Exploration of structure–activity relationship of 2,4‐diaminopyrimidine derivatives as hematopoietic progenitor kinase 1 inhibitors

Hematopoietic progenitor kinase 1 (HPK1) is a critical negative regulator of T‐cell receptor signaling and has emerged as a promising immune checkpoint target for cancer immunotherapy. In this study, we report the design, synthesis, and structure–activity relationship (SAR) exploration of a novel series of 2,4‐diaminopyrimidine derivatives as potent HPK1 inhibitors. Systematic optimization revealed that the incorporation of an (S)‐phenylglycinol moiety and meta‐ or para‐substituted aniline groups at the scaffold significantly enhanced inhibitory potency. Among the synthesized analogs, compound 7h was identified as a lead candidate, exhibiting robust enzymatic inhibition and effectively suppressing the phosphorylation of SLP76 in cellular assays. These results demonstrate that the 2,4‐diaminopyrimidine scaffold provides a viable foundation for the development of next‐generation HPK1‐targeted immunotherapies.