Design And Synthesis Of Novel Quinazoline Compounds

JAK₃protein tyrosine kinase plays an important role in regulating growth,activation, death and function of lymphocyte. It can make lymphocyte to attackexogenous grafts. Inhibit JAK₃selectively can regulate organ transplant rejection andautoimmune disease, avoiding the damage of other tissues and organs. But manyreported JAK₃inhibitors are of generally poor selectivity and high toxicity.Quinazoline compounds have good biological activity, changeful chemicalstructure and wide application, which have become the focus in pharmacy andmedicine research. In order to explor the JAK₃inhibition of quinazoline compoundsand search a kind of new drug used in transplant rejection and autoimmune disease,we had designed and synthesized a novel set of quinazoline compounds on the basisof JAK₃as receptor.We downloaded66₂79and19871quinazoline compounds respectively fromBinding Database and ChemBioFinder, getting the lead compound₂-Chloro-4-Cyclopentylaminoquinazoline by molecular docking virtual screening method. A setof6-R-4-Cyclopentylaminoquinazoline compounds （R: F, CI, Br, CF₃, CH₃, NO₂,NH₂, Acetamide and Benzylidenemethylamine） and6,7-dimethoxy-4-Cyclopentyl-aminoquinazoline were designed based on molecular docking results and structureactivity relationship of reported quinazoline compounds and JAK₃inhibitors.We used₂-Amino-5-R-Benzonitrile （R: F, CI, Br, CF₃, CH₃, NO₂） and₂-Amino-4,5-Dimethoxybenzonitrile as starting material, reacteed with N,N-Dimethyl-formamide dimethyl acetal, getting corresponding amidine intermediations. Theintermediations were used in reacting with cyclopentyl ammonia, getting targetcompounds6-R-4-Cyclopentylaminoquinazolines （R: R: F, CI, Br, CF₃, CH₃, NO₂）and6,7-Dimethoxy-4-Cyclopentylaminoquinazoline.6-Nitro-4-Cyclopentylamino-quinazoline was reduced, getting6-Amino-4-Cyclopentylaminoquinazoline.6-Acetamide-4-Cyclopentylaminoquinazoline and （E）-6-Benzylidenemethylamine-4-Cyclopentylaminoquinazoline were synthesized by the reaction of6-Amino-4-Cyclopentylaminoquinazoline and acetic anhydride and benzaldehyde respectively. We had designed and synthesized10novel quinazoline compounds, and all thetarget compounds were confirmed by1^H NMR and（13）^C NMR. We hope this set ofcompounds will represent high biological activity and selectivity as JAK₃proteintyrosine kinase inhibitors, providing basis for the study of quinazoline compoundstructure activity relationship and further structure alteration and synthesis.