Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor

Abstract Jak3 is a protein tyrosine kinase that is associated with the shared γ chain of receptors for cytokines IL2, IL4, IL7, IL9, and IL13. We have discovered that a pyridone-containing tetracycle ( 6 ) may be prepared from trisubstituted imidazole ( 5 ) in high yield by irradiation with >350 nm light. Compound 6 inhibits Jak3 with K I =5 nM; it also inhibits Jak family members Tyk2 and Jak2 with IC 50 =1 nM and murine Jak1with IC 50 =15 nM. Compound 6 was tested as an inhibitor of 21 other protein kinases; it inhibited these kinases with IC 50 s ranging from 130 nM to >10 μM. Compound 6 also blocks IL2 and IL4 dependent proliferation of CTLL cells and inhibits the phosphorylation of STAT5 (an in vivo substrate of the Jak family) as measured by Western blotting.