Abstract: The abnormal activation of NOD-like receptor protein 3 (NLRP3) inflammasome is related to the development of a variety of inflammatory and autoimmune diseases. In this study, the indole compound A-3 was found to inhibit the activation of the NLRP3 inflammasome pathway. A total of 19 derivatives Ⅰ-1-Ⅰ-4, Ⅱ-1-Ⅱ-6, Ⅲ-1-Ⅲ-3, Ⅳ-1-Ⅳ-6 were synthesized by structural modification of A-3, and 4 compounds Ⅲ-3, Ⅳ-1, Ⅳ-5, Ⅳ-6 could inhibit inflammasome activation at the cellular level. Preliminary mechanistic studies have shown that the compound Ⅳ-5 can inhibit pyroptosis in J774A.1 cell. In addition, we analyzed the structure-activity relationship of the series of compounds based on 3D pharmacophore model. This study provides lead compounds for the development of novel NLRP3 inflammasome pathway inhibitors.