In summary, inspired by a set of highly potent isoquinoline-3,8-diamine HPK1 inhibitors, we generated the quinazoline-2,5-diamine skeleton and explored the SARs at 2-amino group and C7 position. While carbonyl substituent on the 2-amino group was not matched with our quinazoline core, replacing it with five-or six-membered heterocycles could bring high inhibitory activities. SAR exploration at C7 position shed light on some of the potency determinants. Introducing aliphatic amines as putative Asp101-interacting groups to the 2-aniline moiety yielded several tetrahydroisoquinoline derivatives with furtherly improved activities, among which the most potent 9h displayed an IC50 value of 2.7 nM in our internal ADP-Glo kinase assay.