Leveraging selective late-stage functionalization reactions for SAR vector interrogation in BCR/ABL kinase inhibitors

A late-stage diversification strategy for the synthesis of novel BCR/ABL tyrosine kinase inhibitors is reported. A uniquely selective bromination reagent was applied to the functionalization of nilotinib, radotinib, and imatinib at a single site, enabling the facile generation of new derivatives of these scaffolds. The novel derivatives were profiled through enzymatic activity assays, cellular target engagement assays, and ADME assays. By exploring inhibition profiles across a range of ABL mutants, it was found that nilotinib derivatives 20 and 21 exhibit broad inhibitory activity, which is superior to the parent compound for some ABL isoforms.