Carbonyl-substituted triazole compound, preparation method therefor, and use thereof

Abstract

Provided are a carbonyl-substituted triazole compound, a preparation method therefor, and a use thereof. The specific structure of the carbonyl-substituted triazole compound is as shown in formula (II); each substituent group is defined in the description; and the compound is an APJ agonist.

Description

A carbonyl-substituted triazole compound and its preparation method and use Technical Field

[0001] The present invention relates to a carbonyl-substituted triazole compound, a preparation method and use thereof, and belongs to the field of medicine. Background Art

[0002] Apelin is an endogenous ligand of APJ (APLNR, angiotensin receptor-like 1). APJ receptors are members of the rhodopsin-like G protein-coupled receptor (GPCR) family. The Apelin / APJ system has been observed in many tissues, such as the heart, kidneys, pancreas, lungs, gastrointestinal tract, adipose tissue, and the central nervous system. This indicates the different roles of the system in the physiology and pathology of mammals. Apelin has cardioprotective properties that increase myocardial contractility and lower mean arterial pressure. It is a major neuroprotective peptide with the highest abundance in plasma. It is involved in vascular lesions, energy metabolism, and fluid homeostasis, and is downregulated in aging. Apelin activates its receptor (APJ) and triggers various signaling pathways that have protective effects on different organs in metabolic diseases.

[0003] APJ targets have been shown to be associated with a variety of diseases, and APJ agonism or activation may serve as a new approach to prevent or treat such diseases, such as heart failure (Japp, AG et al., Biochem. Pharmacol., 5(10): 1882-1892 (2008)) and its sequelae, especially patients with chronic heart failure and patients with reduced or unchanged ejection fraction, coronary heart disease, myocardial infarction (Donmez Y. et al., Med (Baltimore) 98(43): e17645 (2019)), atherosclerosis, stroke (Ao L. et al., Molecular Biology Reports 50: 1639-1653 (2023)), kidney disease (Chapman FA et al., Nat Rev Nephrol 17(12): 840-53 (2021)), Alzheimer's disease (Ao L. et al., Molecular Biology Reports 50:1639-1653(2023)), Parkinson's disease, amyotrophic lateral sclerosis, diabetes (Zhang H. et al., Human Cell Physiol Biochem(2018)48(3):1347–54(2018)), diabetic complications (Coskun Yavuz Y. et al., Iran J Kidney Dis9(5):369-73(2015)), hypertension (Song JW et al., Chin Med J(Engl)(2021).doi:10.1097 / CM9.0000000000001766)), pulmonary hypertension, and obesity (Yue P. et al., Endocrinology 152(1):59-68(2011)), etc.

[0004] Since the very short half-life of Apelin in the circulation limits its therapeutic utility, there are already some small molecule agonists for APJ receptors in the field. For example, WO 2014 / 044738 discloses a variety of benzimidazole-carboxylic acid amide derivatives that can be used as APJ receptor modulators, and WO2016187308A, WO2018097944A, WO2017192485A, WO2018093576A, WO2018093577A, WO2018097945A, WO2019089335A, WO2019213006A, etc. disclose a class of triazole APJ agonists. Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006] Among them, R 1 Selected from:

[0007] i) C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by one or more R A Substituted, the R A is selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more R 1A Substituted, the R 1A is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0008] ii) Ring C is a 3- to 12-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group (containing 1, 2 or 3 heteroatoms selected from N, O and S), R 9 each independently selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more R B Substituted, the R B is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0009] iii) Ring D is a 6- to 10-membered aryl group or a 5- to 12-membered heteroaryl group (containing 1, 2 or 3 heteroatoms selected from N, O and S), R 10 each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more RC Substituted, the R C is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0010] Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group (containing 1, 2 or 3 heteroatoms selected from N, O and S);

[0011] R 2 each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally replaced by one or more R D Substituted, the R D is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0012] R 3 is hydrogen or C1-C6 alkyl;

[0013] R 4 、R 5 、R 6 and R 7 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy are each independently optionally substituted with one or more deuterium, halogen and hydroxy;

[0014] Ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group (containing 1, 2 or 3 heteroatoms selected from N, O and S);

[0015] R 8 each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more RE Substituted, the R E Selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy;

[0016] Said R' and R" are each independently hydrogen or C1-C6 alkyl;

[0017] m, n, p and q are each independently selected from 0, 1, 2, 3 and 4.

[0018] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one or more R A Substituted, the R A each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl are optionally substituted by one or more R 1A Substituted, the R 1A Each is independently selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl, and C1-C6 alkoxy.

[0019] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C1-C6 alkyl, the C1-C6 alkyl is optionally substituted by one or more R A Substituted, the R A Each independently selected from deuterium, halogen, hydroxyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl and 3 to 6-membered cycloalkyl, wherein the C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl is optionally substituted by one or more R 1A Substituted, the R 1A are each independently selected from deuterium, halogen, and hydroxyl;

[0020] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C1-C6 alkyl group, wherein the C1-C6 alkyl group is optionally substituted by one or more R A Substituted, the R A are each independently selected from deuterium, halogen and hydroxyl.

[0021] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted by one or more R A Substituted, the R A are each independently deuterium or halogen.

[0022] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl, ethyl, propyl and isopropyl.

[0023] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is a methyl group.

[0024] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 For ethyl.

[0025] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is propyl.

[0026] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl.

[0027] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0028] Among them, ring C, ring A, ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , m, n and p are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 12-membered (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) cycloalkyl (monocyclic or bicyclic).

[0030] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 12-membered (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) monocyclic alkyl group.

[0031] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 6-membered (3, 4, 5, or 6) cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0032] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopropyl.

[0033] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0034] Among them, ring A, ring B, R 2 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , p, m and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and t is selected from 1, 2, 3 or 4.

[0035] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 12-membered (5, 6, 7, 8, 9, 10, 11, or 12) bicycloalkyl (a cyclic, spiro, or bridged ring).

[0036] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 12-membered (4, 5, 6, 7, 8, 9, 10, 11, or 12) cycloalkyl group.

[0037] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 12-membered (5, 6, 7, 8, 9, 10, 11, or 12) spirocycloalkyl group.

[0038] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 10-membered (5, 6, 7, 8, 9, or 10) spirocycloalkyl group.

[0039] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- or 6-membered heterospirocycloalkyl group.

[0040] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 5- to 12-membered (5, 6, 7, 8, 9, 10, 11, or 12) bridged cycloalkyl group.

[0041] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 10-membered (4, 5, 6, 7, 8, 9, or 10) heterocycloalkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0042] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 6-membered (4, 5, or 6) heterocycloalkyl group containing 1 or 2 heteroatoms selected from N and O.

[0043] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring C is a 4- to 6-membered (4, 5, or 6) heterocycloalkyl group containing 1 O heteroatom.

[0044] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 9 Each independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6 membered cycloalkyl, said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and 3 to 6 membered cycloalkyl are each independently optionally substituted by one or more R B Substituted, the R B Each is independently selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy.

[0045] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 9 Each independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R B Substituted, the R B Each is independently selected from deuterium, halogen, hydroxyl and C1-C6 alkoxy.

[0046] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 9 Each is independently selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and 3 to 6-membered cycloalkane.

[0047] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 9 Selected from deuterium, fluorine, methyl, ethyl, trifluoromethyl and cyclopropyl.

[0048] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein p is selected from 0, 1, 2 and 3.

[0049] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: Selected from

[0050] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: Selected from

[0051] In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

[0052] Among them, ring D, ring A, ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 10 , m, n and q are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a phenyl group or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0054] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a phenyl group or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N and S.

[0055] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl and pyrazolyl.

[0056] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is phenyl.

[0057] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl and pyrazolyl.

[0058] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is pyridyl.

[0059] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a pyrimidinyl group.

[0060] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is pyrazinyl.

[0061] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a pyridazinyl group.

[0062] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a thienyl group.

[0063] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is thiazolyl.

[0064] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is pyrazolyl.

[0065] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is an 8- to 12-membered (8, 9, 10, 11, or 12) bicyclic heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0066] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is a 9-membered or 10-membered bicyclic heteroaryl group containing 1, 2 or 3 nitrogen atoms (e.g., 5- and 6-, or 6- and 6-).

[0067] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring D is selected from (pyrazolo[1,5-a]pyridinyl), (imidazo[1,2-a]pyridinyl) and (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl).

[0068] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 Each independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R C Substituted, the R C Each is independently selected from deuterium, halogen, hydroxyl and C1-C6 alkoxy.

[0069] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 Each is independently selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and 3 to 6-membered cycloalkane.

[0070] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from deuterium, fluorine, methyl, ethyl, trifluoromethyl and cyclopropyl.

[0071] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein q is selected from 0, 1, 2, and 3.

[0072] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: Selected from

[0073] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0074] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0075] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0076] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0077] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0078] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0079] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0080] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0081] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0082] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: Selected from

[0083] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0084] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0085] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0086] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein: for

[0087] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring A is a phenyl group or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0088] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring A is phenyl or pyridyl.

[0089] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring A is phenyl.

[0090] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1) or pharmaceutically acceptable salts thereof, wherein ring A is phenyl and ring C is cyclopropyl.

[0091] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 2 are each independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3 to 6 membered cycloalkyl and -NR'R", wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are each independently optionally substituted by one or more R D Substituted, the R D is selected from deuterium, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein R' and R" are each independently methyl or ethyl.

[0092] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 2 Each is independently selected from halogen, cyano, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, methylamino, dimethylamino, and deuterated methoxy (trideuterated methoxy).

[0093] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 2 Each is independently selected from fluorine, chlorine, bromine, methoxy and deuterated methoxy (trideuterated methoxy).

[0094] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III), or pharmaceutically acceptable salts thereof, wherein m is selected from 0, 1, 2, and 3.

[0095] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: Selected from

[0096] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: for

[0097] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: for

[0098] In some embodiments, the compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof provided by the present disclosure, R 3 For hydrogen.

[0099] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 4 and R 6 are each independently hydrogen; R 5 and R 7 Each is independently selected from hydroxy, C1-C3 alkyl and C1-C3 alkoxy, and the C1-C3 alkyl and C1-C3 alkoxy are each independently optionally substituted with one or more hydroxy groups.

[0100] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 4 and R 6 are each independently hydrogen; R 5 and R 7Each is independently selected from hydroxy, methyl, methoxy, ethoxy, isopropoxy and hydroxyethoxy.

[0101] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 4 and R 6 are each independently hydrogen; R 5 and R 7 are each independently methyl.

[0102] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: Selected from in It is connected to ring B.

[0103] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: for

[0104] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring B is a phenyl group or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S.

[0105] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring B is phenyl.

[0106] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring B is a 6-membered nitrogen-containing heteroaryl group.

[0107] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring B is a pyrimidinyl group or a pyridinyl group.

[0108] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein ring B is a pyrimidinyl group.

[0109] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1) or pharmaceutically acceptable salts thereof, wherein ring A is phenyl, ring C is cyclopropyl, and ring B is pyrimidinyl.

[0110] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 Each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R E Substituted, the R E Selected from halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

[0111] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 Each is independently selected from deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R E Substituted, the R E is deuterium or a halogen.

[0112] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 are each independently selected from deuterium, C1-C3 alkyl, C1-C3 alkoxy, fluorine, chlorine, bromine and cyano, wherein the C1-C3 alkyl and C1-C3 alkoxy are each independently optionally substituted by one or more R E Substituted, the R E For deuterium.

[0113] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 Each is independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine, chlorine, bromine and cyano.

[0114] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 Each is independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine, chlorine, bromine and cyano.

[0115] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein R 8 are each independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine and chlorine.

[0116] In some embodiments, the present disclosure provides compounds of formula (I), (II), (II-1), (III), or pharmaceutically acceptable salts thereof, wherein n is selected from 0, 1, 2, and 3.

[0117] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: Selected from

[0118] In some embodiments, the present disclosure provides compounds represented by formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof, wherein: for

[0119] In some embodiments, the compounds of formula (I), (II), (II-1), (III) or pharmaceutically acceptable salts thereof provided herein are compounds of formula (IV) or pharmaceutically acceptable salts thereof,

[0120] Among them, R 1 、R 2 、R 4 、R 5 、R 6 、R 7 、R 8 , m and n are respectively defined as in the compounds represented by formula (I), (II), (II-1), (III) or their pharmaceutically acceptable salts.

[0121] In some embodiments, the compounds of formula (I), (II), (II-1) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (II-1-A) or pharmaceutically acceptable salts thereof,

[0122] Among them, R1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D each independently hydrogen or deuterium;

[0123] R 9 is selected from the group consisting of deuterium, fluorine, methyl, ethyl, trifluoromethyl and cyclopropyl;

[0124] R 8 are each independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine, chlorine, bromine and cyano;

[0125] p and n are each independently selected from 0, 1, 2 and 3.

[0126] In an optional embodiment, the present disclosure provides a compound represented by formula (II-1-A) or a pharmaceutically acceptable salt thereof, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D All are hydrogen;

[0127] R 9 selected from deuterium, fluorine and methyl;

[0128] R 8 are each independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine and chlorine;

[0129] p is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3.

[0130] In an optional embodiment, the present disclosure provides a compound represented by formula (II-1-A) or a pharmaceutically acceptable salt thereof, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D All are deuterium;

[0131] R 9 selected from deuterium, fluorine and methyl;

[0132] R 8 are each independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine and chlorine;

[0133] p is selected from 0, 1 or 2; n is selected from 0, 1, 2 or 3.

[0134] In some embodiments, the compounds of formula (I) and (III) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (III-1) or pharmaceutically acceptable salts thereof,

[0135] Among them, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D are each independently hydrogen or deuterium; R 10 is selected from deuterium, fluorine, methyl, ethyl, trifluoromethyl and cyclopropyl; R 8 are each independently selected from methyl, methoxy, fluoro, chloro, bromo and cyano; q is selected from 0, 1, 2 and 3; and n is selected from 0, 1 and 2.

[0136] In an optional embodiment, the present disclosure provides a compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D All are hydrogen; R 10 is selected from deuterium, fluorine and methyl; R 8 are each independently selected from methyl, methoxy, fluorine, chlorine and bromine; p is selected from 0, 1 and 2; and n is selected from 0, 1 and 2.

[0137] In an optional embodiment, the present disclosure provides a compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D All are hydrogen; R 10 is selected from deuterium, fluorine and methyl; R 8 are each independently selected from methyl, methoxy, fluorine, chlorine and bromine; p is selected from 0, 1 and 2; and n is selected from 0, 1 and 2.

[0138] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0139] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0140] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0141] The present disclosure further includes isotopic substitutions of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts. Optionally, the isotopic substitutions are deuterated.

[0142] The present disclosure further provides a pharmaceutical composition comprising a compound represented by the aforementioned formula (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or a pharmaceutically acceptable salt thereof, and / or an isotope substitute and at least one pharmaceutically acceptable excipient.

[0143] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0144] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0145] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0146] The present disclosure further provides a compound represented by the aforementioned formula (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or a pharmaceutically acceptable salt thereof, and / or isotope substitution, and / or pharmaceutical composition as a drug.

[0147] The compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), and (IV) or their pharmaceutically acceptable salts, and / or isotopic substitutions, and / or pharmaceutical compositions provided herein are APJ agonists.

[0148] The present disclosure further provides the use of the compounds represented by the aforementioned formula (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotope substitutions, and / or pharmaceutical compositions in the preparation of drugs for preventing and / or treating cardiovascular diseases.

[0149] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotope substitutions, and / or pharmaceutical compositions in the preparation of drugs for preventing and / or treating nervous system diseases.

[0150] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotope substitutions, and / or pharmaceutical compositions in the preparation of drugs for improving myocardial contractility.

[0151] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotope substitutions, and / or pharmaceutical compositions in the preparation of drugs for increasing ejection fraction.

[0152] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or pharmaceutically acceptable salts thereof, and / or isotopic substitutions, and / or pharmaceutical compositions in the preparation of drugs for diseases associated with activated APJ receptors.

[0153] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotopic substitutions, and / or pharmaceutical compositions in the preparation of drugs for preventing and / or treating obesity or diabetes.

[0154] The present disclosure further provides the use of the compounds represented by the aforementioned formulas (I), (I), (II), (II-1), (II-1-A), (III), (III-1), (IV) or their pharmaceutically acceptable salts, and / or isotope substitutions, and / or pharmaceutical compositions in the preparation of drugs for preventing and / or treating diabetic nephropathy or chronic kidney disease.

[0155] The present disclosure further provides a method for preventing and / or treating cardiovascular disease in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0156] The present disclosure further provides a method for preventing and / or treating a nervous system disease in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0157] The present disclosure further provides a method for improving myocardial contractility in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotope substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0158] The present disclosure further provides a method for increasing the ejection fraction of a subject, comprising administering to a subject in need thereof a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition.

[0159] The present disclosure further provides a method for activating an APJ receptor in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0160] The present disclosure further provides a method for preventing and / or treating obesity or diabetes in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0161] The present disclosure further provides a method for preventing and / or treating diabetic nephropathy or chronic kidney disease in a subject, comprising administering a compound provided by the present disclosure or a pharmaceutically acceptable salt thereof, and / or isotopic substitution, and / or pharmaceutical composition thereof to a subject in need thereof.

[0162] The cardiovascular disease in the present disclosure is selected from the group consisting of stroke, myocardial infarction, heart failure, hypertension, coronary heart disease, and atherosclerosis.

[0163] The heart failure described in the present disclosure is heart failure with reduced ejection fraction.

[0164] The heart failure described in the present disclosure is heart failure with preserved ejection fraction.

[0165] The heart failure described in the present disclosure is chronic systolic heart failure.

[0166] The heart failure described in the present disclosure is chronic diastolic heart failure.

[0167] The heart failure described in the present disclosure is acute heart failure.

[0168] The neurological disease in the present disclosure is selected from Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

[0169] In an optional embodiment, in the method provided by the present disclosure, the compound provided by the present disclosure or its pharmaceutically acceptable salt, and / or isotope substitution, and / or pharmaceutical composition administered to the subject is an "effective amount" or "effective therapeutic amount".

[0170] The present disclosure further provides a method for preparing the compound of the aforementioned formula (I) or its pharmaceutically acceptable salt, and / or isotope-substituted product, and / or pharmaceutical composition, comprising the steps of oxidizing the compound of the formula (IA) or its pharmaceutically acceptable salt to obtain the compound of the formula (I) or its pharmaceutically acceptable salt.

[0171] Optionally, further comprising a compound represented by formula (IB) or a pharmaceutically acceptable salt thereof and a Grignard reagent R 1 MgX reaction to obtain a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof,

[0172] and / or, optionally, further comprising the step of oxidizing the compound represented by formula (IC) or a pharmaceutically acceptable salt thereof to obtain the compound represented by formula (IB) or a pharmaceutically acceptable salt thereof,

[0173] R 1 , Ring A, Ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8, m and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0174] X is halogen.

[0175] In an alternative embodiment, X is bromo.

[0176] In an optional embodiment, the present disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the step of oxidizing a compound of formula (IA) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0177] Among them, R 1 , Ring A, Ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , m and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0178] In an optional embodiment, the present disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or an isotope-substituted product, and / or a pharmaceutical composition, further comprising reacting a compound of formula (IB) or a pharmaceutically acceptable salt thereof with a Grignard reagent R 1 MgX reaction to obtain a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof,

[0179] Among them, R 1 , Ring A, Ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , m, and n are respectively as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and X is a halogen.

[0180] In an alternative embodiment, X is bromo.

[0181] In an optional embodiment, the method for preparing the compound of formula (I) or its pharmaceutically acceptable salt, and / or isotope-substituted product, and / or pharmaceutical composition provided by the present disclosure further comprises the step of oxidizing the compound of formula (IC) or its pharmaceutically acceptable salt to obtain the compound of formula (IB) or its pharmaceutically acceptable salt.

[0182] Among them, ring A, ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , m and n are as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0183] The present disclosure further provides compounds represented by the following formulas (IA), (IB), (IC) or pharmaceutically acceptable salts thereof:

[0184] Among them, R 1 , Ring A, Ring B, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 , m and n are defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0185] The present disclosure further provides a method for preparing a compound of formula (1) or a pharmaceutically acceptable salt or isotope substituted product thereof, comprising the steps of oxidizing a compound of formula (11) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (1) or a pharmaceutically acceptable salt thereof.

[0186] Optionally, further comprising a compound represented by formula (1k) or a pharmaceutically acceptable salt thereof and a Grignard reagent The step of reacting to obtain a compound represented by formula (11) or a pharmaceutically acceptable salt thereof, wherein X is a halogen, preferably bromine;

[0187] and / or, optionally, further comprising the step of oxidizing the compound represented by formula (1j) or a pharmaceutically acceptable salt thereof to obtain the compound represented by formula (1k) or a pharmaceutically acceptable salt thereof,

[0188] In some embodiments, in the aforementioned preparation method of the present disclosure, Dess-Martin reagent can be selected for the oxidation reaction.

[0189] The present disclosure provides a compound shown below or a pharmaceutically acceptable salt thereof,

[0190] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0191] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0192] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0193] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond No configuration is specified, i.e. the bond The configuration can be E-type or Z-type, or include both E and Z configurations.

[0194] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerizations.

[0195] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0196] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0197] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6 The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0198] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0199] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0200] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0201] "Treating" or "treatment" includes treating a disease state in a mammal, particularly a human, and includes: (a) inhibiting the disease state, ie, arresting its development; and / or (b) alleviating the disease state, ie, causing regression of the disease state.

[0202] The term "subject" refers to any human or non-human organism that could potentially benefit from treatment with an APJ agonist.

[0203] "Alkyl" refers to a saturated aliphatic hydrocarbon group, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched chain isomers thereof.

[0204] "Alkenyl" refers to an unsaturated aliphatic straight or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C6 alkenyl. Examples include, but are not limited to, ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like.

[0205] "Alkynyl" refers to an unsaturated aliphatic straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C6 alkynyl, including but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl.

[0206] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0207] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 12 ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, non-limiting examples of "heterocycloalkyl" include:

[0208] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0209] wait.

[0210] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy.

[0211] Similarly, the "alkoxy" in "cycloalkoxy" and "heterocycloalkoxy" has the same meaning as the above-mentioned "alkoxy".

[0212] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0213] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0214] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene" and "heterocycloalkylene" are the same as "alkylene".

[0215] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0216] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0217] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0218] The term "spirocyclic" refers to a compound in which two rings share one atom. Non-limiting examples of spiroalkyl groups include:

[0219] The term "cycloalkyl" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of cycloalkyl groups include:

[0220] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0221] The term "heterocycle" refers to a ring having atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl rings.

[0222] The term "hydroxy" refers to an -OH group.

[0223] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0224] The term "cyano" refers to -CN.

[0225] The term "amino" refers to -NH2.

[0226] The term "nitro" refers to -NO2.

[0227] The term "oxo" refers to a =0 substituent.

[0228] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced. DETAILED DESCRIPTION

[0229] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0230] Example

[0231] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6).

[0232] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0233] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0234] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0235] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0236] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0237] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0238] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0239] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J&K, Accela ChemBio Inc, Shanghai Bid Pharmaceutical, Darui Chemicals, and other companies.

[0240] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0241] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0242] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0243] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0244] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0245] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0246] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0247] The reaction progress in the examples was analyzed using liquid chromatography-mass spectrometry (HPLC-MS).

[0248] Example 1

[0249] (2S,3R)-N-[5-(Cyclopropylcarbonyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0250] first step

[0251] Preparation of compound 1b

[0252] Compound 1a (5.0 g, 38.89 mmol) was dissolved in dioxane (90 mL) and water (30 mL). Potassium (Z)-but-2-en-2-yltrifluoroborate (8.2 g, 50.56 mmol), tricyclohexylphosphine (2.2 g, 7.78 mmol), potassium phosphate (24.7 g, 116.67 mmol), and Pd2(dba)3 (3.56 g, 3.88 mmol) were added at room temperature. The atmosphere was then replaced with nitrogen three times, the temperature was raised to 100°C, and the mixture was stirred under nitrogen for 24 hours. The mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate. Water (30 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography to afford compound 1b (4.0 g, 69.4% yield).

[0253] MS (ESI) m / z = 149.2 [M+H] + .

[0254] Step 2

[0255] Preparation of compound 1c

[0256] Pyrimidine-2-thiol (3.0 g, 26.99 mmol) was dissolved in dichloromethane (80 mL). Sulfuryl chloride (2.19 mL, 26.99 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for another 1 hour. Compound 1b (4.0 g, 26.99 mmol) was added dropwise to the reaction mixture, which was then stirred at room temperature for 16 hours. The reaction mixture was concentrated and dissolved in ethyl acetate. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated by column chromatography to afford compound 1c (5.8 g, 72.9% yield).

[0257] MS (ESI) m / z = 295.2 [M+H] + .

[0258] Step 3

[0259] Preparation of compound 1d

[0260] Compound 1c (5.8 g, 19.67 mmol) was dissolved in dichloromethane (100 mL), cooled to 0°C, and m-chloroperbenzoic acid (8.11 g, 39.94 mmol) was added. The mixture was warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated and dissolved in ethyl acetate. Saturated aqueous sodium sulfite was added for washing, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain compound 1d (5.4 g, 83.9% yield).

[0261] MS (ESI) m / z = 326.2 [M+H] + .

[0262] Step 4

[0263] Preparation of compound 1e

[0264] Compound 1d (5.4 g, 16.52 mmol) was dissolved in methanol (100 mL), and potassium carbonate (4.57 g, 33.05 mmol) was added at room temperature. The mixture was allowed to react for 3 hours. The reaction mixture was concentrated under reduced pressure to afford crude compound 1e (4.14 g), which was used directly in the next reaction.

[0265] MS (ESI) m / z = 213.1 [M+H] + .

[0266] Step 5

[0267] Preparation of compound 1f

[0268] Compound 1e (4.14 g, crude product) was dissolved in water (100 mL). Potassium acetate (1.62 g, 16.54 mmol) and hydroxylamine-O-sulfonic acid (3.74 g, 33.07 mmol) were added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 1f (2.0 g) was isolated and purified by column chromatography.

[0269] MS (ESI) m / z = 228.2 [M+H] + .

[0270] Step 6

[0271] Preparation of compound 1g

[0272] To a pressure-resistant tempered glass hydrogenation bottle was added (E)-3-(5-methylpyrimidin-2-yl)but-2-ene-2-sulfonamide 1f (1.3 g, 5.72 mmol), bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (46 mg, 0.114 mmol), (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(di-1-naphthylphosphino)ferrocene (48 mg, 0.114 mmol), zinc trifluoromethanesulfonate (415 mg, 1.144 mmol), and methanol (80 mL). The atmosphere in the bottle was then replaced once with nitrogen and then three times with hydrogen. Finally, the hydrogen pressure reached 45 psi and the reaction was stirred at 40°C for 24 h. The reaction mixture was filtered through celite, the filter cake was washed again with methanol (20 mL), and the filtrate was concentrated in vacuo at 35°C to obtain the crude product. The crude product was added with ethanol (25 mL), stirred at room temperature for 1 hour, and filtered. The filter cake was washed with ethanol (10 mL) and dried to obtain compound 1 g (800 mg, yield 61%, 92% ee).

[0273] MS (ESI) m / z = 230.0 [M+H] + .

[0274] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=1.0Hz,2H),6.83(s,2H),3.76–3.61(m,2H),2.25(s,3H),1.32(d,J=7.0Hz,3H),1.19(d,J=7.0Hz,3H).

[0275] Step 7

[0276] Preparation of compound 1i

[0277] Compound 1g (493.2 mg, 2.15 mmol) was dissolved in acetonitrile (13 mL). Compound 1h (400.0 mg, crude) was added at room temperature, followed by cesium carbonate (867.8 mg, 2.66 mmol). The mixture was allowed to react at room temperature for 16 hours. 2-Hydroxyacetohydrazide (193.8 mg, 2.15 mmol) and silver nitrate (696.1 mg, 4.10 mmol) were then added to the reaction mixture, and stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, washed with dichloromethane, and the filtrate was concentrated under reduced pressure. Compound 1i (600 mg, 62.9% yield) was isolated by column chromatography.

[0278] MS (ESI) m / z = 481.5 [M+H] + .

[0279] Step 8

[0280] Preparation of compound 1j

[0281] Compound 1i (600 mg, 1.25 mmol) was dissolved in isopropanol (10 mL) and water (5 mL). 1M aqueous sodium hydroxide solution (1.37 mL, 1.37 mmol) was added, and the mixture was heated to 80°C and stirred for 1 hour. After cooling to room temperature, the pH was adjusted to 5 with 1M dilute hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 1j (550 mg, 95.2% yield) was isolated by column chromatography.

[0282] MS (ESI) m / z = 463.4 [M+H] + .

[0283] Step 9

[0284] Preparation of compound 1k

[0285] Compound 1j (125 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin reagent (171.9 mg, 0.41 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a residue, which was separated by column chromatography to afford Compound 1k (90 mg, 72.3% yield) as a white solid.

[0286] MS (ESI) m / z = 461.3 [M+H] + .

[0287] Step 10

[0288] Preparation of compound 11

[0289] Compound 1k (70 mg, 0.15 mmol) was dissolved in tetrahydrofuran (5 mL), and cyclopropylmagnesium bromide (1.52 mL, 0.76 mmol) was added at 0°C. The mixture was heated to 45°C and stirred for 16 hours. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain crude compound 1l (76 mg, crude product), which was used directly in the next reaction.

[0290] MS (ESI) m / z = 503.4 [M+H] + .

[0291] Step 11

[0292] Preparation of compound 1

[0293] Compound 11 (76 mg, crude product) was dissolved in dichloromethane (5 mL), and Dess-Martin reagent (88.6 mg, 0.20 mmol) was added at room temperature. The mixture was then stirred at room temperature for 1 hour. The pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 1 (5.0 mg) was obtained by separation via C18 chromatography.

[0294] MS (ESI) m / z = 501.4 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6) δ13.77(s,1H),8.59(s,2H),7.41(s,1H),6.76(d,J=8 .6Hz,2H),3.70-3.66(m,7H),2.90(s,1H),2.23(s,3H),1.24-0.95(m,11H).

[0296] Preparation of compound 1h

[0297] Dissolve 1,3-dimethoxyaniline (5.0 g, 32.64 mmol) in dichloromethane (50 mL) and water (50 mL). Add sodium bicarbonate (5.48 g, 65.28 mmol) at room temperature. Then cool to 0°C and slowly add thiophosgene (2.75 mL, 35.91 mmol) dropwise. Stir at 0°C for 1 hour. Extract with dichloromethane (30 mL x 3). The organic phases are combined, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The filtrate is concentrated to afford compound 1h (6.0 g, crude product), which is used directly in the next reaction.

[0298] MS (ESI) m / z = 196.2 [M+H] + .

[0299] Example 2

[0300] (2S,3R)-N-(5-Benzoyl-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0301] Compound 2 was synthesized from intermediate 1k and phenylmagnesium bromide according to the route of compound 1.

[0302] MS (ESI) m / z = 537.3 [M+H] + .

[0303] 1 H NMR (400MHz, DMSO-d6) δ13.81(s,1H),8.59(s,2H),8.01(d,J=7.7Hz,2H),7.75(t,J=7.3Hz,1H),7.60(t,J=7.6Hz,2H),7. 43(t,J=8.4Hz,1H),6.79(dd,J=8.9,2.7Hz,2H),3.70–3.62(m,7H),2.23(s,3H),1.26–1.23(m,4H),1.12(d,J=6.8Hz,3H).

[0304] Example 3

[0305] (2S,3R)-N-(5-(cyclobutanecarbonyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0306] first step

[0307] Preparation of compound 3b

[0308] Cyclobutanone 3a (1.0 g, 14.13 mmol) was dissolved in methanol (25 mL). N-amino-4-methylbenzenesulfonamide (2.6 g, 14.27 mmol) was added at room temperature and stirred for 16 hours. The reaction mixture was concentrated to obtain a residue which was separated by column chromatography to afford compound 3b (2.8 g, 82.3% yield).

[0309] MS (ESI) m / z = 239.2 [M+H] + .

[0310] Step 2

[0311] Preparation of compound 3

[0312] Compound 3b (34.1 mg, 0.14 mmol) and compound 1k (60.0 mg, 0.13 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (106.1 mg, 0.33 mmol) was added at room temperature. The atmosphere was then replaced with nitrogen three times, the temperature was raised to 110°C, and stirring was continued under nitrogen for 16 hours. After cooling to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a residue, which was separated by C18 chromatography to afford compound 3 (20.0 mg, 29.8% yield).

[0313] MS (ESI) m / z = 515.4 [M+H] + .

[0314] 1 H NMR (400MHz, DMSO-d6) δ13.67(s,1H),8.58(s,2H),7.43(t,J=8.5Hz,1H),6.79(dd,J=8.4,2.2Hz,2H),4.07(m,1H),3.67(s,6H),3.65-3 .55(m,2H),2.23(s,3H),2.20–2.08(m,4H),2.07–1.93(m,1H),1.75(tq,J=9.6,4.5Hz,1H),1.22(d,J=7.0Hz,3H),1.07(d,J=6.9Hz,3H).

[0315] Example 4

[0316] (2S,3R)-N-(5-(cyclopentanecarbonyl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide

[0317] N-(Cyclopentylideneamino)-4-methylbenzenesulfonamide 4a (27.4 mg, 0.11 mmol) and compound 1k (50 mg, 0.11 mmol) were dissolved in 1,4-dioxane (3 mL), and cesium carbonate (88.4 mg, 0.27 mmol) was added at room temperature. The atmosphere was then replaced with nitrogen three times, the temperature was raised to 110°C, and the mixture was stirred under nitrogen for 16 hours. After cooling to room temperature, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a residue, which was separated by C18 chromatography to afford compound 4 (18.0 mg, 31.4% yield).

[0318] MS (ESI) m / z = 529.4 [M+H] + .

[0319] 1 H NMR (400MHz, DMSO-d6) δ13.70(s,1H),8.59(s,2H),7.42(t,J=8.5Hz,1H),6.78(dd,J=8.4,2.3Hz,2H),3.76(dd,J=11.3,4.7Hz,1H ),3.67(s,6H),3.65-3.55(m,2H),2.24(s,3H),1.91–1.79(m,2H),1.72–1.49(m,6H),1.23(d,J=7.0Hz,3H),1.09(d,J=6.8Hz,3H).

[0320] Example 5

[0321] N-cyclopropyl-4-(2,6-dimethoxyphenyl)-5-((1S,2R)-1-methyl-2-(5-methylpyrimidin-2-yl)propyl)sulfonamido)-4H-1,2,4-triazole-3-carboxamide

[0322] first step

[0323] Preparation of compound 5a

[0324] Compound 1j (50.0 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), water (2 mL), and ethyl acetate (1 mL). Ruthenium trichloride trihydrate (4.5 mg, 0.02 mmol) and sodium periodate (115.6 mg, 0.54 mmol) were added at room temperature. The mixture was then stirred at room temperature for 5 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain crude compound 5a (51.5 mg, 100% yield).

[0325] MS (ESI) m / z = 477.6 [M+H] + .

[0326] Step 2

[0327] Preparation of compound 5

[0328] Compound 5a (51.5 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL). Cyclopropylamine (18.5 mg, 0.32 mmol), diisopropylethylamine (0.072 mL, 0.43 mmol), and n-propylphosphoric anhydride (0.17 mL, 0.32 mmol, 50% ethyl acetate solution) were added at room temperature. The mixture was then stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a residue, which was separated by C18 chromatography to afford compound 5 (4.1 mg, 7.4% yield).

[0329] MS (ESI) m / z = 516.5 [M+H] + .

[0330] Biological evaluation

[0331] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0332] Test Example 1. Human APJ cAMP assay

[0333] Cell culture:

[0334] 1) Remove the CHO-K1 human APJ stable expression cell line (cell source: ATCC) from the incubator and observe the cell status;

[0335] 2) When the cell density reaches 80% to 90%, discard the culture medium and wash the cells with 5 mL of DPBS;

[0336] 3) Aspirate DPBS, then add 3 mL of 0.25% trypsin-EDTA, and then incubate the cells at 37°C for 2-5 minutes;

[0337] 4) Add 10 mL of complete culture medium to the culture plate, centrifuge at 1000 rpm for 4 minutes to collect the cells, and then remove the supernatant;

[0338] 5) Adjust the cell suspension to an appropriate density using stimulation buffer.

[0339] Stimulation Buffer:

[0340] cAMP test:

[0341] 1) The compound was serially diluted using the liquid handling station Echo, starting at a final concentration of 1 μM, followed by 4-fold dilutions, 10 concentrations, and duplicate wells for each concentration;

[0342] 2) Add 10 μL of CHO-K1 human APJ cell solution to a 384-well plate, 5000 cells / well;

[0343] 3) Centrifuge the 384-well plate at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes;

[0344] 4) Use Lane Ultra cAMP kit (Perkin Elmer #TRF0264) for detection, add 5 μL Eu-cAMP tracer solution and 5 μL ULight TM -anti-cAMP solution;

[0345] 5) Centrifuge the 384-well plate at 600 rpm for 3 minutes and incubate at room temperature for 60 minutes;

[0346] 6) Envision was used to detect cAMP signals, and GraphPad Prism 6.0 software was used for data analysis.

[0347] Table 1. APJ cAMP test results of the disclosed compounds

[0348] Test Example 2. Stability test of compounds in hepatocytes

[0349] 1. Experimental steps

[0350] 1) Prepare a high-concentration stock solution of the test substance in DMSO and dilute it to a 100 μM working solution with acetonitrile-water (v:v = 1:1) before use. The final concentration of the test substance is 1 μM.

[0351] 2) Take a tube of cryopreserved hepatocytes (mouse, rat, canine, and human hepatocytes from BioIVT, monkey hepatocytes from RILD) and ensure they remain frozen before thawing. Quickly place the hepatocytes in a 37°C water bath and gently shake until all ice crystals are dispersed. Spray with 70% ethanol and transfer to a biosafety cabinet.

[0352] 3) Pour the contents of the hepatocyte tubules from different species into a centrifuge tube containing 50 mL of recovery medium and centrifuge at 100 g for 10 minutes. After centrifugation, aspirate the recovery medium and add enough incubation medium to obtain a cell density of approximately 1.0 × 10 6 cells / mL of cell suspension.

[0353] 4) Count the hepatocytes and determine the viable cell density using a Cellometer Vision. The viability of the hepatocytes must be greater than 75%. Dilute the hepatocyte suspension with incubation medium to a viable cell density of 0.5 × 10 6 cells / mL.

[0354] 5) Transfer 198 μL of the live cell suspension to a 96-well deep-well plate. Place the plate on a vortex and preheat in an incubator for 10 minutes. Perform the experiment in duplicate.

[0355] 6) Add 2 μL of 100 μM test substance to each well to initiate the reaction, and place the deep-well plate back on the incubator vortexer.

[0356] 7) Incubate the sample. At 0, 15, 30, 60, 90, and 120 minutes, aspirate 25 μL of the suspension and terminate the reaction by adding 150 μL of acetonitrile containing the internal standard. Vortex for 10 minutes and centrifuge at 3220 g at 4°C for 45 minutes. Transfer 100 μL of the supernatant to the injection plate and mix thoroughly with 100 μL of purified water for UPLC-MS / MS analysis.

[0357] 2. Data Analysis

[0358] All data calculations were performed using Microsoft Excel. Peak areas were determined by extracted ion chromatograms. In vitro clearance of the parent drug was determined by linear fitting the natural logarithm of the parent drug elimination percentage versus time.

[0359] In vitro clearance (μL / min / 10 6 cells) were calculated using the following formula:

[0360] In vitro CL int =kV / N

[0361] V = incubation volume per well (0.2 mL);

[0362] N = number of cells per well (0.1 × 10 6 cells)

[0363] Table 2. Metabolic clearance CL of compounds in hepatocytes int (μL / min / 10 6 cells)

[0364] Judging from the results, compound 1 has a significant advantage over BGE-105 in metabolic stability in mouse, rat, dog, monkey and human liver cells.

[0365] BGE-105 Prepared according to the method provided in WO2016187308 A1.

[0366] Pharmacokinetic evaluation

[0367] 1. Pharmacokinetics of the compounds of the present invention in mice

[0368] C57BL / 6J female mice were used as test animals. The drug concentrations in plasma at different time points after oral administration of Example 1 and BGE-105 were determined by LC / MS / MS to study the pharmacokinetic behavior of the disclosed compounds in mice and evaluate their pharmacokinetic characteristics.

[0369] Experimental animals:

[0370] Four C57BL / 6J female mice were equally divided into two groups and purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. with animal production license number: SCXK (Zhejiang) 2019-0001.

[0371] Drug preparation:

[0372] A certain amount of compound was weighed and dissolved in a solvent of 10% DMSO / 60% PEG400 / 30% normal saline to prepare a 2 mg / mL colorless clear solution.

[0373] Dosage:

[0374] The drug was administered orally to C57BL / 6J female mice (freely fed) at a dose of 20 mg / kg and a dosing volume of 0.1 mL / 10 g.

[0375] operate:

[0376] Mice were orally administered with the drug, and 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0 hours after administration. The blood was placed in an EDTA-K2 tube and centrifuged at 4000 g for 5 minutes. The plasma was separated and stored at -80°C.

[0377] Determine the content of the test compound in mouse plasma after injection of different concentrations of the drug: take 10 μL of mouse plasma at each time point after administration, add 200 μL of acetonitrile solution containing internal standard solution verapamil (2 ng / mL) and dexamethasone (50 ng / mL) (China National Institute for the Control of Biological Products), vortex mix for 30 seconds, centrifuge for 15 minutes (3900 RPM), take 100 μL of the supernatant, add 200 μL of aqueous solution to the sample injection plate, vortex mix for 30 seconds, aspirate 2 μL of liquid, and perform LC / MS / MS analysis.

[0378] Table 3. Pharmacokinetic parameters of the compounds disclosed herein

[0379] Note: NA means not available.

[0380] The data in Table 3 show that the pharmacokinetic performance and drug plasma exposure of the compound of Example 1 under oral administration are significantly better than those of BGE-105.

[0381] 2. Pharmacokinetics of the compounds disclosed in this invention in dogs

[0382] Beagle dogs (Source: Beijing Masi Biotechnology Co., Ltd.) were used as test animals. LC / MS / MS was used to determine plasma drug concentrations at different times after oral administration of the test substance. The pharmacokinetic behavior of the test substance in beagle dogs was studied and its pharmacokinetic characteristics were evaluated.

[0383] Experimental animals: Each group consisted of one healthy male and one female beagle dog aged 8 months to 3 years (6.0-13.0 kg).

[0384] Drug preparation: Weigh a certain amount of compound and dissolve it in a solvent of 5% DMSO / 40% PEG400 / 55% saline to prepare a 0.4 mg / mL colorless clear solution.

[0385] Administration: Beagle dogs were fasted overnight and then gavage was performed to administer the test substance at a dose of 2 mg / kg.

[0386] Procedure: Beagle dogs were orally administered with the test substance. Approximately 0.6 mL of blood was collected by peripheral venipuncture before administration and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in a tube containing EDTA-K2 and centrifuged at 2000 g per minute for 10 minutes at about 4°C to separate the plasma, which was then stored at -75±15°C.

[0387] Determination of the test compound content in beagle dog plasma after oral administration of the test substance: 50 μL of beagle dog plasma at each time point after administration was taken, 5 μL of blank solution and 200 μL of acetonitrile solution containing internal standard dexamethasone were added, and the mixture was vortexed for 30 seconds and centrifuged for 15 minutes (3900 rpm). 100 μL of the supernatant of the plasma sample was added to 200 μL of ultrapure water and mixed evenly. Then, 5 μL of the dilution was injected into the syringe for LC / MS / MS analysis.

[0388] Table 4. Pharmacokinetic parameters of the compound after oral administration to dogs (2 mpk)

[0389] From the results, the oral exposure of compound 1 in dogs is significantly better than that of BGE-105.

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof, in, Ring C is a 3- to 12-membered cycloalkyl group or a 4- to 10-membered heterocycloalkyl group; R 9 each independently selected from deuterium, halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more R B Substituted, the R B is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy; Ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 2 each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally replaced by one or more R D Substituted, the R D is selected from deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl and C1-C6 alkoxy; R 3 is hydrogen or C1-C6 alkyl; R 4 、R 5 、R 6 and R 7 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy are each independently optionally substituted with one or more deuterium, halogen and hydroxy; Ring B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; R 8 each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl and -NR'R", said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl are each independently optionally substituted by one or more R E Substituted, the R E Selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy; Said R' and R" are each independently hydrogen or C1-C6 alkyl; m, n and p are each independently selected from 0, 1, 2, 3 and 4.

2. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, in, Ring A, Ring B, R 2 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 , p, m and n are as defined in claim 1, and t is selected from 1, 2, 3 and 4.

3. The compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from 4. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Ring A is phenyl, and ring C is cyclopropyl.

5. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 are each independently selected from deuterium, halogen, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3 to 6 membered cycloalkyl and -NR'R", wherein the C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy are each independently optionally substituted by one or more R D Substituted, the R D is selected from deuterium, halogen, C1-C6 alkyl and C1-C6 alkoxy, wherein R' and R" are each independently methyl or ethyl; Preferably, R 2 Each independently selected from halogen, cyano, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, methylamino, dimethylamino and deuterated methoxy; More preferably, R 2 Each independently selected from fluorine, chlorine, bromine, methoxy and deuterated methoxy; m is selected from 0, 1, 2 and 3.

6. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: Selected from Preferably, 7. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 3 For hydrogen.

8. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4 and R 6 are each independently hydrogen; R 5 and R 7 Each is independently selected from hydroxy, C1-C3 alkyl and C1-C3 alkoxy, and the C1-C3 alkyl and C1-C3 alkoxy are each independently optionally substituted with one or more hydroxy groups; Preferably, R 5 and R 7 each independently selected from hydroxy, methyl, methoxy, ethoxy, isopropoxy and hydroxyethoxy; More preferably, R 5 and R 7 are each independently methyl.

9. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein Selected from Preferably, 10. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: Ring B is phenyl or a 5- to 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O and S, preferably a phenyl group or a 6-membered nitrogen-containing heteroaryl group, more preferably, ring B is selected from phenyl, pyrimidinyl and pyridinyl.

11. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein: R 8 Each independently selected from deuterium, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, 3 to 6-membered cycloalkyl and -NR'R", said C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R E Substituted, the R E Selected from halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl and halo-C1-C6 alkoxy; Preferably, R 8 Each is independently selected from deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy and 3 to 6-membered cycloalkyl are each independently optionally substituted by one or more R E Substituted, the R E is deuterium or a halogen; More preferably, R 8 are each independently selected from deuterium, C1-C3 alkyl, C1-C3 alkoxy, fluorine, chlorine, bromine and cyano, wherein the C1-C3 alkyl and C1-C3 alkoxy are each independently optionally substituted by one or more R E Substituted, the R E for deuterium; n is selected from 0, 1, 2 or 3.

12. The compound of formula (II) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, in, Selected from Preferably, 13. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is a compound of formula (II-1-A) or a pharmaceutically acceptable salt thereof, in, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D each independently hydrogen or deuterium; R 9 is selected from the group consisting of deuterium, fluorine, methyl, ethyl, trifluoromethyl and cyclopropyl; R 8 are each independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine, chlorine, bromine and cyano; p and n are each independently selected from 0, 1, 2 and 3; Preferably, R 1D 、R 2D 、R 3D 、R 4D 、R 5D and R 6D All are hydrogen or all are deuterium; R 9 selected from deuterium, fluorine and methyl; R 8 Each is independently selected from deuterium, methyl, deuterated methyl, methoxy, deuterated methoxy, fluorine and chlorine; p is selected from 0, 1 and 2; n is selected from 0, 1, 2 and 3.

14. The compound of formula (II) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, 15. An isotope substituted compound of the compound of formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14; preferably, the isotope substituted compound is a deuterated compound.

16. A pharmaceutical composition comprising the compound of formula (II) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and / or the isotope substitution according to claim 15 and at least one pharmaceutically acceptable excipient.

17. Use of the compound of formula (II) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and / or the isotope substituted product according to claim 15, and / or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing and / or treating cardiovascular diseases, nervous system diseases, improving myocardial contractility or increasing ejection fraction, preventing and / or treating obesity or diabetes, preventing and / or treating diabetic nephropathy or chronic kidney disease.

18. The use according to claim 17, wherein The cardiovascular disease is selected from the group consisting of stroke, myocardial infarction, heart failure, hypertension, coronary heart disease and atherosclerosis; The neurological disease is selected from Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis; Preferably, the heart failure is selected from the group consisting of heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, chronic systolic heart failure, chronic diastolic heart failure and acute heart failure.

19. Use of the compound of formula (II) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and / or the isotope-substituted product according to claim 15, and / or the pharmaceutical composition according to claim 16 in the preparation of a medicament for a disease associated with activated APJ receptors.

20. A method for preparing a compound of formula (1) or a pharmaceutically acceptable salt or isotope-substituted product thereof, comprising the steps of oxidizing a compound of formula (11) or a pharmaceutically acceptable salt thereof to obtain a compound of formula (1) or a pharmaceutically acceptable salt thereof. Optionally, further comprising a compound represented by formula (1k) or a pharmaceutically acceptable salt thereof and a Grignard reagent The step of reacting to obtain a compound represented by formula (11) or a pharmaceutically acceptable salt thereof, wherein X is a halogen, preferably bromine; and / or, optionally, further comprising the step of oxidizing the compound represented by formula (1j) or a pharmaceutically acceptable salt thereof to obtain the compound represented by formula (1k) or a pharmaceutically acceptable salt thereof, 21. A compound as shown below or a pharmaceutically acceptable salt thereof,

Images