Discovery and synthesis of N2,N4-substitued-cycloalkyl[d]pyrimidine-2,4-diamine analogs: The first examples of small-molecular FGFR-1 activator

A series of novel, cycloalkyl-modified pazopanib analogs 2 and 3 were designed and synthesized. Their kinase modulatory effects on FGFR-1, VEGFR-2, PDGFR-β, and c-KIT were evaluated by the caliper mobility shift assay. Introduction of cycloalkyl into the pyrimidine linker of pazopanib almost abolished the four kinases inhibitory potency of compounds 2 and 3, but surprisingly, resulted in good activation effects on FGFR-1. Compounds 3d and 3g showed double-digit, nanomolar, selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.

Graphical abstractA series of novel, cycloalkyl-modified pazopanib analogs were designed and synthesized. Compounds 3d and 3g showed double-digit, nanomolar selective activation effects on FGFR-1, and could be classified as first-generation small molecular activators of FGFR-1 kinase.Figure optionsDownload full-size imageDownload as PowerPoint slide