Discovery efforts paid by the pharmaceutical industry and academia have translated into the emergence of clinic HPK1 inhibitors. So far, five small-molecule compounds have advanced into clinical trials, however, their structures are undisclosed . Meanwhile, a few ATP-competitive HPK1 inhibitors have been reported in recent literatures (Fig. ). Reverse indazole compound 1 from Merck was well balanced between potency and kinase selectivity, but its efficacy in immune cells was not mentioned in the article . Spiro-azaindoline inhibitor 2 discovered by Genetech displayed high binding affinity HPK1, and it could dose-dependently increase the IL-2 secretion of human pan T cells . Diaminopyrimidine carboxamide derivative 3 from Merck exhibited excellent IC50 values in biochemical and cell-based assays, but unfortunately, the unsatisfying pharmacokinetic (PK) property might impede it from oral administration . Aminopyridine compound ZYF0033 presented good in vitro activities, and it was effective in vivo when dosed intraperitoneally as well . Finally, isofuranone derivative 5, a potent and orally active HPK1 inhibitor developed by Bristol-Myers Squibb, could markedly enhance the efficacy of PD-1 antibody in murine tumor model . Thus, for the development of HPK1 inhibitors, referable information is still limited, especially the detailed structure-activity relationship (SAR) explorations and biological evaluations of other chemotypes. Herein, we describe our efforts on the development of potent HPK1 inhibitors bearing quinazoline-2,5-diamine scaffold. We hope that our SAR explorations and the related biological evaluations will contribute to the drug discovery targeting HPK1.