Fluorination of cyclic compounds represents a potent strategy in drug discovery, offering fine control over physicochemical properties and pharmacological profiles. In this work, we demonstrated this by a comprehensive study of gemdiflurinated saturated O-heterocyclic building blocks (carboxylic acids and primary amines) along with their non-fluorinated and carbocyclic counterparts. Increments of introducing an Oxygen atom or a gem-CF2 group to the compound's physicochemical properties were established for each position of five-and sixmembered saturated ring. It was found that whereas for acidity (pKa), these increments demonstrated additivity and correlated with the substituent's inductive effects, for lipophilicity (LogP), a more complex behavior was characteristic. In particular, while gem-fluorination of cyclohexane-and cyclopentane-derived amides typically led to decrease in their lipophilicity, gem-difluorinated O-heterocyclic derivatives were typically more lipophilic than their non-fluorinated counterparts. Finally, we demonstrated potential of gem-difluorinated O-heterocyclic substituents for bioisosteric replacements by the synthesis and evaluation of was demonstrated by the synthesis of p38α MAPK inhibitorsanalogs of Roshe's clinical candidate R-1487. The synthesized fluorinated mimetics retained nanomolar potency against their biological target, had somewhat higher lipophilicity and lower aqueous solubility but improved metabolic stability. We believe that these results will help the fluorinated five-and six-membered O-heterocyclic fragments to find their place in the medicinal chemists' toolbox and promote their wider applications in early drug discovery.