Abstract: In this study, compound F22, previously discovered by our group, was selected as the lead compound. Based on the principles of bioisosterism and fragment-based drug design, four series comprising 14 novel Asundexian derivatives, not previously reported in the literature, were designed and synthesized. Their structures were confirmed by ¹H NMR and MS. The inhibitory activities of the target compounds against FXIa were evaluated using a chromogenic substrate assay. Among them, compound FD-1 exhibited the most potent activity, with an IC₅₀ value of 2.8 nmol/L, which was superior to that of the lead compound F22 (IC₅₀ = 4.5 nmol/L) and the reference drug Asundexian (IC₅₀ = 5.0 nmol/L). Furthermore, in the aPTT assay, FD-1 demonstrated excellent anticoagulant activity (EC_2x = 0.5 µmol/L), outperforming Asundexian (EC_2x = 0.6 µmol/L), while showing no significant effect on PT. These findings provide valuable insights for the further structural optimization and rational design of small-molecule FXIa inhibitors.