Apelin receptor (APJ) agonists and uses thereof

A method of therapeutically treating one or more of acute decompensated heart failure (ADHF), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, burn injuries, sunburn, cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, ischemic heart failure, diabetes, gestational diabetes, dyslipidemia, HIV neurodegeneration, hypertension, pulmonary arterial hypertension, inflammation, ischemic cardiovascular diseases, liver disease, alcoholic liver disease, toxicant-induced liver disease, viral-induced liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, pulmonary hypertension, renal dysfunction, polycystic kidney disease, restenosis, transient ischemic attacks, traumatic brain injuries, vein-related disorders, pulmonary veno-occlusive disease, angioma, venous insufficiency, stasis, thrombosis, ventricular tachycardia, and water retention in a patient in need thereof, comprising administering a therapeutically effective amount of a compound represented by the Formula IV:

• or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a salt of a prodrug thereof,
• wherein
• R1 is represented by the formula:
• wherein
• is a monocyclic aryl or heteroaryl group;
• each A is independently fluoro substituted C1-C3 alkoxy, or fluoro substituted C1-C3 alkyl;
• n is 1 or 2;
• R2 is optionally substituted C3-8 alkyl, optionally substituted C1-8 alkyl (C3-8 cycloalkyl), optionally substituted C3-8 cycloalkyl, or optionally substituted heteroaryl;
• R3 is absent;
• R4 is optionally substituted C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, C2-8 alkyl(aryl), C1-8 alkyl(C3-8 cycloalkyl), C1-8 alkyl(heteroaryl), or (CH2)xNR7R8;
• R5 is optionally substituted adamantanyl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl(C3-8 cycloalkyl), C1-8 alkyl(C3-8 cycloalkyl)-CO2R7, C1-8 alkyl(guanidinyl), C1-8 alkyl(heteroaryl), C1-8 alkyl(tetrazol-5-one), C2-4 alkyl(heterocycloalkyl), C1-8 alkyl(thioether), C1-8 alkyl(thiol), C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, NHCO2R7, (CH2)x SO2NR7R8, or (CH2)xxCO2R7;
• R6 is H;
• or
• R4 and R5 together make a 5-8 member nitrogen-containing ring with one or more carbonyl groups;
• R7 and R8 each are independently H, C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl tetrazol-5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, 01-8 alkyl thiol, C2-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl;
• or
• R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms;
• or
• R7 and R8 together make a 5-8 member nitrogen-containing ring with one or more carbonyl groups;
• R9 is H, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, aryl, heteroaryl, or hydroxyl;
• each x is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
• each xx is independently 1, 2, 3, 4, 5, 6, 7, or 8;
• each y is independently 1, 2, 3, 4, 5, 6, 7, or 8;
• and
• Z is =0.