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1. (WO2019032720) APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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What is claimed is:

1. A compound of structural Formula I, or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof:


(I)

wherein:

R1 and R2 are each independently selected from the group consisting of H, halogen, cyano, optionally substituted alkyl, aryl, alkoxy, phenoxy, amino, aniline, -C02H, -C02R6, or-CON(R7)2 ;

R3 is selected from the group consisting of hydrogen, -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

R4 is selected from the group consisting of hydrogen, -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

R5 is selected from the group consisting -C02H, -C02R8, or-CON(R9)2; optionally substituted alkyl, aryl, and alkoxy; and

R6- R9 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, optionally substituted amino, and optionally substituted 5- or 6-membered heteroaryl. 2. A compound selected from the group consisting of methyl 7-(tert-butyl)-2-methyl-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 7-(tert-butyl)-2-methyl-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2,7-dimethyl-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2-methyl-7-(methylethyl)-3-(4-methylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 7-cyclopropyl -2 -methyl - 3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(4-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(4-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(4-methoxyphenyl)-2-methyl-5-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-7-carboxylic acid, ethyl 2-cyclopropyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2-cyclopropyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2-ethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2-methyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxamide, N-methyl[2-methyl-7-(methylethyl)-3-phenyl(8-hydropyrazolo[l,5-a]pyrimidin-5-yl)]carboxamide, N,N-dimethyl[2-methyl-7-(methylethyl)-3-phenyl(8-hydropyrazolo[l,5-a]pyrimidin-5-yl)]carboxamide, 2-{[2-methyl-7-(methylethyl)-3 -phenyl -8-hydropyrazolo[l,5-a]pyrimidin-5-yl]carbonylamino}acetic acid, ethyl 3-(3-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2-chlorophenyl)-2-methyl-7-(m ethyl ethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2-methyl-7-(methylethyl)-3-(2-methylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(3-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(3-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(3-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 2-methyl-7-(methylethyl)-3-(3-methylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2-methyl-7-(methylethyl)-3-(3-methylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(3-chlorophenyl)-2-methyl-7-(m ethyl ethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(3-chlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 7-ethyl-2-methyl-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 7-ethyl-2-methyl-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 2-methyl-3-phenyl-7-propyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2-methyl-3-phenyl-7-propyl-8-

hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 2,6-dimethyl-7-(m ethyl ethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2,6-dimethyl-7-(methylethyl)-3-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2,6-dimethoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 4-(methylethyl)-5,7,8,9, 10-pentahydro-5H-pyrimidino[l,2-b]indazole-2-carboxylic acid, ethyl 3-(2,4-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,4-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(4-methoxy-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(4-fluoro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(4-methoxy-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(6-fluoro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(4-fluoro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(6-fluoro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-propyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-propyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2,7-dimethyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2,7-dimethyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-7-ethyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2,6-dimethylphenyl)-7-cyclopropyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2,6-dimethylphenyl)-7-cyclobutyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-cyclobutyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, [3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidin-5-yl]methan-l-ol, l-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)(8-hydropyrazolo[l,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan-l-ol, l-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)(8-hydropyrazolo[l,5-a]pyrimidin-5-yl)]-2,2,2-trifluoroethan-l-one, ethyl 3-(6-methoxy-2- methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(4-chloro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-[2-(ethoxycarbonyl)-6-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-cyclopentyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-7-cyclopentyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(4-chloro-2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-cyclopropyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-ethyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 2,7-bis(methylethyl)-3-(2,6-dimethylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-ethyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-m ethyl -7-(methyl ethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carbohydroxamic acid, 3-(2-methoxy-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-[6-(ethoxycarbonyl)-2-methylphenyl]- 2- methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-7-(methylethyl)-2-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate,

3- (2,6-dimethylphenyl)-7-(methylethyl)-2-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2,7-bis(methylethyl)-3-(2,6-dimethylphenyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-cyclobutyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-phenyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-cyclopropyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2-carboxy-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-(hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-(hydroxymethyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-2-(methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-(methoxymethyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 2-[(dimethylamino)methyl]-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(6-fluoro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(6-fluoro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-

hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(6-chloro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(6-chloro-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-2-(methoxycarbonyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-2,5-dicarboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-morpholin-4-yl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-morpholin-4-yl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-methoxy-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 2-(N,N-dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 2-(N,N-dimethylcarbamoyl)-3-(2,6-dimethylphenyl)-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-(methylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 7-(dimethylamino)-3-(2,6-dimethylphenyl)-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-difluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-difluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-(4-methylpiperazinyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-m ethyl -7-phenoxy-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-(4-methylpiperazinyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2,6-dimethylphenyl)-2-methyl-7-phenoxy-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-ylamine, N-[3-(2,6-dimethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidin-5-yl]acetamide, ethyl 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2-chloro-6-fluorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-dichlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dichlorophenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2,6-diethylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, ethyl 3-(2,6-dimethylphenyl)-2-m ethyl -7-(phenylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-(phenylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(6-chloro-2-methoxyphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2-cyano-6-fluorophenyl)-2-methyl-7- (methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(6-ethyl-2-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-pyrrolidinyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-pyrrolidinyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-piperidyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-piperidyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-(4-pyridyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-cyclopent-l-enyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-[6-(hydroxymethyl)-2-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, ethyl 3-(2-bromo-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2-bromo-6-methylphenyl)-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-[6-(methoxymethyl)-2-methylphenyl]-2-methyl-7-(methylethyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-7-[(4-chlorophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-[(4-methylphenyl)amino]-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-7-[(4-methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-{[4- (trifluoromethyl)phenyl]amino}-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-7-[(4-cyanophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-[(4-chlorophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-[(4-methylphenyl)amino]-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-[(4-methoxyphenyl)amino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethyl)phenyl]amino}-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-{[4-(trifluoromethoxy)phenyl]amino}-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-[(4-cyanophenyl)amino]-2-methyl-8-hydropyrazolo[l,5-

a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-(methylphenylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, methyl 3-(2,6-dimethylphenyl)-2-m ethyl -7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[ 1,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-[methyl(4-methylphenyl)amino]-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-[(4-fluorophenyl)methylamino]-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-piperazinyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-2-methyl-7-(methylpropylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-cyclohex-l-enyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-cyclohexyl-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, 3-(2,6-dimethylphenyl)-7-(2-furyl)-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid, methyl 3-(2,6-dimethylphenyl)-2-methyl-7-(methylpropylamino)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate, 3-(2,6-dimethylphenyl)-2-methyl-7-(4-l, 2,5,6-tetrahydropyridyl)-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylic acid and methyl 3-(2,6-dimethylphenyl)-7-chloro-2-methyl-8-hydropyrazolo[l,5-a]pyrimidine-5-carboxylate.

3. A pharmaceutical composition comprising a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

4. A method of preventing or treating in a subject an apelin-mediated disease or disorder, comprising administering to the subject a pharmaceutical a compound of claim 1 or 2, thereby preventing or treating the disease or disorder.

5. The method of claim 4, wherein the disease or disorder is a cardiovascular disease or disorder, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction, left ventricular dysfunction after myocardial infarction, cardiac hypertrophy, myocardial remodeling, myocardial remodeling after infarction, myocardial remodeling after cardiac surgery or valvular heart disease.

6. The method of claim 4, wherein the disease or disorder is a metabolic disease or disorder, metabolic syndrome, insulin resistance, diabetes mellitus, diabetic late complications, diabetic macro- and micro-vasculopathies, diabetic nephropathy, diabetic retinopathy, diabetic neuropathies or cardiac autonomic neuropathy.

7. The method of claim 4, wherein the disease or disorder is caused by CNS- dependent or CNS-independent disturbed fluid homeostasis, acute or chronic renal failure, hypertension, pulmonary hypertension, portal hypertension or systolic hypertension.

8. The method of claim 4, wherein the disease or disorder is a vascular disease or disorder, vascular permeability, nonfunctional blood vessels, vascular hypertrophy, vascular remodeling, vascular stiffness, atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis, thrombosis, vascular permeability disorders, ischemia, reperfusion damage, ischemia or reperfusion damage of the heart, kidney or retina, or a combination thereof.

9. The method of claim 4, wherein the disease is an infectious disease.