Design, synthesis, and evaluation of novel hydrazide hydrochlorides of 6-aminopyrazolo[1,5-a]pyrimidine-3-carboxamides as potent Aurora kinase inhibitors

摘要

The Aurora kinases play a key role in mitosis and are overexpressed in multiple human tumor types; there has been considerable interest in developing Aurora kinase inhibitors as antitumor agents, particularly Aurora A and Aurora B kinases. A series of novel hydrazide hydrochlorides of pyrazolo[1,5-a]pyrimidine carboxamides were designed and synthesized and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited low micromolar to nanomolar activity with respect to the inhibition of Aurora A kinase. The most potent compound in this series was found to be a potent inhibitor of Aurora A in an HTRF enzymatic assay with an IC50 as low as 23 nM. A structure-activity relationship study indicated that halogen substitution in the benzene ring of amide plays an important role in kinase inhibitory potency.