showed furtherly enhanced potency that comparable to 6 and five-times more potent than 5. Moreover, IC50 values were well maintained when these secondary amines were methylated (9h vs 9f, 9i vs 9g), and 9h which harbors a 2-methyl-1,2,3,4tetrahydroisoquinolin-7-yl substituent exhibited an IC50 value of 2.7 nM. Further exploration based on 9h was also conducted, but the activities of 9j-9l revealed that bulkier N-alkyl groups or a 6-methoxy group in the tetrahydroisoquinoline moiety were not beneficial. Finally, to test our hypothesis of producing an additional interaction, we carried out a molecular docking study using the most potent 9h. As Fig. depicts, 9h could maintain the key hydrogen bonds that predicted for 6 and 9a, more importantly, this model suggested that the tetrahydroisoquinoline N atom could create salt bridge contact with Asp101, which provided a molecular explanation for the high potency of binding mode of 9h in the ATP-binding site of HPK1. Hydrogen bonds are illustrated with yellow dash lines, measurements are illustrated with light-pink and pale-cyan dash lines, and salt bridge interaction is illustrated with magenta dash line.