Design, Synthesis, and Biological Evaluation of Macrocyclic 2‑Amino-4-phenylaminopyrimidine Derivatives as Potent JAK2 Inhibitors

Janus kinase 2 with the activating mutation V617F is
a potential
target for the treatment of myeloproliferative neoplasms. Current
JAK2 inhibitors often suffer from multiple pharmacological limitations
such as limited selectivity and rapid metabolic clearance. In this
study, we describe the design, synthesis, and biological evaluation
of a series of macrocyclic 2-amino-4-phenylaminopyrimidine derivatives
as JAK2 inhibitors. Among them, compound 11 showed potent
inhibitory activity against JAK2 kinase (IC50 = 54.70 nM), as well as JAK2-dependent HEL and SET-2 cells, with
IC50 values of 0.57 μM and 1.07 μM,
respectively. Besides, compound 11 downregulated the
expression of p-STAT3 and p-STAT5 in HEL cells. Importantly, compound 11 also exhibited good bioavailability (F = 54.8%) and potent inhibition of rhEPO-induced extramedullary erythropoiesis
and polycythemia vera in vivo. In summary, the macrocyclic
design introduces structural innovation and provides a more efficient
and selective strategy for JAK2 inhibition.