1,2,3-triazole compound and use thereof as APJ receptor agonist

Abstract

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

Description

1,2,3-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 agonist drugs 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 the 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 receptors are 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 the 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), and 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, 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 triazolyl-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuteride, hydrate, or solvate thereof.

[0010] Another object of the present application includes providing the use of the above-mentioned triazolyl-containing compound or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuteride, hydrate, or solvate thereof, or the above-mentioned pharmaceutical composition in the manufacture of a medicament for preventing and / or treating obesity, hypertension, pulmonary arterial hypertension, sarcopenia, and the like, or a medicament for preventing and / or treating an APJ receptor-related disease.

[0011] To achieve the above-mentioned objects, the technical solutions adopted by the present application include:

[0012] In some embodiments, a compound as shown in formula (I) or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuteride, hydrate, or solvate thereof is provided,

[0013] wherein X is selected from O or NR2;

[0014] R1 is unsubstituted C5-C 12 heteroaryl, C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, -SO2R5; or the aforementioned groups are substituted with one or more R 1a groups;

[0015] R 1a is independently selected from halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12 heteroaryl; the aforementioned C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C10 aryl, C5-C 12 heteroaryl is optionally substituted with one or more halogen, cyano, hydroxy, nitro, C1-C4alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12 heteroaryl is optionally substituted with one or more halogen, cyano, hydroxy, nitro, C1-C4alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C

[0016] R2is hydrogen, C1-C 10 alkyl, C1-C 10 heteroalkyl, C3-C 10 cycloalkyl, C4-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, C5-C 12 heteroaryl; wherein the above C1-C 10 alkyl, C1-C 10 heteroalkyl, C3-C 10 cycloalkyl, C4-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, C5-C 12 heteroaryl is optionally substituted with one or more halogen, cyano, nitro, C1-C6alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12Heteroaryl substitution; the aforementioned C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5-C 12 The heteroaryl group is optionally surrounded by one or more halogens, cyano, hydroxyl, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 heteroaryl substitution;

[0017] R3 is selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl, C5-C 12 heteroaryl, -(CR 11 R 12 )-(CR 13 R 14 )-R 15 -NR2-(CR 12 R 13 )-R 15 、-(CR 11 R 12 )-C(=O)-R 15 -(C5-C 12 (heteroaryl)-R 15 -(C6-C 10 (aryl)-R 15 -(C5-C 10 (heterocyclic alkyl)-R 15 -(C5-C 10 (cycloalkyl)-R 15 ; wherein C1-C 10 Alkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl, C5-C 12 heteroaryl, -(C5-C 12 (heteroaryl)-R 15 -(C6-C 10 (aryl)-R 15 -(C5-C10 heteroaryl)-R 15 , -(C5-C 10 cycloalkyl)-R 15 is unsubstituted or substituted by one or more R 1a substituents;

[0018] R4is selected from hydrogen, C1-C8alkyl;

[0019] R5, R6, R7are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl; the aforementioned C1-C6alkyl, C1-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl are optionally substituted by one or more halogen, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR8C(O)NR9R 10 , -NR8C(NH)NR9R 10 , -C(O)R8, -COOR8, -C(O)NHR8, -C(O)NR8R9, -SR8, -SO2R8, -SO2NR8R9, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12 heteroaryl;

[0020] R8, R9, R 10 are independently selected from hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl; the aforementioned C1-C6alkyl, C1-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl are optionally substituted by one or more halogen, cyano, hydroxy, carboxy, amino, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryl, heteroaryl;

[0021] R 11 , R12 R 13 R 14 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 Heteroaryl; the above C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5-C 12 The heteroaryl group is optionally surrounded by one or more halogens, cyano, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 heteroaryl substitution;

[0022] R 15 C6-C is a single-ring or double-ring C6-C 10 Aryl, monocyclic to tricyclic C5-C 12 Heteroaryl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, wherein the monocyclic or bicyclic C6-C 10 Aryl, monocyclic to tricyclic C5-C 12 The heteroaryl group, C3-C6 cycloalkyl group, and C4-C6 heterocycloalkyl group are unsubstituted or contain one or more R groups. 1a Substituted by a substituent.

[0023] In some embodiments, the compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated derivative, hydrate, or solvate thereof, wherein R1 is a C5-C6 heteroaryl group containing one nitrogen atom, said heteroaryl group being unsubstituted or surrounded by one or more R1 atoms. 1a Substituent substitution.

[0024] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is unsubstituted pyridyl or pyridyl substituted with 1 to 3 R 1a substituted with 1 to 3 R

[0025] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is pyridyl having the formula:

[0026] substituted with 1 to 3 R 1a substituted with 1 to 3 R is intended to indicate the point of attachment to the remainder of the molecule when drawn across a bond.

[0027] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R 1a is independently selected from the group consisting of -CH3, -CH2CH3, -OCH3, -OH2CH3, -F, -Cl.

[0028] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is phenyl or C5-C6 heteroaryl containing 1-2 nitrogen atoms substituted with 1 or 2 -OR5substituents.

[0029] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is phenyl or pyrimidinyl substituted with 1 or 2 OR5substituents.

[0030] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R2is preferably the following structure:

[0031] substituted with 1 to 3 R is intended to indicate the point of attachment to the remainder of the molecule when drawn across a bond.

[0032] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is selected from the group consisting of unsubstituted or substituted with one or more R 1asubstituted C1-C6alkyl or C6-C8aryl; said R 1a independently selected from -F, -Cl, -Br, cyano, -OR5, C1-C6alkyl, phenyl, C4-C6heterocycloalkyl containing 1-2 heteroatoms, C5-C6heteroaryl containing 1-2 nitrogen atoms; said phenyl, C4-C6heterocycloalkyl containing 1-2 heteroatoms, or C5-C6heteroaryl containing 1-2 nitrogen atoms are unsubstituted or substituted with 1-2 substituents selected from -F, -Cl, -Br, cyano, -OR5, or C1-C6alkyl; wherein R5is independently selected from hydrogen or C1-C6alkyl.

[0033] In some embodiments, provided herein is a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is selected from:

[0034] Symbol is intended to indicate the point of attachment to the remainder of the molecule when drawn across a bond.

[0035] In some embodiments, provided herein is a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein the compound is optionally selected from:

[0036] In some embodiments, provided herein is a pharmaceutical composition (also referred to herein as “a first pharmaceutical composition”) comprising a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

[0037] In some embodiments, provided herein is another pharmaceutical composition (also referred to herein as “a second pharmaceutical composition”) comprising a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, or the pharmaceutical composition described above (i.e., the first pharmaceutical composition described above), and another drug that can agonize GLP-1 receptor (i.e., glucagon-like peptide-1 receptor).

[0038] In some preferred embodiments, the drug that can agonize GLP-1 receptor described herein is tirzepatide.

[0039] In some embodiments, there is provided a use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first and second pharmaceutical compositions described above) as a medicament (i.e., for therapy).

[0040] In some embodiments, there is provided a use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first and second pharmaceutical compositions described above) in the manufacture of an APJ receptor agonist.

[0041] In some embodiments, there is provided a use of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first and second pharmaceutical compositions 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 the APJ receptor.

[0042] In some embodiments, there is provided a method of preventing and / or treating obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia, or a disease associated with the APJ receptor, comprising administering to a patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, or a pharmaceutical composition described herein (including the first and second pharmaceutical compositions described above).

[0043] In some preferred embodiments, the disease associated with the APJ receptor is obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia.

[0044] Definitions of terms:

[0045] Unless otherwise indicated, all terms used herein have the same meaning as they would to one skilled in the art of the present invention.

[0046] The term "C1-C 10"Alkyl" refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by removal of one hydrogen atom from a parent alkane containing from 1 to 10 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl (such as propan-1-yl and propan-2-yl), butyl (such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, t-butyl), and the like. In certain embodiments, an alkyl group contains from 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms); while in other embodiments, an alkyl group contains from 1 to 4 carbon atoms; in other embodiments, an alkyl group contains 1 or 2 carbon atoms. Branched alkyl groups contain at least 3 carbon atoms and typically contain from 3 to 7 carbon atoms (e.g., 3, 4, 5, 6, 7 carbon atoms), or in some embodiments, from 3 to 6 carbon atoms. An alkyl group having from 1 to 6 carbon atoms can be referred to as a C1-C6alkyl group; an alkyl group having from 1 to 4 carbon atoms can be referred to as a C1-C4alkyl group.

[0047] The term "C3-C 10 "Cycloalkyl" refers to a saturated cyclic alkyl radical derived by removal of one hydrogen atom from a parent monocyclic or fused ring cycloalkane containing from 3 to 10 carbon atoms. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups can be described by the number of carbon atoms in the ring. For example, a cycloalkyl group having from 3 to 10 ring members can be referred to as a C3-C10cycloalkyl group; a cycloalkyl group having from 3 to 6 ring members can be referred to as a C3-C6cycloalkyl group; and a cycloalkyl group having from 4 to 6 ring members can be referred to as a C4-C6cycloalkyl group. 3- C 10 Cycloalkyl; a cycloalkyl group having from 4 to 7 ring members can be referred to as a C4-C7cycloalkyl group; a cycloalkyl group having from 4 to 6 ring members can be referred to as a C4-C6cycloalkyl group; and a cycloalkyl group having from 5 to 6 ring members can be referred to as a C5-C6cycloalkyl group. 4- C 10 Cycloalkyl; a cycloalkyl group having from 4 to 7 ring members can be referred to as a C4-C7cycloalkyl group; a cycloalkyl group having from 4 to 6 ring members can be referred to as a C4-C6cycloalkyl group; and a cycloalkyl group having from 5 to 6 ring members can be referred to as a C5-C6cycloalkyl group. 10 Cycloalkyl; a cycloalkyl group having from 4 to 7 ring members can be referred to as a C4-C7cycloalkyl group; a cycloalkyl group having from 4 to 6 ring members can be referred to as a C4-C6cycloalkyl group; and a cycloalkyl group having from 5 to 6 ring members can be referred to as a C5-C6cycloalkyl group.

[0048] The term "C4-C 10 "Heterocycloalkyl" refers to a heterocycloalkyl radical derived by removal of one hydrogen atom from a C4-C 10 Cycloalkyl; a cycloalkyl group having from 4 to 7 ring members can be referred to as a C4-C7cycloalkyl group; a cycloalkyl group having from 4 to 6 ring members can be referred to as a C4-C6cycloalkyl group; and a cycloalkyl group having from 5 to 6 ring members can be referred to as a C5-C6cycloalkyl group.

[0049] The term "C4-C 10 "Heterocyclyl" refers to a heterocyclyl radical derived by removal of one hydrogen atom from a C4-C 10Cycloalkyl refers to a saturated or unsaturated but non-aromatic ring radical derived by the removal of one hydrogen atom from a parent cycloalkane ring. Typical cycloalkyl groups include, but are not limited to, cyclopropan-1-yl, cyclopropan-2-yl, cyclobutan-1-yl, cyclobutan-2-yl, cyclopentan-1-yl, cyclopentan-2-yl, cyclohexan-1-yl, cyclohexan-2-yl, cycloheptan-1-yl, cycloheptan-2-yl, and the like. In certain embodiments, a cycloalkyl group has 3 to 8 carbon atoms; while in other embodiments, a cycloalkyl group contains 4 to 6 carbon atoms.

[0050] The term "C5-C 12 Spirocyclyl refers to a spirocyclic radical derived by the removal of one hydrogen atom from a parent spirocyclic ring comprising 5 to 12 carbon atoms; wherein the above "parent spirocyclic ring" 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]hexan-1-yl, spiro[2.3]hexan-4-yl, spiro[2.3]hexan-5-yl; spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl; spiro[3.5]nonan-1-yl, spiro[3.5]nonan-2-yl, spiro[3.5]nonan-5-yl, spiro[3.5]nonan-6-yl, spiro[3.5]nonan-7-yl; and the like. In certain embodiments, a spirocyclyl group has 5 to 12 carbon atoms; while in other embodiments, a spirocyclyl group contains 7 to 11 carbon atoms.

[0051] The term "C5-C 12 Heterospirocyclyl refers to a spirocyclic radical derived by the removal of one hydrogen atom from a parent spirocyclic ring in a C5-C 12 Heterospirocyclyl refers to a spirocyclic radical derived by the removal of one hydrogen atom from a parent spirocyclic ring in a C5-C Typical heteroatoms include oxygen, nitrogen, and sulfur. Typical heterospirocyclyl groups include, but are not limited to, 2,6-diazaspiro[3.3]heptan-1-yl, 1-azaspiro[4.4]octan-2-yl, 2-azaspiro[4.4]octan-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, and the like. In certain embodiments, a heterospirocyclyl group has 4 to 11 carbon atoms and 1 heteroatom; while in other embodiments, a heterospirocyclyl group contains 3 to 11 carbon atoms and 2 to 3 heteroatoms.

[0052] 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.

[0053] 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.

[0054] The term "C5-C" 12"Heteroaryl" refers to a monovalent heteroaromatic group derived by removal of one hydrogen atom from a 5- to 12-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 12-membered aromatic ring, monocyclic, bicyclic, and tricyclic, comprising 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, a monocyclic heteroaryl group can comprise 5, 6, 7, or 8 ring members, and can comprise 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 contain a heteroatom, but not necessarily both rings. In a tricyclic heteroaryl group, all three rings are aromatic, and at least one ring contains 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, indazole, indole, benzofuran, benzothiophene, isoindole, quinoline, isoquinoline, naphthridine, 2H-benzo[D][l,2,3]triazole, phthalazine, 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 12-membered heteroaryl group, referred to as a C5-C 12 heteroaryl. In certain embodiments, a heteroaryl group can be a 5- to 8-membered heteroaryl group, referred to as a C5-C8 heteroaryl.

[0055] 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 groups encompass monocyclic carbocyclic aromatic rings, such as benzene. Aryl groups also encompass bicyclic carbocyclic ring systems in which each ring is aromatic, such as naphthalene. Aryl groups can thus comprise fused ring systems in which the rings are carbocyclic aromatic rings. In certain embodiments, an aryl group comprises 6 to 10 carbon atoms (e.g., 6, 7, 8, 9, 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 comprising at least one heteroatom, the resulting ring system is a heteroaryl group, as defined herein, rather than an aryl group.

[0056] The term "halogen" or "halo" refers to a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) radical.

[0057] The term "amino" refers to a -NH2 group.

[0058] The term "hydroxy" refers to an -OH group.

[0059] The term "nitro" refers to a -NO2group.

[0060] The term "cyano" refers to a -CN group.

[0061] The term "substituted" means that one or more of the hydrogen atoms present in the given structure are each, independently of one another, replaced with a specified substituent. Unless otherwise indicated separately, one substituent group can be replaced with one 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 specified group, the substituents can be the same or different at each position.

[0062] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "C5-C10alkyl optionally substituted with one or more halogens" means that the halogen can or can not be present, and that the description includes instances where the C5-C10alkyl group is substituted with one or more halogens, and instances where the C5-C10alkyl group is not substituted with a halogen. 12 The term "heteroaryl optionally substituted with one or more halogens" means that the halogen can or can not be present, and that the description includes instances where the C5-C10alkyl group is substituted with one or more halogens, and instances where the C5-C10alkyl group is not substituted with a halogen. 12 The term "heteroaryl optionally substituted with one or more halogens" means that the halogen can or can not be present, and that the description includes instances where the C5-C10alkyl group is substituted with one or more halogens, and instances where the C5-C10alkyl group is not substituted with a halogen. 12 The term "heteroaryl optionally substituted with one or more halogens" means that the halogen can or can not be present, and that the description includes instances where the C5-C10alkyl group is substituted with one or more halogens, and instances where the C5-C10alkyl group is not substituted with a halogen.

[0063] The term "pharmaceutically acceptable salt" means a salt that is appropriate for use with human and lower animals with no display of 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, see 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 salts derived from appropriate inorganic and organic acids and bases. Pharmaceutically acceptable, nontoxic acid salts are, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bicarbonate, 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 the like.

[0064] The term "isomers" refers to compounds having the same molecular formula but different physical structures or configurations. Isomers that are not mirror images of one another are termed "diastereomers" or "geometric isomers." The term "stereoisomers" refers to isomers having the same molecular formula but different spatial arrangement of atoms. Stereoisomers that are mirror images of one another are termed "enantiomers" or "mirror image isomers." A pair of enantiomers can be considered as a single compound that can be described as a racemic mixture. The racemic mixture is a mixture of equal amounts of each enantiomer. The term "enantiomeric excess" refers to a mixture of enantiomers in which one enantiomer is present in an amount greater than 50% of the total amount of enantiomers present.

[0065] The term "tautomer" refers to a compound that is an interchangeable form of a particular compound structure and that varies in the placement 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.

[0066] 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 continue after symptoms have resolved, for example to delay their recurrence.

[0067] 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.

[0068] The term "pharmaceutically acceptable excipient" refers to a conventional pharmaceutical excipient, suitable for the desired pharmaceutical formulation. They serve a variety of key purposes in a formulation, such as improving the solubility of the drug, increasing the stability, enhancing the bioavailability, maintaining the pH value. Commonly used, for example: diluents, vehicles such as water, various organic solvents, etc., fillers such as starch, sucrose, etc., binders such as cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.

[0069] The beneficial technical effects achieved are:

[0070] (1) The compound of the present application has good activity of activating APJ receptor, and has high bias to G protein signaling pathway, not only excellent treatment effect, but also can reduce the side effects (such as myocardial hypertrophy) caused by the activation of β-arrestin pathway, and has better safety.

[0071] (2) The compound of the present application has good pharmacokinetic properties compared with the compound disclosed in the prior art, for example, has good parameters such as C0, CL, Cmax, AUC, bioavailability, etc.

[0072] (3) The compound of the present application has significant weight loss effect, and can significantly reduce the 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. DETAILED DESCRIPTION

[0073] The compounds of the present application can be prepared from readily available starting materials and reagents by employing standard synthetic procedures and steps. It is to be understood that, unless otherwise specified, the usual or preferred reaction conditions (e.g., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are employed, but that other suitable conditions can be used as needed depending on the reactants or solvents. The optimal reaction conditions can be determined by one skilled in the art through routine optimization procedures. In addition, to protect certain functional groups from undesirable reactions, it can be necessary to use conventional protecting groups, which are well known in the art. The selection of appropriate protecting groups and the conditions for protection and deprotection are familiar to those skilled in the art.

[0074] For the preparation of the above-defined compounds of the present application and comparative examples thereof, the following are detailed preparation methods. These compounds can be synthesized by those skilled in the art of organic synthesis using known or commercially available starting materials and reagents. The structural confirmation of the compounds of the present application is carried out by the following analytical means: nuclear magnetic resonance spectrum (NMR) detection is completed using a Bruker ASCEND 400 type superconducting nuclear magnetic resonance instrument, the test solvent system is deuterated dimethyl sulfoxide (DMSO-d6), and tetramethylsilane (TMS) is used as an internal standard substance, and the obtained chemical shift value is measured in ppm (10 -6 ) as a measurement unit; mass spectrometry (MS) analysis is carried out using an SQD type electrospray ionization mass spectrometer (equipment model number: 6120) produced by Agilent Corporation, the ionization mode is ESI source, and the accuracy of the molecular weight determination is ensured.

[0075] Example 1.0 Synthesis of 1,3-dimethoxy-2-(2-nitrovinyl)benzene

[0076] To a solution of compound 2,6-dimethoxybenzaldehyde (3.32 g, 20.0 mmol) in acetic acid (50 mL) was added ammonium acetate (0.77 g, 10.0 mmol) and nitromethane (1.46 g, 23.92 mmol). The reaction was stirred at 110 °C for 4 h. The reaction was cooled to room temperature and poured into ice water. The reaction was filtered to give yellow solid product (3.34 g, 15.97 mmol, 80.0% yield). ESI-LCMS: m / z calcd for C9H10NO3: 210.1 [M+H] + , found: 210.1.

[0077] Synthesis of compound DA-A-524 of example 1

[0078] First step: 3-azido-5-methylpyridine

[0079] To a solution of 5-methylpyridin-3-amine (5.32 g, 49.2 mmol) in dioxane hydrochloride (20 mL, 6.0 N) was added sodium nitrite (5.66 g, 82.03 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, then sodium azide (5.0 g, 76.91 mmol) was added at 0 °C and stirred for 16 h. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash silica gel chromatography (EA / PE = 0-25%, v / v) to give the product compound 2 as a brown solid (3.2 g, 23.86 mmol, 48.5% yield). ESI-LCMS: m / z calcd for [M+H]: 135.2, found: 135.1. +

[0080] Second step: 3-(5-(2,6-dimethoxyphenyl)-4-nitro-1H-1,2,3-triazol-1-yl)-5- methylpyridine

[0081] A mixture of 3-azido-5-methylpyridine (1.92 g, 14.34 mmol), 1,3-dimethoxy-2-(2- nitrovinyl)benzene (3.0 g, 14.34 mmol), copper acetate (0.52 g, 2.87 mmol) in a mixture of N,N-dimethylformamide:acetic acid = 5:1 (v / v) (20 mL) was stirred at 110 °C for 6 h. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash silica gel chromatography (EA / PE = 0-40%, v / v) to give the product compound 4 as a brown solid (1.8 g, 5.27 mmol, 36.8% yield). ESI-LCMS: m / z calcd for [M+H]: 342.0, found: 342.0. +

[0082] Third step: 5-(2,6-dimethoxyphenyl)-1-(5-methylpyridin-3-yl)-1H-1,2,3-triazol-4- amine

[0083] ​​To a solution of compound 4 (1.5 g, 4.40 mmol) in methanol (20 mL) was added palladium on carbon (0.3 g) and the reaction was stirred at room temperature for 16 h under nitrogen. The reaction was filtered and the filtrate was evaporated to give the product compound 5 (1.2 g, 3.85 mmol, 87.5% yield) as a yellow solid. ESI-LCMS: m / z calculated for [M+H]: 312.0, found: 312.0. + , found: 312.0.

[0084] Fourth step: N-(l-(2,6-dimethoxyphenyl)-lH-imidazo[4,5-b]pyridin-2-yl)-2-(5- methylpyrimidin-2-yl)ethane-l -sulfonamide (DA-A-524)

[0085] To a solution of compound 5 (0.3 g, 0.96 mmol) in acetonitrile (10 mL) was added 2,6-dimethylpyridine (412.8 mg, 3.85 mmol) and compound 10 (319 mg, 1.45 mmol), the solution was stirred at 25 °C for 2 min under nitrogen, dimethyl sulfoxide (7.5 mg, 0.096 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h under nitrogen. The reaction was diluted with water and evaporated to give the crude product; the crude product was purified by preparative high performance liquid chromatography (column type: Gemini-C18 150 x 21.2 mm, 5 pm; mobile phase: acetonitrile-water (0.1% formic acid) 30 min from 50% to 70%, v / v) to give the final product N-(l-(2,6-dimethoxyphenyl)-lH-imidazo[4,5-b]pyridin-2-yl)-2-(5- methylpyrimidin-2-yl)ethane-l -sulfonamide DA-A-524 (60.0 mg, 0.12 mmol, 12.6% yield) as a white solid. ESI-LCMS: m / z calculated for [M+H]: 496.1, found: 496.1. + , found: 496.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.59 (d, J = 0.5 Hz, 2H), 8.48 (d, J = 1.1 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 7.67 (t, J = 1.6 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 3.63 - 3.59 (m, 2H), 3.58 (s, 6H), 3.27 - 3.22 (m, 2H), 2.31 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.52, 157.53, 156.58, 150.02, 140.27, 140.16, 135.52, 131.04, 127.85, 126.10, 103.58, 101.09, 55.19, 50.41, 31.45, 16.95, 14.17.

[0086] Synthesis of compound DA-Y-867 of Example 2

[0087] Intermediate 5 (0.45 g, 1.45 mmol) and anhydrous acetonitrile (20 mL) were added into a 100 mL dry three-necked flask, after stirring thoroughly, 3-bromobenzenesulfonyl chloride (0.56 g, 2.18 mmol), 2,6-dimethylpyridine (0.62 g, 5.80 mmol) and dimethyl sulfoxide (0.5 mL) were added in turn. After addition, the reaction was carried out at room temperature for 6 hours under nitrogen protection, and the reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was diluted with dichloromethane (50 mL), then the reaction solution was washed with water (50 mL), 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, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 15:1, v / v) to give the product DA-Y-867 (0.55 g, 1.04 mmol, yield 71.7%). ESI-LCMS: m / z calculated: 530.0 [M+H] + , found: 529.9. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.46 (d, J = 1.1 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.80 (t, J = 1.8 Hz, 1H), 7.75 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.68 (ddd, J = 7.9, 1.6, 0.9 Hz, 1H), 7.61 (s, 1H), 7.38 (dt, J = 16.9, 8.2 Hz, 2H), 6.56 (d, J = 8.5 Hz, 2H), 3.53 (s, 6H), 2.29 (s, 3H).

[0088] Synthesis of compound DA-Y-832 of Example 3

[0089] First step:

[0090] In a 250 mL three-necked flask, compound DA-Y-867 (2.50 g, 4.71 mmol), bis(pinacolato)diboron (3.59 g, 14.13 mmol), potassium acetate (1.39 g, 14.13 mmol), palladium (Pd) tetrakis(triphenylphosphine) (340 mg, 0.47 mmol) and anhydrous 1,4-dioxane (60 mL) were added successively, and the mixture was replaced with nitrogen for three times and reacted at 110 °C for 6 h under nitrogen atmosphere. After the reaction was completed as indicated by TLC and LCMS, the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (100 mL), washed with water (100 mL), and separated by standing. The aqueous phase was extracted with dichloromethane (100 mL x 3), and the combined organic phase was washed successively with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 15:1, v / v) to give compound Int-PSZ (2.08 g, 3.60 mmol, 76.4% yield). ESI-LCMS: m / z calcd for [M+H]: 578.2, found: 578.1. + , found: 578.1.

[0091] Second step:

[0092] In a 100 mL dry three-necked flask, intermediate Int-PSZ (100 mg, 0.17 mmol) was added, followed by 2-bromo-5-methylpyrimidine (44 mg, 0.26 mmol), [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (13 mg, 0.02 mmol), potassium carbonate (47 mmol, 0.34 mmol), dioxane (10 mL) and water (2 mL), and the mixture was replaced with nitrogen for three times, slowly warmed to 100 °C and reacted for 6 h. The reaction was monitored by TLC and LCMS. After the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, which was then washed with water (50 mL), 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, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 8:1, v / v) to give compound DA-Y-832 (42 mg, 0.08 mmol, 47.1% yield). ESI-LCMS: m / z calcd for [M+H]: 544.2, found: 544.2. + , found: 544.2. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2H), 8.70 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.41 (s, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 10.1, 5.1 Hz, 2H), 7.18 (t, J = 8.4 Hz, 1H), 6.44 (d, J = 8.4 Hz, 2H), 3.47 (s, 6H), 2.35 (s, 3H), 2.26 (s, 3H).

[0093] Synthesis of compound DA-Y-833 of Example 4

[0094] Intermediate Int-PSZ (100 mg, 0.17 mmol) was added into a 100 mL three-necked flask, followed by the addition of 2-bromo-5-methoxy-pyrimidine (48 mg, 0.26 mmol), Pd(PPh3)2Cl2(13 mg, 0.02 mmol), potassium carbonate (47 mmol, 0.34 mmol), dioxane (10 mL) and water (2 mL) successively. Nitrogen was replaced for three times, and the reaction was slowly warmed to 100 °C for 6 hours. TLC and LCMS were used to monitor the reaction. After the reaction was completed, dichloromethane (50 mL) and water (50 mL) were added into the reaction solution and stirred for 5 minutes. After standing and separation, 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, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 8:1, v / v) to obtain compound DA-Y-833 (40 mg, 0.07 mmol, 41.2% yield). ESI-LCMS: m / z calculated: 560.2 [M+H], found: 560.2. + 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.64 (t, J = 1.7 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 6.43 (d, J = 8.5 Hz, 2H), 3.99 (s, 3H), 3.47 (s, 6H), 2.27 (s, 3H).

[0095] Synthesis of compound DA-Y-834 of Example 5

[0096] ​Intermediate Int-PSZ (0.16 g, 0.28 mmol) was added into a 100 mL dry flask, followed by the addition of 2-bromo-5-fluoropyrimidine (74 mg, 0.42 mmol), Pd(PPh3)2Cl2(44 mg, 0.06 mmol), potassium carbonate (0.15 g, 1.12 mmol), dioxane (10 mL) and water (2 mL) in sequence. The reaction was heated to 100 °C for 6 h after three times of nitrogen replacement. The reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was washed with dichloromethane (50 mL) and water (50 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound DA-Y-834 (88 mg, 0.16 mmol, 57.1% yield). ESI-LCMS: m / z calculated: 548.1 [M+H] + , found: 548.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 8.65 (t, J = 1.7 Hz, 1H), 8.42 (d, J = 6.4 Hz, 2H), 8.04 (d, J = 2.3 Hz, 1H), 7.88 - 7.76 (m, 1H), 7.56 (dd, J = 10.3, 5.2 Hz, 2H), 7.14 (t, J = 8.4 Hz, 1H), 6.41 (d, J = 8.5 Hz, 2H), 3.46 (s, 6H), 2.27 (d, J = 9.6 Hz, 3H).

[0097] Synthesis of compound DA-Y-835 in Example 6

[0098] Intermediate Int-PSZ (100 mg, 0.17 mmol) and acetonitrile (10 mL) were added into a 100 mL dry flask, followed by the addition of morpholine (19 mg, 0.22 mmol), copper acetate (40 mg, 0.22 mmol) and triethylamine (34 mg, 0.34 mmol) in sequence. After addition, the reaction was heated to 80 °C for 6 h. The reaction was monitored by TLC and LCMS. After the reaction was completed, the reaction solution was washed with dichloromethane (50 mL) and water (50 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound DA-Y-835 (38 mg, 0.07 mmol, 41.2% yield). ESI-LCMS: m / z calculated: 537.2 [M+H]+ 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).

[0099] Synthesis of compound DA-Y-868

[0100] Compound DA-Y-867 (100 mg, 0.19 mmol) was added into a 100 mL dry three-necked flask, then N,N-dimethylpiperidin-4-amine (32 mg, 0.25 mmol), methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.04 mmol) and N,N- dimethylformamide (8 mL) were added in turn. After addition, nitrogen was replaced for three times, then bis-trimethylsilylamide (570 μL, 0.57 mmol, 1.0 M) was injected, and the reaction was slowly warmed to 90 °C, TLC and LCMS were used to monitor the reaction. After the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, then the reaction solution was washed with water (50 mL), the aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 8:1, v / v) to give compound DA-Y-868 (30 mg, 0.05 mmol, 26.3% yield). ESI-LCMS: m / z calculated: 578.2 [M+H] + Found: 578.1. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 1.1 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.38 - 7.33 (m, 1H), 7.28 - 7.22 (m, 2H), 7.13 (dd, J = 8.3, 2.0 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.5 Hz, 2H), 3.73 (d, J = 12.7 Hz, 2H), 3.52 (s, 6H), 2.72 (t, J = 11.4 Hz, 3H), 2.45 (s, 6H), 2.29 (s, 3H), 1.97 (d, J = 11.8 Hz, 2H), 1.64 - 1.52 (m, 2H).

[0101] Synthesis of compound DA-Y-869 of example 8

[0102] Compound DA-Y-867 (100 mg, 0.19 mmol) was added into a 50 mL dry three-necked flask, then 3-(dimethylamino)azetidine dihydrochloride (43 mg, 0.25 mmol), methane sulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34 mg, 0.04 mmol) and N,N-dimethylformamide (8 mL) were added in turn. After addition, nitrogen was replaced for three times, then bis-trimethylsilyl amide lithium (570 μL, 0.57 mmol, 1.0 M) was injected, and the reaction was slowly warmed to 90 °C, and TLC and LCMS were used to monitor the reaction. After the reaction was completed, dichloromethane (50 mL) was added to the reaction solution, then the reaction solution was washed with water (50 mL), the aqueous phase was extracted with dichloromethane (50 mL x 3), the combined organic phase was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol = 8:1, v / v) to obtain compound DA-Y-869 (40 mg, 0.07 mmol, yield 36.8 %). ESI-LCMS: m / z calcd for [M+H]: 550.2, found: 550.2. + 1 ​H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.45 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.59 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.63 - 6.50 (m, 3H), 3.89 (t, J = 7.2 Hz, 2H), 3.65 - 3.43 (m, 8H), 3.23 (s, 1H), 2.28 (s, 3H), 2.17 (s, 6H).

[0103] Synthesis of compound DA-Y-870 of Example 9

[0104] In a 100 mL three-necked flask, compound DA-Y-870 (100 mg, 0.19 mmol), 3- fluorazetidine hydrochloride (29 mg, 0.26 mmol), cesium carbonate (186 mg, 0.57 mmol), Ruphos Pd G4 (16 mg, 0.02 mmol) and anhydrous 1,4-dioxane (1 mL) were added successively. After three times of nitrogen replacement, the reaction was heated to 100 °C for 5 hours. LCMS and TLC monitoring showed that the reaction was complete. The reaction was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1, v / v) to collect the crude product 90 mg. Subsequently, the product was slurried in dichloromethane / methanol solution (20 / 1, 5 mL, v / v), filtered and dried to obtain white solid DA-Y-870 (20 mg, 0.04 mmol, yield 21.1%). ESI-LCMS: m / z calcd for C28H30FN5O4 525.2 [M+H], found: 525.1. + 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.72 (t, J = 2.0 Hz, 1H), 6.62 - 6.58 (m, 1H), 6.56 (d, J = 8.5 Hz, 2H), 5.65 - 5.35 (m, 1H), 4.19 - 4.05 (m, 2H), 3.95 - 3.80 (m, 2H), 3.51 (s, 6H), 2.29 (s, 3H).

[0105] ​AMG986 is Example 263.0 in patent CN 108137545B, and AMG986 used herein is purchased from MedChemExpress LLC (MCE) company.

[0106] Experimental Example 1 In vitro biological activity determination-cAMP experiment

[0107] In this experiment, a CHO cell line stably expressing APJ receptor was incubated with different concentrations of samples, and the agonism of the samples on the G protein signal pathway downstream of the APJ receptor was determined by a cAMP kit.

[0108] Experimental method: 1x Stimulation Buffer was prepared according to the LANCE Ultra cAMP Kit (Revvity) instructions. Sample preparation: positive control (AMG986) and test compounds were gradient diluted to 10 concentrations. 1‰ concentration of DMSO was used as a negative control. The CHO cell strain stably expressing APJ receptor (CHO cell line from ATCC; stable expression cell strain was constructed as follows: an expression plasmid containing the DNA sequence of APJ receptor was constructed, the expression plasmid was transfected into CHO cells, and then a stable expression cell strain was obtained by resistance screening) was cultured to 80% confluence, trypsinized and collected, counted and then inoculated 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 with Detection buffer to 4x working concentration, 4 μL / well was added to the corresponding experimental wells; ULight-anti-cAMP antibody was diluted with Detection buffer to 4x working concentration, 4 μL / well was added to the corresponding experimental wells, and after centrifugation, it was incubated at room temperature for 1 hour; after incubation, the enzyme marker 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. The signal value was calculated according to the average value of the highest concentration well of the positive control, 50 and the average value of the negative control. The signal value was calculated according to the average value of the highest concentration well of the positive control,

[0109] Experimental Example 2 In vitro biological activity determination-β-Arrestin2 experiment

[0110] This study used the HEK293T cell line, which stably expresses APJ receptor and β-arrestin2, to incubate samples of different concentrations. The changes in fluorescence intensity were detected by the NanoBiT method to investigate the effect of the samples on the recruitment of β-arrestin2 by human APJ receptor.

[0111] Experimental Methods: HEK293T-APJ-β-Arrestin2 stably expressed cells (HEK293T cell line from ATCC, the stable expression cell line was constructed as follows: expression plasmids containing the DNA sequences of the APJ receptor-NanoBiT subunit and the β-Arrestin2-NanoBiT subunit were constructed, co-transfected into HEK293T cells, and then stable expression cell lines were obtained through antibiotic selection) were cultured to 80% confluence, triedpsin digestion was performed to collect cells, and after counting, 70 μL / well was seeded into 96-well plates, 30,000 cells / well, incubated overnight in Opti-MEM + 4% FBS. Sample Preparation: Positive control (AMG986) and test compounds were serially diluted with Opti-MEM to 10 concentrations. 1‰ DMSO was used as a negative control. Once the cell density reaches approximately 80%, dilute the substrate 20-fold according to the Nano-Glo Live Cell Substrates (Promega) instructions, add 20 μL to each well, and mix well. Add 10 μL of the prepared sample to the corresponding well and incubate in the dark for 10 minutes. After incubation, read the Luminescence signal value using a microplate reader. The average value of the highest concentration wells in the positive control. The signal value was calculated using the average value of the negative control. A graph was plotted between the signal value and the compound concentration, and curve fitting was performed using the nonlinear regression method in GraphPad Prism software, along with EC50 calculations. 50 Calculation. To facilitate comparison of the degree of bias, the EC value for this experimental example was calculated. 50 Value and EC of Experimental Example 1 50 The ratio of values, i.e. EC 50 (β-Arrestin2) / EC 50 (cAMP), the results are shown in Table 1. Table 1 presents the in vitro bioactivity data of some compounds. The results show that the compounds of the present invention can effectively activate APJ receptors and have a high bias towards G protein signaling pathways, which helps to achieve better efficacy and higher safety.

[0112] Table 1. In vitro bioactivity data of the compounds of the present invention.

[0113] (+++): EC 50<25 nM; (++): 25 nM < EC 50 <500 nM; (+): EC 50 ≥ 500 nM.

[0114] Experimental Example 3 Pharmacokinetic Test

[0115] The pharmacokinetic test of the compound 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. Pharmacokinetic calculation was carried out using WinNonlin (PhoenixTM, version 8.3) or other similar software. The pharmacokinetic parameters shown in Table 2 were calculated according to the plasma concentration and time data, and the parameter data were statistically calculated and described using mean value and other descriptive statistics.

[0116] Table 2 shows the initial blood drug concentration (C0), clearance (CL) of intravenous administration, and the maximum blood drug concentration (Cmax), area under the curve (AUC) data of oral administration, and the results show that the compounds of the present application have good pharmacokinetic properties, which are significantly better than AMG986. max

[0117] Table 2 Pharmacokinetic data of the compounds of the present application

[0118] Experimental Example 4 Animal Pharmacodynamic Test

[0119] This experiment evaluated the effect of combination of the compound and GLP-1 receptor agonist on weight loss and body composition in DIO mouse model.

[0120] 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, 8 animals per group, and the food and water intake was measured 1 day before administration, the body fat was detected, and the body weight was measured.

[0121] Experimental grouping:​

[0122] Tirzepatide (MW = 4813.45, 10 nmol / kg = 0.048 mg / kg) was purchased from Selleck (P1206). Tirzepatide was administered by subcutaneous injection (sc) once every three days (q3d). The compound was dissolved in drinking water containing 5 mM sucralose, pH = 8.5, and the mice had free access to the water. Vehicle 1 was 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% normal saline, sc, q3d. Vehicle 2 was drinking water containing 5 mM sucralose, pH = 8.5, free access. The start date of administration was considered day 0. After grouping, the body weight, food intake, water intake, and the health status of the animals were recorded once a day. The experiment ended after 14 days of continuous administration, and the body weight (Body Weight), the percentage of body weight change (Body Weight Change %), and the changes in body composition (Lean Mass, Fat Mass, Lean %, Fat %) of the animals in each group were recorded.

[0123] The experimental results show that, compared with the G1 group, the body weight (Body Weight), fat weight (Fat Mass), and fat / weight ratio (Fat %) of the G2 and G3 groups decreased significantly, and the decrease in the G3 group was greater. In addition, compared with the G1 group, the G3 group significantly increased the lean body weight / weight ratio (Lean %) of the DIO mice.

Claims

1. A triazoles compound represented by Formula (I) or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated analog, hydrate, or solvate thereof, wherein X is selected from O or NR2; R1is unsubstituted C5-C 12 heteroaryl, C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 spirocyclyl, C5-C 12 heterospirocyclyl, C5-C 12 bridged cyclyl, C5-C 12 heterobridged cyclyl, -SO2R5; or the preceding groups are substituted by one or more R 1a groups; R 1a Independently selected from halogen, cyano, nitro, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 Heteroaryl; the above C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5-C 12 The heteroaryl group is optionally surrounded by one or more halogens, cyano, hydroxyl, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 heteroaryl substitution; R2is hydrogen, C1-C 10 alkyl, C1-C 10 heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C5-C 12 spirocyclic, C5-C 12 heterospirocyclic, C5-C 12 bridged cyclic, C5-C 12 heterobridged cyclic, C6-C 10 aryl, C5-C 12 heteroaryl; wherein the foregoing C1-C 10 alkyl, C1-C 10 heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C5-C 12 spirocyclic, C5-C 12 heterospirocyclic, C5-C 12 bridged cyclic, C5-C 12 heterobridged cyclic, C6-C 10 aryl, C5-C 12 heteroaryl are optionally substituted with one or more halogen, cyano, nitro, C1-C6alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12 heteroaryl; wherein the foregoing C1-C6alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl are optionally substituted with one or more halogen, cyano, hydroxyl, nitro, C1-C4alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 aryl, C5-C 12 heteroaryl; wherein the foregoing C1-C4alkyl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, C6-C R3is selected from the group consisting of C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl, -(CR 11 R 12 )-(CR 13 R 14 )-R 15 , -NR2-(CR 12 R 13 )-R 15 , -(CR 11 R 12 )-C(=O)-R 15 , -(C5-C 12 heteroaryl)-R 15 , -(C6-C 10 aryl)-R 15 , -(C5-C 10 heterocycloalkyl)-R 15 , -(C5-C 10 cycloalkyl)-R 15 ; wherein said C1-C 10 alkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl, -(C5-C 12 heteroaryl)-R 15 , -(C6-C 10 aryl)-R 15 , -(C5-C 10 heterocycloalkyl)-R 15 , -(C5-C 10 cycloalkyl)-R 15 are unsubstituted or substituted by one or more R 1a substituents; R4 is selected from hydrogen, C1-C8 alkyl; R5, R6, and R7 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, and C3-C6... 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl, C5-C 12 Heteroaryl; the above C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 Heterocyclic alkyl, C6-C 10 Aryl, C5-C 12 The heteroaryl group is optionally surrounded by one or more halogens, cyano, nitro, alkyl, cycloalkyl, heterocycloalkyl, -OR8, -OC(O)R8, -OC(O)NR8R9, -NR8R9, -NR8C(O)R9, -NR8C(O)OR9, -NR8C(O)NR9R 10 -NR8C(NH)NR9R 10 , -C(O)R8, -COOR8, -C(O)NHR8, -C(O)NR8R9, -SR8, -SO2R8, -SO2NR8R9, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 heteroaryl substitution; R8, R9, R 10 independently selected from hydrogen, Ci-C6alkyl, Ci-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl; said Ci-C6alkyl, Ci-C6heteroalkyl, C3-C 10 cycloalkyl, C4-C 10 heterocycloalkyl, C6-C 10 aryl, C5-C 12 heteroaryl are optionally substituted with one or more halogen, cyano, hydroxyl, carboxyl, amino, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryl, heteroaryl; R 11 R 12 R 13 R 14 Each is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 Heteroaryl; the above C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, C6-C 10 Aryl, C5-C 12 The heteroaryl group is optionally surrounded by one or more halogens, cyano, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocycloalkyl, -OR5, -OC(O)R5, -OC(O)NR5R6, -NR5R6, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -NR5C(NH)NR6R7, -C(O)R5, -COOR5, -C(O)NHR5, -C(O)NR5R6, -SR5, -SO2R5, -SO2NR5R6, -S(O)(NR5)R6R7, C6-C 10 Aryl, C5-C 12 heteroaryl substitution; R 15 monocyclic or bicyclic C6-C 10 aryl, monocyclic to tricyclic C5-C 12 heteroaryl, C3-C6cycloalkyl, C4-C6heterocycloalkyl, wherein the monocyclic or bicyclic C6-C 10 aryl, monocyclic to tricyclic C5-C 12 heteroaryl, C3-C6cycloalkyl, C4-C6heterocycloalkyl are unsubstituted or substituted by one or more R 1a substituents.

2. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is a C5-C6 heteroaryl containing 1 nitrogen atom, which is unsubstituted or substituted with one or more R 1a substituents; Preferably, R1is unsubstituted pyridyl or is pyridyl substituted with 1 to 3 R 1a substituted with 1 to 3 R 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R1is pyridyl having the formula: wherein said pyridyl is unsubstituted or substituted with 1 to 3 R 1a substituted with 1 to 3 R to indicate the point of attachment to the rest of the molecule when drawn across a bond; preferably, R 1a independently selected from -CH3, -CH2CH3, -OCH3, -OH2CH3, -F, -Cl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated form, hydrate, or solvate thereof, wherein R2 is phenyl or C5-C6 heteroaryl containing 1-2 nitrogen atoms substituted with 1 or 2 -OR5 substituents; the C5-C6 heteroaryl containing 1-2 nitrogen atoms is preferably pyrimidinyl; Further, R2is preferably the following structure: Symbols to indicate the point of attachment to the rest of the molecule when drawn across a bond.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is selected from the group consisting of unsubstituted or substituted C1-C6alkyl or C6-C8aryl; said R 1a substituted C1-C6alkyl or C6-C8aryl; said R 1a is independently selected from the group consisting of -F, -Cl, -Br, cyano, -OR5, C1-C6alkyl, phenyl, C4-C6heterocycloalkyl containing 1-2 heteroatoms, C5-C6heteroaryl containing 1-2 nitrogen atoms; said phenyl, C4-C6heterocycloalkyl containing 1-2 heteroatoms, or heteroaryl containing 1-2 nitrogen atoms is unsubstituted or substituted with 1-2 substituents selected from -F, -Cl, -Br, cyano, -OR5, or C1-C6alkyl; wherein R 5 is independently selected from hydrogen or C1-C6 alkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein R3is selected from: Symbols to indicate the point of attachment to the rest of the molecule when drawn across a bond.

7. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated isotope, hydrate, or solvate thereof, wherein the compound is optionally selected from:

8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated form, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

9. Use of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated form, hydrate, or solvate thereof, or the pharmaceutical composition of claim 8, for 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 the APJ receptor; Preferably, the disease associated with the APJ receptor is obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia.

10. Use of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated form, hydrate, or solvate thereof, or the pharmaceutical composition of claim 8, for the manufacture of an APJ receptor agonist; Preferably, the APJ receptor agonist is for the prevention and / or treatment of obesity, hypertension, pulmonary arterial hypertension, heart failure, diabetes, atherosclerosis, osteoporosis, kidney disease, and / or sarcopenia.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, prodrug, stereoisomer, tautomer, deuterated form, hydrate, or solvate thereof, or the pharmaceutical composition of claim 8, and another drug that can agonize the GLP-1 receptor; Preferably, the drug that can agonize the GLP-1 receptor is tirzepatide.

12. Use of the pharmaceutical composition of claim 11 for 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.

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