Extracellular signal-regulated kinases (ERKs) are pivotal signaling molecules in the RAS-RAF-MEK-ERK signaling pathway and have emerged as potential antitumor targets, providing a promising strategy for tumor therapy. Therefore, the development of antitumor drugs targeting ERK protein has received extensive attention. Here, we developed a compound library based on a series of novel aromatic urea-imidazole salt derivatives and conducted phenotypic screening against various cancer cell lines. Notably,