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

Abstract

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.