Abstract: Based on the known IRAK4 inhibitors MK-32 and AU-5, we designed and synthesized 12 pyridine-based target compounds by adopting open-ring and hybrid strategies, and combining molecular docking technology. The bioassays determined by radioisotope labeling demonstrated that the target compounds displayed good inhibitory activity against IRAK4. Among them, the IC₅₀ value of 5 compounds was less than 1 μmol/L, suggesting that these compounds may be candidates for further investigation.