Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure−activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases. [Display omitted] •Co-crystal structure of imidazo [1,2-b]pyridazine 17 complexed with DYRK1A solved.•DYRK1A binding affinity increased by C-3 substitution under P-loop.•DYRK1A selectivity increased by C-2 substitution with a methyl group.•A series of potent, selective and cell-active inhibitors of DYRK1A are described.