Furthermore, we have evaluated if the above increments are additive by prediction of ΔpKa and ΔLogP of gem-diflurinated O-heterocyclic compounds 1-4[2-4,-] relatively to parent nonfluorinated cycloalkane derivatives 1-4[0,0] (Figure , B; Table ). For the ΔpKa values, the additivity was confirmed: the corresponding prediction error (ΔΔpKa = -0.08±0.56) was within the 3 confidence interval, which correlated with the literature data. For the LogP values, the predictions had much larger errors (ΔΔLogP=0.56±0.79) and were systematically higher than the corresponding experimental values. In other words, the lipophilicity decrease from both O and CF2 moieties acting simultaneously was lower than anticipated from the separate increments of these fragments. Notably, higher prediction errors were observed for the amine and benzamide series. These results show that mutual influence of both Oxygen and gem-CF2 fragments should be taken into account when discussing their effects on the compound's lipophilicity. Interestingly, the prediction error (ΔΔLogP) of the simple additive model was higher for the compounds with higher ΔpKa values (see the Supporting Information, Figure ). Since ΔpKa correlates with electronic distribution changes in the molecules of the corresponding building blocks (and hence in partof their model derivatives), this result shows that the properties of the amide functional group attached to the saturated ring may be also important for the compound's lipophilicity. It should be noted that we have already observed similar trends for the gemdifluorinated cycloalkane series. Biological evaluation. To evaluate the utility of the discussed building blocks for bioisosteric replacements, we prepared five analogs of R-1487 (10a)a known highly potent and selective p38α mitogen-activated protein kinase (MAPK) inhibitor developed by Roche scientists. R-1487 (10a) and its analogs 10b-f were prepared by SNAr reaction of known key intermediate 9 (synthesized in five steps from a commercially available pyrimidine derivative) and amines 3 or 4. As in the case of model amide derivatives 7 and 8, replacing the tetrahydropyran moiety in the molecule of 10a with gemdifluorinated analogs resulted in slightly increased lipophilicity. Notably, the changes in LogD7.4 values of compounds 10a-f in correlated with LogP trends observed for benzamides 7 and 8 (with a single exception of compounds 10d/3 [3,0]). This result confirms suitability of the model systems used by us in this work for the lipophilicity studies.