Patent NZ-603884-A (NZ)
Title: Soluble guanylate cyclase activators
Inventor: RAGHAVAN SUBHAREKHA
IPC: A61K31/4015
Filed: 2011-05-24
Abstract: Disclosed are 4-amino-5-methyl-2-[heteroaryl]-5-((hetero)aryl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one derivatives as represented by the general formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is a bicyclic heteroaryl group as defined herein; each Rx and Ry is independently H, cycloalkyl, or alkyl; each R1 is independently H, halo, OR, alkyl, monocyclic aryl, 5- or 6- membered heterocyclyl containing 1-4 N, O or S heteroatoms, 5- or 6-membered heteroaryl containing 1-4 N, O or S heteroatoms, cycloalkyl, CN, NRaC(O)Rb, or -C(O)NRaRb, said aryl, heteroaryl, and cycloalkyl optionally being substituted with one to three substituents selected from halo, alkyl, -OR, -CN, and -CF3; R2 is -(CRd2)t-alkyl, alkenyl, alkynyl, -(CRd2)t-OR, -(CRd2)t-SR, -(CRd2)t-CF3, -(CRd2)t-cycloalkyl, -(CRd2)t-aryl wherein the aryl is a monocyclic ring, -(CRd2)t-heterocyclyl, wherein the heterocyclyl is a 5- or 6-membered ring containing 1-4 N, O or S heteroatoms or -(CRd2)t-heteroaryl, wherein heteroaryl is a 5- or 6-membered ring containing 1-4 N, O or S heteroatoms, said alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl being optionally substituted with one to three substituents selected from halo, alkyl, CF3, CN or -OR; R3 is -(CRd2)t-aryl, wherein the aryl is a monocyclic ring, -(CRd2)t-heteroaryl, wherein heteroaryl is a 5- or 6-membered ring containing 1-4 N, O or S heteroatoms, -(CRd2)t-heterocyclyl, wherein the heterocyclyl is a 5- or 6-membered ring containing 1-4 N, O or S heteroatoms, -(CRd2)t-cycloalkyl, -(CRd2)t-CN, -(CRd2)t-C(O)NRaRb, -(CRd2)t-NRaC(O)Rb, -(CRd2)t-C(S)NRaRb, -(CRd2)t-C(O)ORa, -(CRd2)t-NRaC(O)NRb, -(CRd2)t-NRaC(O)ORa, -(CRd2)t-NRaRb, or -ORa, said, aryl, heteroaryl or heterocyclyl are optionally substituted with from one to three substituents selected from R5; R4 is alkyl, cycloalkyl, halo or CF3; m is an integer selected from 1, 2, or 3; and wherein the remaining substituents are as defined herein. Representative compounds include 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-N-cyclopropyl-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-5-cyclopropyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-5-methyl-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(1,3,4-thiadiazol-2-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, 4-amino-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, 4-amino-5-methyl-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidin-2-yl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, 4-amino-5-(1-ethyl-1H-1,2,3-triazol-4-yl)-5-methyl-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, 4-amino-5-[1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl]-5-methyl-2-[1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one, 4-amino-N-cyclopropyl-5-methyl-6-oxo-2-[1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-5-methyl-6-oxo-N-(pyridin-3-yl)-2-[1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, 4-amino-N-cyclopropyl-5-methyl-2-[6-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and 4-amino-N-cyclopropyl-2-[6-methoxy-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. Also disclosed is a pharmaceutical composition comprised of a compound as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for treatment of one or more conditions selected from cardiovascular disease, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, heart failure, pulmonary hypertension, pulmonary arterial hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes or cirrhosis of the liver in a patient.