The Design, Synthesis, and Biological Evaluation of Pim Kinase Inhibitors.

Abstract A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3 , 5m , and 6d , we were able to guide the SAR and identify the alkyl benzofuropyrimidinone ( 6l ) with good PIM potencies, permeability, and oral exposure.