Kinetic aqueous solubility of compounds 10a-f correlated with the LogD7.4 data: more lipophilic gem-difluorinated representatives were by 30-100 μM less soluble in PBS as compared to non-fluorinated counterparts. Metabolic stability (measured as intrinsic clearance, CLint) demonstrated 1.5-fold improvement for some representatives (14 and 15 µL/min/mg for 10e and 10f vs 23 µL/min/mg for 10a). Importantly, the potency of all the fluorinated derivatives against human recombinant fulllength p38α MAPK remained in the nanomolar range, albeit 5-to 8-fold decrease was observed. These results show that gemdifluorinated O-heterocyclic substituents discussed in this work can indeed be used for isosteric replacements in medicinal chemistry.