A class of tri-substituted triazine and pyrimidine derivativeshas been characterized as hepatitis C virus (HCV) inhibitors that interfere with the viral entry process.  Previous studies established the SARs associated with the substitution pattern of the triazine/pyrimidine core on antiviral activity.  In this study, the impact of structural variation of the benzamide moiety was investigated.  The results revealed that a variety of functional groups were tolerated and EC50 values reached sub-nM for optimized compounds.  Additionally, subtle changes were found to lead to significant alteration of potency.  For example, moving the two terminal methyl groups from the 1,3-propyl diamine moiety in 4-((4-((4-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(3-(diethylamino)propyl)benzamide to the middle of the 1,3-propyl diamine fragment, as in 4-((4-((4-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(3-(dimethylamino)-2,2-dimethylpropyl)benzamide, led to an improvement of 4-6 fold in activity against genotype 1a/1b HCV subtypes.

Novel hepatitis C virus entry inhibitors, part 3: Triazine- and pyrimidine-containing aryl amides

245th National Meeting (2013)

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