Furo[3,2‐b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

Core competence: The furo[3,2‐b]pyridine core has been identified as a novel scaffold for potent and highly selective inhibitors. A diverse target compound set was prepared by synthetic sequences based on chemoselective metal‐mediated couplings. The 3,5‐disubstituted furo[3,2‐b]pyridine sub‐series afforded potent, cell‐active, and highly selective inhibitors of cdc‐like kinases (CLKs). And the kinase‐inactive subset of 3,5,7‐trisubstituted furo[3,2‐b]pyridines afforded sub‐micromolar modulators of the Hedgehog pathway.

Abstract

Reported is the identification of the furo[3,2‐b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc‐like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal‐mediated couplings, including assembly of the furo[3,2‐b]pyridine scaffold by copper‐mediated oxidative cyclization. Optimization of the subseries containing 3,5‐disubstituted furo[3,2‐b]pyridines afforded potent, cell‐active, and highly selective inhibitors of CLKs. Profiling of the kinase‐inactive subset of 3,5,7‐trisubstituted furo[3,2‐b]pyridines revealed sub‐micromolar modulators of the Hedgehog pathway.

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