gem-Difluorinated Saturated O-Heterocycles – Promising Fragments for Bioisosteric Replacements in Drug Discovery

A comprehensive study on the physicochemical properties of gem-fluorinated O-heterocyclic substituents is reported. Systematic additive effects of introducing O- and gem-CF2 group introduction on acidic properties (pKa) of the corresponding carboxylic acids / protonated primary amines was demonstrated. The impact of the O/CF2 moieties on lipophilicity (LogP) were found to be complex; significant mutual influence of the corresponding polar moieties governed the compound’s overall properties in this case. Biological evaluation of MAPK kinase inhibitors incorporating the title substituents demonstrated their utility as promising fragments for bioisosteric replacements in drug discovery campaigns.