Tetrahydro-Dewar Pyridines (THDPs): Conformationally Programmable Piperidine Isosteres

Abstract Bioisosteric replacement is an indispensable tool in a 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 is a valuable motif but often requires bioisosteric replacement to improve its ADME (absorption, distribution, metabolism, excretion) profile. Despite recent advances in the field, practitioners still rely on the limited pool of commercially available piperidine isosteres that often have imperfect geometrical overlay. Herein, we explore tetrahydro-Dewar pyridines (THDPs) as rigid, programmable isosteres of piperidines. These building blocks are readily accessible from dihydro-Dewar pyridines (DHDPs), which can be synthesized from pyridine in only two steps using batch or flow photochemistry. Developed synthetic routes provide access to new building blocks and bifunctional linkers suitable for incorporation into various structural contexts. By applying the THDP scaffold to three distinct classes of kinase inhibitors, we demonstrate that THDPs offer a robust solution for testing advanced SAR hypotheses by stabilizing exit vectors while preserving physicochemical properties.