Bioisosteric replacement is an indispensable tool in the medicinal chemist’s arsenal to strike a fine balance in multiparameter optimization campaigns and to deliver the best molecules for further preclinical development. The piperidine heterocycle, a dominant fragment in drug discovery, is often targeted for such replacement in attempts to improve potency and ADME (absorption, distribution, metabolism, excretion) profile. In this manuscript we explore 4H-Dewar pyridines (4H-DP) as rigid programmable isosteres of equatorially and elusive axially substituted piperidines. These fragments are readily accessible via pyridine dearomatization without the need for expensive catalysts and reagents. A wide spectrum of available reactivities enables incorporation of 4H-DP in various structural contexts. Exit vector analysis (EVA) underscores topological similarity with the parent piperidine as well as complementarity with the previously reported bioisosteres.
Experimental Procedures and Characterization of Compounds