Adaptation of the Mitsunobu Reaction for Facile Synthesis of Dorsomorphin-Based Library

Pyrazolo[1,5-a]pyrimidine is a nitrogen-containing fused heterocycle that imitates the nitrogenous base adenine with varying degrees of reliability. This fact determines its frequent use in drug design, including the development of ATP-competitive kinase inhibitors. These include dorsomorphin which shows compromised kinase selectivity but is still widely used as an AMPK inhibitor. ATP-binding pockets of many proteins have a fairly conservative spatial structure and there is a high probability of obtaining a compound with low target selectivity during drug development. In the case of a common scaffold, the careful selection of side substituents that determine the activity and selectivity of the final compound plays an important role. In this work, a convergent strategy for the synthesis of dorsomorphin and its close analogs was developed and implemented. The resulting small series of compounds is distinguished by the maximum possible diversification and allows for an assessment of the biological activity towards AMPK. An original route to obtain variants of the phenoxy-alkylamine moiety of dorsomorphin via the Mitsunobu reaction will be useful for generating targeted-focused libraries of ATP-competitive kinase inhibitors and highly active receptor ligands.