Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML)

Abstract

Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1<i>H</i>-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound <b>8t</b> showed strong activity against FLT3 (IC₅₀: 0.089 nM) and CDK2/4 (IC₅₀: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC₅₀: 2.33 nM; CDK2/4, IC₅₀: 1.02/0.39 nM). Compound <b>8t</b> also showed excellent inhibitory activity against a variety of FLT3 mutants (IC₅₀ < 5 nM), and potent anti-proliferative effect within the nanomolar range on acute myeloid leukemia (MV4-11, IC₅₀: 1.22 nM). In addition, compound <b>8t</b> significantly inhibited the proliferation of most human cell lines of NCI60 (GI₅₀ < 1 μM for most cell lines). Taken together, these results demonstrated the potential of <b>8t</b> as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.