7-Aminopyrazolo[1,5-<i>a</i>]pyrimidines as Potent Multitargeted Receptor Tyrosine Kinase Inhibitors

7-Aminopyrazolo[1,5-a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure−activity relationships of the pyrazolo[1,5-a]pyrimidine nucleus led to a series of 6-(4-N,N′-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED50 = 1.4 mg/kg).