.84, 129.56, 105.41, 56.81, 40.64, 40.44, 40.23, 40.02, 39.81, 39.60, 39.39, 18.16, 15.48, 0.60.

[0447] Synthesis of compound 63 of Example 63

[0448] First Step: Synthesis of intermediate 63b

[0449] ​Intermediate 1i (200 mg, 0.643 mmol) was dissolved in tetrahydrofuran (10 mL), potassium bis(trimethylsilyl)amide (154 mg, 0.772 mmol) was added, and stirred at room temperature for 1 h, compound 63a (246 mg, 0.965 mmol) was added and the reaction was continued for 2 h. The reaction was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1, v / v) to give intermediate 63b (150 mg, 0.283 mmol, 44% yield). MS-ESI [M+H] calculated for C26H25FN6, 531.2 found, 531.2. + : 531, found: 531.

[0450] Second Step Synthesis of compound 63

[0451] Intermediate 63b (240 mg, 0.453 rnmol), 5-methyl-2-(tributylstannyl)pyrimidine (216 mg, 0.906 mmol), X-Phos (65 mg, 0.136 mmol) and Pd2(dba)3(41 mg, 0.0453 mmol) were dissolved in acetonitrile (10 mL). Heated to 120 °C and reacted under microwave for 1 h, the reaction was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography on silica gel (dichloromethane:methanol = 10:1, v / v) and high pressure preparative liquid chromatography (column: Xbridge-C18 150 x 19 mm, 5 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 10%-90% over 15 min) to give compound 63 (30 mg, 0.055 mmol, 12% yield). MS-ESI [M+H] calculated for C26H21FN6, 545.2 found, 545.2. + : 545, found: 545. 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.99 (d, J = 2.1 Hz, 1H), 8.92 (t, J = 2.1 Hz, 1H), 8.82 (d, J = 0.7 Hz, 2H), 8.36 (s, 1H), 8.10 (d, J = 3.6 Hz, 1H), 7.50 (s, 1H), 7.44 (t, J = 8.5 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 3.55 (s, 6H), 2.32 (s, 3H), 2.16 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.99, 158.42, 156.40, 150.70, 148.53, 146.94, 144.33, 139.45, 134.97, 133.61, 133.07, 132.79, 132.46, 130.94, 105.39, 56.66, 18.18, 15.53.

[0452] Synthesis of compound 64

[0453] Synthesis of intermediate 64b in the first step

[0454] Compound 64a (3.0 g, 23.44 mmol), (2-fluoropyridin-4-yl)boronic acid (3.96 g, 28.13 mmol) and cesium carbonate (15.28 g, 46.88 mmol) were added into a mixed solvent of 1,4-dioxane / water (80:20, 100 mL), Pd(dppf)Cl2(1.68 g, 0.23 mmol) was added and the reaction was carried out at 90 °C for 3 h. The resulting reaction solution was concentrated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10:1, v / v) to obtain intermediate 64b (3.0 g, 15.8 mmol, yield 67.7%). MS-ESI [M+H] calculated for C17H13FN3, 190.1, found 190.1. +

[0455] Synthesis of intermediate 64c in the second step

[0456] Benzyl mercaptan (1.71 g, 14 mmol) and sodium hydride (0.55 g, 14 mmol) were dissolved in tetrahydrofuran (30 mL) at 0 °C under a nitrogen atmosphere, and intermediate 64b (2 g, 10.5 mmol) was added. The reaction was continued to be carried out at 25 °C for 16 h, water (20 mL) was added, and extraction was carried out with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:1, v / v) to obtain intermediate 64c (2.0 g, 6.81 mmol, yield 58%). MS-ESI [M+H] calculated for C21H19FN3S, 294.1, found 294.1. +

[0457] Synthesis of intermediate 64d in the third step

[0458] ​​Intermediate 64c (1 g, 3.40 mmol) was added into a mixed solvent of dichloromethane / 4N hydrochloric acid (80:20, 15 mL), sodium hypochlorite aqueous solution (8 mL) was added, after reaction at room temperature for 1 h, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1, v / v) to give intermediate 64d (470 mg, 1.74 mmol, 51.4% yield). MS-ESI [M+H] calculated for C19H13FN4O2, 269.0 found, 269.1. + : 269.0, found: 269.1.

[0459] Fourth step Synthesis of compound 64

[0460] Intermediate 1i (200 mg, 0.64 mmol) was added into dichloromethane (10 mL), replaced by nitrogen and kept in nitrogen atmosphere, sodium bis(trimethylsilyl)amide (1 mL, 1.93 mmol) was added in batches at 0 °C, after reaction for 30 min, intermediate 64d (347 mg, 1.28 mmol) was added, continued to react at room temperature for 16 h, added water (1 mL), concentrated, purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v) to give compound 64 (58.94 mg, 0.11 mmol, 16.8% yield). MS-ESI [M+H] calculated for C32H21FN6O2, 545.2 found, 545.1. + : 269.0, found: 269.1. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 8.76 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.26-8.24 (m, 2H), 8.09 (s, 1H), 7.41-7.39 (m, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.61 (s, 6H), 2.37 (s, 3H), 2.16 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 158.78, 158.55, 156.38, 152.40, 152.22, 151.06, 150.32, 146.66, 144.54, 135.32, 133.80, 132.77, 132.03, 123.85, 118.23, 105.48, 56.71, 18.23, 15.62.

[0461] Example 65 Synthesis of compound 65

[0462] First step Synthesis of intermediate 65b

[0463] Compound 65a (7 g, 33.6 mmol) was added into chlorosulfonic acid (30 mL) and reacted at 130 °C for 48 h. After the reaction was quenched with ice water (100 mL) and extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude intermediate 65b (3.4 g, 11.1 mmol, 33.0% yield). MS-ESI Calcd for [M+H] + : 305.9, found: 305.9.

[0464] Second Step: Synthesis of intermediate 65c

[0465] To a solution of intermediate 1i (0.6 g, 1.93 mmol) in DMF (10 mL) was added sodium hydride (308 mg, 7.71 mmol, 60%) at 0 °C and stirred at 0 °C for 0.5 h. Then intermediate 65b (886 mg, 2.89 mmol) was added and the reaction was continued at 25 °C for 3 h. After the reaction was quenched with ice water, purification by C-18 flash column chromatography (acetonitrile: water = 25:75, v / v) gave intermediate 65c (420 mg, 0.72 mmol, 37.5% yield). MS-ESI Calcd for [M+H] + : 581.1, found: 581.0.

[0466] Third Step: Synthesis of compound 65

[0467] To a solution of intermediate 65c (420 mg, 0.72 mmol) in acetonitrile (10 mL) was added 5-methyl-2-(tributylstannyl)pyrimidine (332 mg, 0.87 mmol), X-Phos (138 mg, 0.29 mmol) and Pd2(dba)3(133 mg, 0.15 mmol) and the reaction was heated to 120 °C under nitrogen atmosphere for 16 h. The resulting reaction mixture was concentrated and purified by reverse phase high performance liquid chromatography (acetonitrile: 0.1% aqueous FA = 0:100-30:70, v / v) to give compound 65 (25.3 mg, 0.04 mmol, 5.9% yield). MS-ESI Calcd for [M+H] + : 595.2, found: 595.1. 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 9.30 (d, J = 1.5 Hz, 1H), 9.16 (s, 1H), 8.85 (s, 3H), 8.68 (d, J = 8.2 Hz, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 7.69 (dd, J = 8.2, 4.1 Hz, 1H), 7.63 (s, 1H), 7.35 (t, J = 8.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 3.25 (s, 6H), 2.36 (s, 3H), 2.25 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 160.08, 158.30, 156.31, 152.32, 152.02, 151.73, 145.86, 144.70, 144.33, 141.49, 138.07, 135.52, 134.38, 133.93, 132.54, 131.56, 130.39, 128.92, 128.18, 122.86, 122.24, 109.68, 105.23, 56.19, 18.18, 15.49.

[0468] Synthesis of compound 66

[0469] Compound 5 (400 mg, 0.75 mmol), 1-methylpiperazine (227 mg, 2.26 mmol), Pd2(dba)3(69 mg, 0.075 mmol), Ruphos (70 mg, 0.15 mmol) and Cs2CO3(737 mg, 2.26 mmol) were added into 1,4-dioxane (10 mL). The resulting reaction mixture was stirred at 105 °C for 16 h under nitrogen atmosphere. The resulting reaction mixture was concentrated and purified by column chromatography on silica gel (dichloromethane:methanol = 100:0-90:10, v / v) to give compound 66 (200 mg, 0.36 mmol, 48.3% yield). MS-ESI Calcd for [M+H] + : 550.2, found: 550.2. 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.44 (s, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.56 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.33 (dd, J = 9.1, 6.8 Hz, 2H), 7.17 - 7.06 (m, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.61 (s, 6H), 3.24 - 3.16 (m, 4H), 2.54 (s, 4H), 2.28 (s, 3H), 2.22 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 156.44, 152.21, 150.96, 146.6, 144.92, 144.45, 135.14, 133.72, 132.60, 129.67, 118.28, 116.58, 112.76, 110.08, 105.43, 56.72, 54.49, 47.78, 45.54, 40.62, 40.41, 40.21, 40.00, 39.79, 39.58, 39.37, 18.18.

[0470] Synthesis of compound 67

[0471] Compound 5 (600 mg, 1.1 mmol), 1-methyltetrahydro-2(lH)-pyrimidinone (259 mg, 2.2 mmol), Xantphos-G3-Pd (54 mg, 0.06 mmol) and Cs2CO3(1.1 g, 3.3 mmol) were added into 1,4-dioxane (20 mL) and reacted at 100 °C for 16 h under nitrogen atmosphere. The resulting reaction solution was filtered, concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 100:0-90:10, v / v) to obtain compound 67 (76.8 mg, 0.14 mmol, 12.1% yield). MS-ESI [M+H] expected: 564.2, found: 564.1. + : 564.2, found: 564.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 8.46 (d, J = 1.3 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.52 - 7.42 (m, 4H), 6.81 (d, J = 8.6 Hz, 2H), 3.68 - 3.64 (m, 2H), 3.62 (s, 6H), 3.36 (d, J = 6.1 Hz, 2H), 2.86 (s, 3H), 2.23 (s, 3H), 2.08 - 2.00 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 156.37, 154.62, 152.50, 151.29, 146.82, 145.04, 144.60, 143.80, 135.43, 133.84, 132.88, 128.84, 128.32, 122.34, 121.72, 109.47, 105.41, 56.69, 48.46, 48.01, 35.77, 22.62, 18.15.

[0472] Synthesis of compound 68

[0473] Compound 61 (500 mg, 0.89 mmol) was added to purified water (10 mL), potassium hydroxide solid (80 mg, 1.43 mmol) was added, after the reaction system was clear, continue to stir until white solid precipitated, stirring overnight, the resulting reaction solution was freeze-dried, to obtain the potassium salt of compound 61, compound 68 (520 mg, 0.87 mmol, 97.4% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (t, J = 1.6 Hz, 3H), 8.36 - 8.31 (m, 1H), 7.90 (ddd, J = 10.6, 6.0, 4.4 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.53 - 7.45 (m, 2H), 7.27 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 6.51 (dd, J = 8.0, 0.8 Hz, 1H), 3.59 (d, J = 4.4 Hz, 6H), 3.00 (s, 3H), 2.32 (s, 3H).

[0474] Synthesis of compound 69

[0475] Compound 5 (500 mg, 0.94 mmol) was added to purified water (10 mL), potassium hydroxide solid (80 mg, 1.43 mmol) was added, after the reaction system was clear, continue to stir until white solid precipitated, stirring overnight, the resulting reaction solution was freeze-dried, to obtain the potassium salt of compound 5, compound 69 (529 mg, 0.93 mmol, 98.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.91 (t, J = 1.6 Hz, 1H), 7.79 - 7.70 (m, 1H), 7.56 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.39 (ddd, J = 20.4, 14.0, 40 Hz, 3H), 6.79 (d, J = 8.4 Hz, 2H), 3.64 (s, 6H), 2.17 (s, 3H).

[0476] AMG986 is Example 263.0 in patent CN 108137545B, and AMG986 used herein is purchased from MedChemExpress LLC (MCE) company.

[0477] In vitro bioactivity assay - cAMP experiment

[0478] In this experiment, a CHO cell line stably expressing APJ receptor was incubated with different concentrations of samples, and the agonism of samples on the G protein signal pathway downstream of APJ receptor was determined by cAMP kit.

[0479] Experimental method: 1x Stimulation Buffer was prepared according to the LANCE Ultra cAMP Kit (Revvity) instruction manual. Sample preparation: positive control (AMG986) and test compounds were gradient diluted to 10 concentrations. 1‰ concentration of DMSO was used as negative control. Stable APJ receptor expressing CHO cell line (CHO cell line from ATCC; stable cell line was constructed as follows: APJ receptor DNA sequence containing expression plasmid was constructed, the expression plasmid was transfected into CHO cells, and then stable cell line was obtained by resistance screening) was cultured to 80% confluence, trypsinized, counted and seeded 10 μL / well in a 384-well plate, 4000 cells / well. The prepared sample was transferred to the well plate, 10 nL per well, and incubated at 37°C for 10 minutes. Then 10 nL of 0.6 mM Forskolin (MCE) was added to each well, and incubated for 30 minutes to induce cAMP production. The reagents in the LANCE Ultra cAMP Kit (Revvity) were used to detect cAMP: Eu-cAMP was diluted to 4x working concentration with Detection buffer, and 4 μL / well was added to the corresponding experimental wells; ULight-anti-cAMP antibody was diluted to 4x working concentration with Detection buffer, and 4 μL / well was added to the corresponding experimental wells, and after centrifugation, incubated at room temperature for 1 hour; after incubation, the enzyme label instrument was used to detect the wavelength 330 nm excitation, 665 nm and 620 nm reading value. The signal value was calculated according to the average value of the highest concentration well of the positive control, the average value of the negative control well, The signal value was calculated according to the average value of the highest concentration well of the positive control, 50 The results of experimental example 1 are shown in Table 1.

[0480] In vitro biological activity determination of experimental example 2 - β-Arrestin2 experiment

[0481] In this study, HEK293T cell lines stably expressing APJ receptor and β-Arrestin2 were incubated with different concentrations of samples, and the change in fluorescence intensity was detected by the NanoBiT method to study the effect of the samples on the recruitment of β-arrestin2 by human APJ receptor.

[0482] Experimental method: HEK293T-APJ-β-Arrestin2 stable cell line (HEK293T cell line from ATCC, stable expression cell line was constructed as follows: DNA sequences containing APJ receptor-NanoBiT subunit, β-Arrestin2-NanoBiT subunit were constructed into expression plasmids, and the expression plasmids were co-transfected into HEK293T cells, and then the stable expression cell line was obtained by resistance screening) was cultured to 80% confluence, and the cells were collected by trypsin digestion, counted and inoculated 70 μL / well in a 96-well plate, 30,000 cells / well, the culture medium was Opti-MEM+4% FBS, and the cells were incubated overnight. Preparation of samples: dilute positive control (AMG986) and test compounds with Opti-MEM gradient, 10 concentration points. 1‰ concentration of DMSO as negative control. When the cell density reaches about 80%, according to the Nano-Glo Live Cell Substrates (Promega) instructions, dilute the substrate 20 times, add 20 μL / well into the hole, mix well. Take 10 μL of prepared sample and add it to the corresponding experimental hole, avoid light incubation for 10 minutes. After incubation, use the enzyme marker to read the luminescence signal value. Calculate the signal value according to the average value of the highest concentration well of the positive control , the average value of the negative control . Plot the signal value against the compound concentration, and use GraphPad Prism software to perform nonlinear regression curve fitting and EC 50 calculation. In order to facilitate the comparison of the degree of bias, the ratio of the EC 50 value of this experimental example to the EC 50 value of experimental example 1 is calculated, that is, EC 50 (β-Arrestin2) / EC 50 (cAMP). The results are shown in Table 1.

[0483] Table 1 shows the in vitro biological activity data of some compounds, and the results show that the compounds of the application can effectively agonize the APJ receptor and have high bias to the G protein signaling pathway, which helps to obtain better efficacy and higher safety.

[0484] Table 1 In vitro biological activity data of compounds of the application (+++): EC 50 <5 nM; (++): 5 nM≤EC 50 <50 nM; (+): 50 nM≤EC 50 <500 nM; (-): EC 50 ≥500 nM;

[0485] Experimental example 3 pharmacokinetic detection

[0486] Compound pharmacokinetic detection was carried out in 6-8 week old male CD1 mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.). The test compound was dissolved in 10% hydroxypropyl-β-cyclodextrin aqueous solution containing 10% DMSO, 3 mice per administration group, and administered by intravenous injection (1 mg / kg) or gavage (5 mg / kg), wherein the intravenous injection group was collected at 0.033 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration. The gavage group was collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration. The compound concentration in the plasma sample obtained after centrifugation was analyzed by LC-MS / MS method. WinNonlin (PhoenixTM, version 8.3) or other similar software was used for pharmacokinetic calculation. The pharmacokinetic parameters shown in Table 2 were calculated according to the plasma concentration and time data, and the parameter data were statistically calculated using mean value and other descriptive statistics to describe.

[0487] Table 2 shows the maximum blood drug concentration (C max ), area under the curve (AUC) and bioavailability (F) data of oral administration, and the results show that the compound of the present application has good pharmacokinetic properties, which is significantly better than AMG986.

[0488] Table 2 Pharmacokinetic data of the compound of the present application

[0489] Experimental Example 4 Animal efficacy test

[0490] This experiment evaluates the effect of compound combined with GLP-1 receptor agonist on weight loss and body composition in DIO mouse model.

[0491] Experimental method: 90 male 17-19 week old DIO C57BL / 6J mice (purchased from Southern Model Organism Technology Co., Ltd.) and 11 wild type C57BL / 6J mice of the same age were adaptively fed for 1-3 weeks, weighed 2 days before administration, and selected animals with body weight greater than 40 g for grouping, with 8 animals per group. The food and water intake was measured 1 day before administration, and the body fat was detected, and the body weight was measured.

[0492] Experimental grouping:

[0493] Tirzepatide (Tirzepatide) was purchased from Selleck Company (P1206), MW = 4813.45, 10 nmol / kg = 0.048 mg / kg, Tirzepatide administration mode is subcutaneous injection (sc), once every three days (q3d). Compound 68, 69 was dissolved in drinking water containing 5 mM sucralose, pH = 8.5, and the mice were free to drink water. Solvent 1 is 5% DMSO + 40% PEG300 + 5% Tween80 + 50% normal saline, sc, q3d. Solvent 2 is drinking water containing 5 mM sucralose, pH = 8.5, free to drink water. The start date of administration is considered as day 0. After grouping, the body weight, food intake, water intake and animal health status were recorded once a day. The experiment ended after 14 days of continuous administration, and the body weight (Body Weight), body weight loss percentage (Body Weight Change %), and the change of body composition of each group of animals (Lean Mass, Fat Mass, Lean %, Fat %) were recorded.

[0494] Experimental results: In the DIO mouse pharmacodynamic model, DIO mice were injected subcutaneously with 10 nmol / kg of Tirzepatide alone (G2 group) compared with DIO vehicle group (G1 group), there was a significant decrease in body weight. Tirzepatide combined with compound 68 and 69 respectively had obvious synergistic effect in reducing body weight; the combined group (G3 group and G4 group) of mice almost reduced to the level of normal mice (G0 group) after two weeks of continuous administration (Figure 1). The body weight of Tirzepatide single drug group (G2 group), Tirzepatide combined with compound 68 group (G3 group), Tirzepatide combined with compound 69 group (G4 group) decreased by 10.7g, 17.1g and 17.6g respectively (Figure 1), and the percentage change in body weight was-18%, -32% and -35% respectively (Figure 2). After 14 days of continuous administration, body composition analysis was performed on mice in each group, and it was found that compared with the DIO vehicle group (fat weight was 16.33g), the fat weight of Tirzepatide combined with compound 68 or 69 group was significantly reduced, to 5.7g (p<0.0001), 6.43g (p<0.0001) respectively; compared with the Tirzepatide single drug group (fat weight was 11.25g), the fat weight was also significantly improved (Figure 3). According to the data of body composition, the fat / body weight ratio (Fat%) and lean body weight / body weight ratio (Lean%) were statistically analyzed. As shown in Figure 4, compared with the DIO vehicle group, the fat / body weight ratio (Fat%) of the Tirzepatide single drug group after 14 days of continuous administration (10 nmol / kg, q3d) did not significantly improve, while the Tirzepatide combined with compound 68 or 69 group significantly improved the fat ratio of DIO mice (p<0.0001 and p<0.001 compared with the DIO vehicle group respectively); and compared with the DIO mice, the combined group significantly increased the lean body weight / body weight ratio (Lean%) of DIO mice, and the Tirzepatide combined with compound 68 group even restored to the level of normal mice (no statistical difference between the two groups).

Claims

1. A triazole compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate thereof, or solvate thereof. in: R1 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C2-C 10 alkenyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Heterobridged cycloalloys or C5-C groups other than furanyl groups 15 Heteroaryl; or the above groups are surrounded by one or more R 4a Group substitution; R2 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are surrounded by one or more R 4b replace; R3 is C3-C 10 cycloalkyl, C5-C 12 Spirocyclic group, C5-C 12 Bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are surrounded by one or more R 4c Group substitution; R a It is hydrogen or C1-C4 alkyl; X is oxygen or nitrogen; When X is oxygen, R b It does not exist; when X is nitrogen, R b Selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are affected by one or more halogens, cyano, nitro, oxonyl, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Heterobridged cyclic groups, oxy subunits, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; R 4a R 4b R 4c Independently selected from C1-C 10 Alkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are affected by one or more halogens, cyano, nitro, oxonyl, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridge ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; Or, R 4a R 4b R 4c It is independently selected from hydrogen, halogen, cyano, nitro, oxonyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6 or -S(O)(NR7)R5R6; Or, when R1 is C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl groups or C5-C groups other than furanyl groups 15 In heteroaryl cases, two or more R 4a Optionally, together with the atoms bonded to it, they form C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above-mentioned common constituent groups are substituted by one or more halogens, C1-C6 alkanoyl, C3-C6 cycloalkanoyl, hydroxyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C6 alkanoyloxy, C3-C6 cycloalkanoyloxy, amino, C1-C6 alkanoylamino, C1-C6 haloalkanoylamino, bisC1-C6 alkanoylamino, C1-C6 alkanoylamino, C3-C6 cycloalkanoylamino or oxonyl subunit; Or, when R2 is C3-C 10 cycloalkyl, C6-C 10 Aryl or C5-C 15 In heteroaryl cases, two or more R 4b Optionally, the atoms connected thereto together constitute a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or the aforementioned constituent groups are substituted by one or more halogens, C1-C6 alkanoyl, C3-C6 cycloalkanoyl, hydroxyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C6 alkanoyloxy, C3-C6 cycloalkanoyloxy, amino, C1-C6 alkylamino, C1-C6 haloalkamino, bisC1-C6 alkylamino, bisC1-C6 haloalkamino, C1-C6 alkanoylamino, C3-C6 cycloalkanoylamino, or oxonyl groups; R5, R6, and R7 are independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are affected by one or more halogens, cyano, nitro, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Heterobridged cyclic groups, oxygen subunits, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR 10 C(O)NR8R9、-NR 10 C(NH)NR8R9, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SR8, -SO2R8, -SO2NR8R9, -S(O)(NR 10 R8R9, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; Alternatively, R5 and R6, together with the N atom they are connected to, can form a C4-C group. 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C5-C 12 Heterospirocycloalkyl or C5-C 15 Heteroaryl; or the groups formed by the above are substituted by one or more halogens, C1-C6 alkanoyl, C3-C6 cycloalkanoyl, hydroxyl, C1-C5 alkoxy, C1-C5 haloalkoxy, C1-C6 alkanoyloxy, C3-C6 cycloalkanoyloxy, amino, C1-C6 alkanoylamino, C1-C6 haloalkanoylamino, bisC1-C6 alkanoylamino, bisC1-C6 haloalkanoylamino, C1-C6 alkanoylamino, C3-C6 cycloalkanoylamino or oxonyl subunit; R8, R9, R 10 Independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are surrounded by one or more halogens, cyano, hydroxyl, carboxyl, amino, C1-C6 alkylamino, C1-C6 haloalkylamino, bisC1-C6 alkylamino, bisC1-C6 haloalkylamino, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C3-C 10 Cycloalkoxy, C4-C 10 Heterocyclic alkoxy groups, oxygen subunits, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; Alternatively, R8 and R9, together with the N atom they are connected to, can form C4-C. 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C5-C 12 Heterospirocycloalkyl or C5-C 15 The heteroaryl group; or the group formed by the above is substituted by one or more halogens, C1-C6 alkanoyl groups, C3-C6 cycloalkanoyl groups, hydroxyl groups, C1-C5 alkoxy groups, C1-C5 haloalkoxy groups, C1-C6 alkanoyl groups, C3-C6 cycloalkanoyl groups, amino groups, C1-C6 alkanoylamino groups, C1-C6 haloalkanoylamino groups, bisC1-C6 alkanoylamino groups, C1-C6 alkanoylamino groups, C3-C6 cycloalkanoylamino groups, or oxy subunits.

2. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein R1 is C3-C. 10 cycloalkyl, C4-C 10 Heterocyclic alkyl groups or C5-C groups other than furanyl groups 15 Heteroaryl; or the above groups are surrounded by one or more R 4a Group substitution; Preferably, R1 is a C5-C group other than furanyl. 10 Heteroaryl; or the above groups are surrounded by one or more R 4a Group substitution; More preferably, R1 is a pyridinyl group; or the above group is surrounded by one or more R groups. 4a Group substitution; More preferably, R1 is a pyridinyl group having the following formula: The pyridinyl group is unsubstituted or surrounded by one or two R groups. 4a Substituent substitution, and symbol When drawn at the end of a bond, it indicates the point of connection with the rest of the molecule.

3. The compound of claim 2 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4a In each case, it is independently selected from hydrogen, halogen, cyano, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl groups, -OR5, -OC(O)R5, -NR5R6 or -NR5C(O)R6; Or when R 4a Selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 In the case of heterocyclic alkyl groups, the above groups are optionally replaced by one or more halogens, cyano groups, oxonides, C1-C... 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl groups, -OR5, -NR5R6, -NR5C(O)R6, -C(O)R5, -C(O)OR5 or -C(O)NR5R6 are substituted; Preferably, R 4a In each case, it is independently selected from hydrogen, halogen, methyl, ethyl, propyl, trifluoromethyl, 2,2,2-trifluoroethyl, isopropyl, cyclopropyl, cyclobutyl, 2,2-difluorocyclopropyl, methoxy, ethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy, cyclobutoxy, amino, methylamino, dimethylamino, methaminoyl, ethaminoyl, 2-hydroxyethoxy, 2-hydroxy-2-methylpropoxy, 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propoxy, 2-methoxyethoxy, 2-(dimethylamino)ethoxy, 2-morpholinoethoxy, 2-(4-methylpiperazin-1-yl)ethoxy, aziridine, oxaziridine, or 2,6-diazaspiro[3.3]heptane-2-yl.

4. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate or solvate thereof, wherein R1 is a pyridinyl group; or the pyridinyl group is surrounded by one or two R1 groups. 4a Replace; where R 4a In each case, it is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, or C1-C3 haloalkoxy.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein R2 is C6-C. 10 Aryl or C5-C 10 Heteroaryl; or the above groups are surrounded by one or more R 4b Group substitution; Preferably, R2 is a C6 aryl or C6 heteroaryl; or the above group is surrounded by one or more R 4b Group substitution; More preferably, R2 is R 4b As defined in any one of claims 1-4, and the symbol When drawn at the end of a bond, it indicates the point of connection with the rest of the molecule.

6. The compound of claim 5 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein R 4b In each case, it is independently selected from hydrogen, halogen, C1-C3 alkyl, C3-C5 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -NR5R6, -NR5C(O)R6, -C(O)OR5 or -C(O)NR5R6.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R3 is C6-C. 10 Aryl or C5-C 15 Heteroaryl; or the above groups are surrounded by one or more R 4c Group substitution; Preferably, R3 is a C6 aryl or C5-C6 heteroaryl, more preferably an aryl; or the above group is surrounded by one or more R 4c Group substitution, more preferably R 4c The number ranges from 1 to 3.

8. The compound of claim 7 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4c Selected independently from C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Miscellaneous bridge ring base, C6-C 10 Aryl or C5-C 15 Heteroaryl; or the above groups are affected by one or more halogens, cyano, nitro, oxonyl, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridge ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; Or R 4c It is independently selected from hydrogen, halogen, cyano, nitro, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6 or -S(O)(NR7)R5R6; Preferably, R 4c The quantity is 1 to 3; of which 0 or 1 R 4c For C6-C 10 Aryl or C5-C 15 heteroaryl; or the above C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, or C. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridge ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6 or C5-C 15 Heteroaryl substitution; additional 0 to 3 R 4c Independently selected from hydrogen, halogen, cyano, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C1-C5 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, bisC1-C3 alkylamino, C3-C6 cycloalkanoylamino; More preferably, R 4c The quantity is 2; one of them is R 4c For C6-C 10 Aryl or C5-C 15 heteroaryl, or the above C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, or C. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Mixed bridge ring bases, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6 or C5-C 15 heteroaryl substitution; another R 4c Selected from hydrogen, halogen, cyano, C 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C1-C5 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, bisC1-C3 alkylamino or C3-C6 cycloalkanoylamino.

9. A triazole compound of formula (I') or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate or solvate thereof, in: R1 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C2-C 10 Alkenyl or C5-C except furanyl 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C2-C 10 Alkenyl or C5-C except furanyl 15 Heteroaryl groups are substituted with one or more R groups. 4a Group substitution; R2 is C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are substituted with one or more R groups. 4b replace; R3 is C3-C 10 cycloalkyl, C6-C 10 Aryl or C5-C 15 heteroaryl; or the aforementioned C3-C 10 cycloalkyl, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are substituted with one or more R groups. 4c Group substitution; R a It is hydrogen or C1-C4 alkyl; R 4a R 4b R 4c Independently selected from C1-C 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 heteroaryl; or the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C3-C 10 cycloalkyl, C3-C 10 Cycloalkenyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, nitro groups, oxonyl groups, or C1-C groups. 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Hybrid bridged ring group, -O(CH2) j R5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -(CH2) q C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR7)R5R6, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; Or, R 4a R 4b R 4c It is independently selected from hydrogen, halogen, cyano, nitro, oxonyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR7C(O)NR5R6, -NR7C(NH)NR5R6, -C(O)R5, -C(O)OR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6 or -S(O)(NR7)R5R6; R5, R6, and R7 are independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, nitro groups, or C groups. 1- C 10 Alkyl, C 3- C 10 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C5-C 12 Spirocyclic group, C5-C 12 Heterospirocyclic group, C5-C 12 Bridge ring base, C5-C 12 Heterobridged cyclic groups, oxygen subunits, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR 10 C(O)NR8R9、-NR 10 C(NH)NR8R9, -C(O)R8, -C(O)OR8, -C(O)NR8R9, -SR8, -SO2R8, -SO2NR8R9, -S(O)(NR 10 R8R9, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; R8, R9, R 10 Independently selected from hydrogen, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 heteroaryl; or the C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl or C5-C 15 Heteroaryl groups are affected by one or more halogens, cyano groups, hydroxyl groups, carboxyl groups, amino groups, C1-C6 alkylamino groups, C1-C6 haloalkylamino groups, bis(C1-C6) alkylamino groups, bis(C1-C6) haloalkylamino groups, C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C3-C 10 Cycloalkoxy, C4-C 10 Heterocyclic alkoxy groups, oxygen subunits, C6-C 10 Aryl or C5-C 15 heteroaryl substitution; j and q are each independently selected from 0, 1, 2, 3 or 4.

10. The compound of claim 9 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R1 is a C5-C6 heteroaryl group containing one nitrogen atom, preferably pyridyl; or the C5-C6 heteroaryl group is surrounded by one or two R1 atoms. 4a Replace; where R 4a In each case, it is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, or C1-C3 haloalkoxy; Preferably, R1 is in, symbol When drawn at the end of a bond, it indicates the point of connection with the rest of the molecule.

11. The compound of claim 9 or 10 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein R2 is a C6-C8 aryl or C6-C8 heteroaryl; or the C6-C8 aryl or C6-C8 heteroaryl is affected by one or more R2 groups. 4b Group substitution; R2 is preferred in, R 4b As defined in any one of claims 9 or 10, and the symbol When drawn at the end of a bond, it indicates the point of connection with the rest of the molecule; Preferably, R 4b It is hydrogen or -OR5, where R5 is an unsubstituted C1-C6 alkyl or a halogen-substituted C1-C6 alkyl.

12. The compound of any one of claims 9-11, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R3 is C6-C. 10 Aryl or C5-C 10 heteroaryl; or the aforementioned C6-C 10 Aryl or C5-C 10 Heteroaryl groups are substituted with one or more R groups. 4c Group substitution; Preferably, R3 is a C6-C8 aryl or a C5-C6 heteroaryl, more preferably a C6 aryl; or the C6-C8 aryl or C5-C6 heteroaryl is surrounded by one or more R3 groups. 4c Group substitution, more preferably R 4c The number ranges from 1 to 3.

13. The compound of any one of claims 9-12, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein R3 is in, R 4c As defined in any one of claims 9-12, R 11 It can be independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy, and is symbolized by... When drawn at the end of a bond, it indicates the point of connection with the rest of the molecule.

14. The compound of any one of claims 9-13, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4c Independently selected from hydrogen, C 1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 2- C4 alkenyl, C 3- C6 cycloalkyl, C4-C6 cycloalkenyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 10 heteroaryl; or the C 1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 2- C4 alkenyl, C 3- C6 cycloalkyl, C4-C6 cycloalkenyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 10 Heteroaryl groups are affected by one or more halogens, cyano groups, oxonides, or C. 1- C6 alkyl, C 3- C6 cycloalkyl, C 4- C 10 Heterocyclic alkyl, -OR5, -NR5R6, C6-C 10 Aryl or C5-C 10 heteroaryl substitution; Or R 4c It is independently selected from hydrogen, halogen, cyano, nitro, -OR5 or -NR5R6; R5 and R6 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 10 Heteroaryl; or the C1-C6 alkyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C6-C 10 Aryl or C5-C 10 Heteroaryl groups are affected by one or more halogens, C1-C6 alkyl groups, C 3- C6 cycloalkyl, C 4- C 10 Heterocyclic alkyl, C 4- C 10 Heterocyclic group, C6-C 10 Aryl, -OR8, -NR8R9 substitutions; R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4c Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C3 alkoxy, C 2- C4 alkenyl, C 3- C6 cycloalkyl, C4-C6 cycloalkenyl, phenyl, oxacyclobutyl, azacyclobutyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzopyrroleyl, benzoimidazolyl, benzopyrazolyl, pyrimidinidazolyl, pyrimidopyrazolyl or indoleyl; or the R 4c The optional group is occupied by one or more halogens, cyano groups, oxonides, C 1- C6 alkyl, C 3- C6 cycloalkyl, -OR5, -NR5R6, phenyl, oxetane, azirane, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl or isoxazolyl substituted; Or R 4c It is independently selected from hydrogen, halogen, cyano, nitro, -OR5 or -NR5R6; R5 and R6 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, phenyl, oxetane, azirnebutane, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl; or optional groups of R5 and R6 are affected by one or more halogens, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, phenyl, oxetane, pyridinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl; 3- C6 cycloalkyl, -OR8, -NR8R9, oxetane, azirane, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl or isoxazolyl substituted; R8 and R9 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.

16. The compound of any one of claims 9-15, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R 4c Selected from halogens, -OR5, -NR5R6, C 1- C6 alkyl, C2-C4 alkenyl, C1-C6 haloalkyl, C 3- C6 cycloalkyl or the following cyclic groups: The R 4c The optional groups are optionally surrounded by one or more halogens, cyano groups, or C. 1- C6 alkyl substitution; Y is selected independently from NR 10 Or O; R5, R6, R 10 Independently selected from hydrogen, amino, C1-C6 alkyl, C1-C6 haloalkyl, bis(C1-C3) alkylamino, C3-C6 cycloalkyl, C 4- C 10 Heterocyclic alkyl or C5-C 10 Heteroaryl; wherein the C1-C6 alkyl group is optionally divided by one or more C3-C6 cycloalkyl groups, C 4- C 10 Heterocyclic alkyl or C5-C 10 heteroaryl substitution; m, n, and n1 are each independently selected from 0, 1, 2, 3, or 4; Preferably, R5, R6, R 10 The group is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, oxetyl, aziridine, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl; wherein the C1-C6 alkyl group is optionally substituted with one or more C3-C6 cycloalkyl, oxetyl, aziridine, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyridinyl, hexahydropyrazinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl.

17. The compound of any one of claims 9-16, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein the triazole compound represented by formula (I') has the structure shown in formula (I'-1) or (I'-2): in, R a R 4a R 4b R 4c Each is independently defined as in any one of claims 9-16; Preferably, R 4c Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkylamino or the following cyclic groups: The cyclic group may optionally be substituted with one or more halogens, cyano groups, or C1-C6 alkyl groups.

18. A compound or a pharmaceutically acceptable salt thereof, a prodrug, a stereoisomer, a mixture of stereoisomers, a tautomer, a deuterated derivative, a hydrate thereof, or a solvate thereof, wherein the compound is selected from:

19. The compound according to any one of claims 9-18, or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate, or solvate thereof, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable potassium or sodium salt; Preferably, the pharmaceutically acceptable salt is a pharmaceutically acceptable potassium salt having the structure shown in formula (II): in, R1, R2, and R3 are each independently defined as in any one of claims 9-17; More preferably, the pharmaceutically acceptable potassium salt has the structure shown in formula (II-1) or formula (II-2): Among them, R 4a R 4b R 4c Each is independently defined as in any one of claims 9-17.

20. A pharmaceutical composition comprising a compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, a prodrug, a stereoisomer, a mixture of stereoisomers, a tautomer, a deuterated compound, a hydrate thereof, or a solvate thereof, and a pharmaceutically acceptable excipient.

21. Use of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate or solvate thereof, or the pharmaceutical composition of claim 20 in the preparation of a medicament for the prevention and / or treatment of obesity, hypertension, pulmonary hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, nephropathy and / or sarcopenia, or in a medicament for the prevention and / or treatment of APJ receptor-related diseases.

22. Use of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt, prodrug, stereoisomer, mixture of stereoisomers, tautomer, deuterated product, hydrate or solvate thereof, or the pharmaceutical composition of claim 20 in the preparation of an APJ receptor agonist; Preferably, the APJ receptor agonist is used for the prevention and / or treatment of obesity, hypertension, pulmonary hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease and / or sarcopenia.

23. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated compound, hydrate or solvate thereof, or a pharmaceutical composition as described in claim 20, and another or more drugs that can activate GLP-1 receptors; Preferably, the drug that can activate the GLP-1 receptor is telpolide.

24. Use of the pharmaceutical composition of claim 23 in the preparation of a medicament for the prevention and / or treatment of obesity, hypertension, pulmonary hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease and / or sarcopenia.

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