Non-oxime inhibitors of B-RafV600E kinase

The development of inhibitors of B-RafV600E serine–threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.

Inhibitors of B-RafV600E kinase are reported for which indanone oximes are replaced with tricyclic pyrazoles and indazoles.Figure optionsDownload as PowerPoint slide