We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e,9d,9p,9j and 9k (IC_(50)≤0.005μmol/L) were equal to or greater than that of the lead compound 9a.Less hydrophobic compounds showed weaker potency,which can be explained by the hydrophobic nature of the cathepsin K binding pockets. We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e, 9d, 9p, 9j and 9k (IC 50 (50) ≤ 0.005 μmol / L) were equal to or greater than that of the lead compound 9a. Let hydrophobic compounds showed weaker potency, which can be explained by the hydrophobic nature of the cathepsin K binding pockets.