Discovery of N‑(4-(Aminomethyl)phenyl)-5-methylpyrimidin-2-amine Derivatives as Potent and Selective JAK2 Inhibitors

The JAK2V617F mutation leads to JAK2 autophosphorylation and activation of downstream pathways, eventually resulting in myelo­proliferative neoplasms (MPNs). Selective inhibitors showed advantages in terms of side effects; therefore, there is an urgent need to develop novel selective JAK2 inhibitors for treating MPNs. In this study, we described a series of N-(4-(aminomethyl)­phenyl)­pyrimidin-2-amine derivatives as selective JAK2 inhibitors. Systematic exploration through opening the tetrahydro­isoquinoline based on the previous lead compound 13ac led to the discovery of the optimal compound A8. Compound A8 showed excellent potency on JAK2 kinase, with an IC50 value of 5 nM, and inhibited the phosphorylation of JAK2 and its downstream signaling pathway. Moreover, A8 exhibited 38.6-, 54.6-, and 41.2-fold selectivity for JAK1, JAK3, and TYK2, respectively. Compared to the lead compound, A8 demonstrated much better metabolic stabilities, with a bioavailability of 41.1%. These findings suggest that A8 is a relatively selective JAK2 inhibitor, deserving to be developed for treating MPNs.