Design of 7-amino-6-chloro-3H-imidazo[4,5-b]pyridine scaffold from 5-chloro-2,4-diaminopyrimidine pharmacophore: identification of potent inhibitors of anaplastic lymphoma kinase

A series of potent anaplastic lymphoma kinase (ALK) inhibitors based on a 7-amino-6-chloro-3H-imidazo[4,5-b]pyridine scaffold were identified through rational design from a 5-chloro-2,4-diaminopyrimidine pharmacophore, maintaining key binding elements, favourable lipophilic interactions and orienting the side chains into favoured trajectories. Importantly, potency and selectivity determinants from the parent series were directly applicable to the new scaffold. This highly focused strategy led to the identification of several lead inhibitors that displayed potent activity in enzyme and cellular assays as well as pronounced oral bioavailability.