Cyclic systems are fundamental structural motifs prevalent in a vast array of pharmacologically active compounds. By introduction of the fully saturated cyclic fragments the potential drug molecule, one could modulate the most important drug substance properties, including but not limited to alterations in molecular conformations, physicochemical characteristics or metabolic stability. Saturated cyclic ethers represent a broad subclass of cyclic motifs that have garnered significant attention in modern drug discovery. Widely distributed among natural products, O-heterocyclic compounds rapidly became one of the key components in numerous synthetic drugs (Figure ). Often being used as mimetics of naturally occurring fragments, saturated oxygen heterocycles can improve the compound's hydrophilicity, enhance its metabolic stability or biological activity when introduced into a molecule of interest. Incorporation of fluorine atoms into cyclic compounds has recently emerged as a cornerstone strategy in medicinal chemistry for enhancing therapeutic efficacy. Fluorination offers unique opportunities to modulate the physicochemical characteristics of (hetero)cyclic structures, thereby influencing their interactions with biological targets and pharmacokinetic behavior. Along with notable influence on the acidity/basicity of ionizable groups and lipophilicity of the whole molecule, fluorination-based strategy could offer the possibility of radio-labelling active therapeutics for in vivo probing purposes or eliminate the instable functionalities via the bioisosteric replacement approach. Despite the growing number of examples of late-stage fluorination of the complex organic structures, fluorinated building blocks are still keeping their dominating role as a source of Fluorine in complex fluorinated compounds. Extensive application of the fluorinated fragments raised a question of their rational exploitation, thus encouraging a series of systematic studies in this area. The groups of Müller, O'Hagan, Linclau, and others revealed a number of valuable insights on the effects of the fluorination pattern on the compound's physicochemical properties (Figure ). In our group, we continuously extended this knowledge by investigation of fluorinated alicyclic, aza-heterocyclic, and (recently) oxetane-derived (3,3-diFox) building blocks. As a part of this ongoing project, in this work we performed a comprehensive characterization of gem-difluorinated five-and six-membered O-heterocycles. We studied physicochemical parameters of their model derivatives (i.e., pKa and LogP) with a focus on the gem-difluorination and O-substitution effects. Furthermore, we have performed synthesis and biological evaluation of fluorinated analogues of p38α mitogen-activated protein kinase (MAPK) inhibitor R-1487 to illustrate the utility of the title fluorinated building blocks for the pharmacokinetic properties modulation.