Hit to lead optimization of pyrazolo[1,5-a]pyrimidines as B-Raf kinase inhibitors

Abstract

Our continued effort towards optimization of the pyrazolo[1,5-a]pyrimidine scaffold as B-Raf kinase inhibitors is described. Structure guided design was utilized to introduce kinase hinge region interacting groups in the 2-position of the scaffold. This strategy led to the identification of lead compound 9 with enhanced enzyme and cellular potency, while maintaining good selectivity over a number of kinases. © 2009 Elsevier Ltd. All rights reserved.