Due to the limitations of existing anti-EV71 targets, we have been eager to discover a new anti-EV71 agent based on mTOR (the mammalian target of rapamycin), which is an important target for finding antiviral agents based on host cells. Torin2 is a second-generation ATP competitive mTOR kinase inhibitor (IC50 = 0.25 nM). Our research team tested the anti-EV71 activity of Torin2 in vitro for the first time. The result showed that Torin2 had significant anti-EV71 activity (IC50 = 0.01 μM). In this study, thirty novel Torin2 derivatives were synthesized and evaluated for anti-EV71 activity. Among them, 11a, 11b, 11d, 11e and 11m displayed similar activity to Torin2. 11e displayed the most potent activity, with an IC50 value of 0.027 μM, which was closest to Torin2, and displayed potent mTOR kinase inhibitory activity. A molecular modeling study showed that 11e interacted with Val2240 and Lys2187 via hydrogen bonds and had a good match with the receptor. Additionally, a mechanism study showed that most of the compounds had significant inhibition for the mTOR pathway substrates p70S6K and Akt. The water solubility test of compounds with potent activity revealed that 11a and 11m were improved by approximately 5-15-fold compared to Torin2. These data suggest that 11a and 11m may be potential candidates for anti-EV71 treatment.