SAR studies on a series of N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamides: Potent inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus

Described herein is the initial optimization of (+/−) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)piperazine-2-carboxamide (1), a hit discovered in a high throughput screen run against the NS5B polymerase enzyme of the hepatitis C virus. This effort resulted in the identification of (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)phenylsulfonyl)piperazin-1-yl)pyridazine-3-carboxamide (2), that displayed potent replicon activities against HCV genotypes 1b and 1a (EC50 1b/1a = 7/89 nM).

Graphical abstractDescribed herein is the initial optimization of the screening hit (+/−) N-benzyl-4-heteroaryl-1-(phenylsulfonyl)-piperazine-2-carboxamide (1) that led to the discovery of the potent NS5B inhibitor (S)-N-sec-butyl-6-((R)-3-(4-(trifluoromethoxy)benzylcarbamoyl)-4-(4-(trifluoromethoxy)-phenylsulfonyl)-piperazin-1-yl)pyridazine-3-carboxamide (2).Figure optionsDownload full-size imageDownload as PowerPoint slide