Modification And Synthesis Of Phenylaminoimidazoisoquinolinone As New Lck-Inhibitors

P56lck, a member of the src family of nonreceptor protein tyrosine kinases, is expressed primarily in T cells. An agent inhibiting lck would block T cell function effectively. Act as an immunosuppressive agent, it has potential utility in autoimmune diseases, the transplant rejection, allergic diseases as well as cancers.2-(2,6-Dichlorophenylamino)-1,6,7-trimethyl-1,8-dihydroimidazo[4,5-h]isoquinoline-9-one, one compound of phenylaminoimidazoisoquinolinones as a new class of lck inhibitors, has nanomolar inhibiting activity which is disclosed recently.Modifications produce2-(2,6-Dichlorophenylamino)-7-(3-diethylamin-opropenyl)-1,6-dimethyl-1,8- dihydroimidazo[4,5-h]isoquinolin-9-one that improves in vitro potency to subnanom- olar levels and also has oral efficacy.According to the reported synthetic route, we used 2,6-dichloro-3-nitrobenzonitrile as the starting material and synthesized two compounds described above successfully. Their structures were confirmed by 1H-NMR spectra. Through the use of the binding models, we made new modifications of the dichlor- ophenyl moiety, substitution with methyl and amide group, and designed a new class of compounds,2-(2-methyl-5-amidephenylamino)-1,6,7-trimethyl-1,8-dihydroimidazo [4,5-h]isoquinoline-9-one, attempting a significant improvement of potency. We have designed a synthetic route and accomplished our goal. Five new structural target compounds were achieved and confirmed by 1H-NMR spectra.The reactive conditionsand the synthesis of some key intermediates were discussed.