In consideration of the satisfying IC50 of 7m, along with the high synthetic accessibility for structural derivatization based on intermediate 28j (see Scheme 4 for detailed synthetic route), we tentatively kept R 1 as 1-cyclopropyl-1H-pyrazol-4-yl and explored the SAR at quinazoline C7 position (Table ). When comparing the activities of 8a-8d, we noticed an apparent advantage for pyridin-3-yl compound 8c, which supported the prediction of forming a hydrogen bond with Lys46. Incorporating a 4methyl group to the pyridin-3-yl substituent could further boost the potency, yielding 8e with an IC50 value of 17.9 nM, and whether shifting or extending the length of this methyl group could result in nearly 10-fold decrease in potency (8f-8h). Thus, we considered that this methyl might force the pyridine ring to rotate by an angle from the quinazoline core, thereby assisting the hydrogen bond formation. As for Nmethylpyrazole derivatives, 8i and 8j displayed moderate IC50 values, but still about three-times weaker than the 4-methylpyridine counterpart 8e. 8k and 8l were poor inhibitors in comparison with 8i and 8j, indicating that the methyl groups located between the activity-essential N atom and the attachment site were not tolerable. To investigate the role of the morpholine moiety in the original bicyclic substituent, we synthesized the 5-aminopyridin-3-yl compound 8m, potency of which was doubled from 8e. Unexpectedly, the activity dropped sharply when another 6-methoxy was introduced (8n), which reminded us that conformational restriction of this freely rotatable methoxy group was vital for the potency. The IC50 value reached to 10.4 nM when both 4-methyl and 5-amino group were incorporated to the pyridine ring (8o), but despite such improvement, the original bicyclic substituent was still the optimal R 2 (8o vs 7m).