In the treatment of echinoderm microtubule-associated protein-like 4 
(EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer 
(NSCLC), secondary mutations within the ALK kinase domain have emerged as a 
major resistance mechanism to both first- and second-generation ALK inhibitors. 
This report describes the design and synthesis of a series of 
2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating 
in identification of the investigational clinical candidate brigatinib. A unique 
structural feature of brigatinib is a phosphine oxide, an overlooked but novel 
hydrogen-bond acceptor that drives potency and selectivity in addition to 
favorable ADME properties. Brigatinib displayed low nanomolar IC50s against 
native ALK and all tested clinically relevant ALK mutants in both enzyme-based 
biochemical and cell-based viability assays and demonstrated efficacy in 
multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell 
lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically 
advanced phosphine oxide-containing drug candidate to date and is currently 
being evaluated in a global phase 2 registration trial.