A series of cyclopropane-1,1-diamide derivatives containing imidazo[1,2-a]pyridine were synthesized in this work. The inhibitory effects of these compounds on FLT3-ITD kinase and their anti-proliferative activities against two acute myeloid leukemia cell lines expressing FLT3-ITD were evaluated. Focused on the different substitutions of imidazo[1,2-a]pyridine, a preliminary exploration of the structure-activity relationship was conducted for 22 compounds. The results revealed that compounds 11e-11h, 11j, and 12a-12c exhibited certain inhibitory effects on FLT3-ITD kinase, with IC₅₀ values below 0.5 µM. Among them, compound 12a demonstrated the most potent FLT3-ITD kinase inhibitory activity and the strongest anti-proliferative effect on the MV4-11 and MOLM-13 cell lines expressing FLT3-ITD, with IC₅₀ values of 0.06 µM and 0.2 µM, respectively. Moreover, compound 12a didnot exhibit anti-proliferative activity against cell lines without FLT3 mutations, such as THP-1, HCT-116, A549, HepG2, K562, and MCF-7, and it displayed non-cytotoxicity towards normal HK-2 (human renal tubular epithelial cells), HepaRG (human liver progenitor cells), and HEK293 (human embryonic kidney cells). Although 12a exhibits inferior inhibitory activity against FLT3-ITD kinase and anti-tumor cell proliferation compared to Cabozantinib in this study, it can provide a reference for further research into FLT3-ITD inhibitors.

Key words: Imidazole[1,2-a]pyridine, Antiproliferative activity, Inhibition, FLT3 kinase, Acute myeloid leukemia