Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors

  • Bioorg Med Chem Lett. 2009 Dec 1;19(23):6519-23. doi: 10.1016/j.bmcl.2009.10.049.
Dan M Berger  1 ,  Nancy Torres ,  Minu Dutia ,  Dennis Powell ,  Greg Ciszewski ,  Ariamala Gopalsamy ,  Jeremy I Levin ,  Kyung-Hee Kim ,  Weixin Xu ,  James Wilhelm ,  YongBo Hu ,  Karen Collins ,  Larry Feldberg ,  Steven Kim ,  Eileen Frommer ,  Donald Wojciechowicz ,  Robert Mallon
Affiliations
PMID: 19864136 DOI: 10.1016/j.bmcl.2009.10.049
Abstract

As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.

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