We next explored the ability of various phenyl derivatives in R2 to optimize the compound binding profile, while maintaining a difluorophenol group in R1 (Table ). Our results confirmed that polar groups in R2 are important for binding the VRKs and indicated that, overall, these groups were better tolerated in the meta position (10 vs. 11; 12 vs. 13; 14 vs. 15 and 16), although the addition of a carboxylic group in this position was detrimental to binding (17). For VRK2-KD, the best compound had a para-sulfonamide group on the R2 phenyl ring (18), although a benzothiazole fused ring (19) was also tolerated in this position. VRK1-FL tolerated both of these groups in R2 equally well. Nevertheless, for VRK1, we could not find a R2 substituent that improved on the difluorophenol moiety (5). For VRK2-KD, further attempts to modify the difluorophenol in R1 while maintaining the sulfonamide group in R2 were unsuccessful (20, 21 and 22).