Colony-stimulating factor 1 receptor (CSF1R) is a key regulator of macrophage-driven liver inflammation. Here, we report a series of CSF1R inhibitors discovered through a structure-guided optimization strategy for the acute-phase treatment of acetaminophen-induced liver injury. For instance, compound C52 exhibited potent CSF1R inhibition, a kinome-wide selective profile, and low cellular cytotoxicity. C52 rapidly suppressed M-CSF-induced phosphorylation events and downstream signal