Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

series of new 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)-maleimides were synthesized and evaluated for their inhibitory activity against IDH1-R132H. Most compounds exhibited significant potency to IDH1-R132H inhibition. Among these, 3-(1-(3-(1H-imidazol-1-yl)propyl)-6-bromo-1H-indol-3-yl)-4-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-pyrrole-2,5-dione (compound IXb ), was the most promising IDH1-R132H inhibitor (IC 50 = 0.031 μM) and could significantly inhibit the production of 2-HG in U87MG IDH1-R132H cells. Preliminary structure–activity relationships and molecular modeling studies are discussed based on the experimental data obtained.