Synthesis and JAK2 inhibitory activities of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives

A series of 4-phenyl-pyrrolo［2, 3-d］pyrimidine derivatives were synthesized through modifying the structure of the lead compound ruxolitinib by molecular hybridization strategy. It was synthesized from pyrimidine-4, 6-diol by Vilsmeier-Haack reaction, S_NAr reaction, cyclized, dehydration, Suzuki coupling and finally acylated to give 12 new compounds( 12a - 12l ). All structures of the synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS analysis. The biological activities were evaluated in vitro. Their JAK2 inhibitory activities were studied using JAK2 enzymatic and TF1-GMCSF cellular assays. The results indicated that compounds 12b , 12e and 12h showed moderate activity. The anti-tumor activities were studied against JAK2-independent A549 cell line by the MTT assay. Results showed that the title compounds exhibited potent antiproliferative effect on A549, especially compound 12c (IC₅₀=0. 12 μmol/L), suggesting that this series compounds might be promising anti-tumor agents for futher investigation.