-(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms.

In this study, we described a series of -(pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine derivatives as selective JAK2 (Janus kinase 2) inhibitors. Systematic exploration of the structure-activity relationship though cyclization modification based on previously reported compound led to the discovery of the superior derivative . Compound showed excellent potency on JAK2 kinase, SET-2, and Ba/F3 cells (high expression of JAK2 mutation) with IC values of 3, 11.7, and 41 nM, respectively. Further mechanistic studies demonstrated that compound could downregulate the phosphorylation of downstream proteins of JAK2 kinase in cells. Compound also showed good selectivity in kinase scanning and potent in vivo antitumor efficacy with 82.3% tumor growth inhibition in the SET-2 xenograft model. Moreover, significantly ameliorated the disease symptoms in a Ba/F3-JAK2 allograft model, with 77.1% normalization of spleen weight, which was more potent than Ruxolitinib.