Synthesis and evaluation of heteroaryl-ketone derivatives as a novel class of VEGFR-2 inhibitors

A novel series of potent heteroaryl-ketone derivatives active against VEGFR-2 kinase is described. The best compounds were demonstrated to be inactive against a panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase. Selected representatives displayed acceptable exposure levels when administered orally to mice. We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.