Abstract: Coagulation factor XIa (FXIa) plays a crucial role in thrombus formation; therefore, the development of potent and safe FXIa inhibitors is of great significance. 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. The structures of the target compounds were confirmed by ¹H NMR and HRMS, and their inhibitory activities against FXIa were evaluated using chromogenic substrate assay. Results showed that 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 activated partial thromboplastin time (aPTT) assay, compound FD-1 demonstrated excellent anticoagulant activity, outperforming Asundexian, showing no significant effect on prothrombin time (PT). These findings provide valuable insights for further structural optimization and rational design of small-molecule FXIa inhibitors.