Synthesis and biological evaluation of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues as Ser/Thr kinase inhibitors

A useful and rapid access to libraries of N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amines and their pyrido and pyrazino analogues was designed and optimized for the first time via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with N′-(2-cyanoaryl)-N,N-dimethylformimidamides obtained by reaction of thiophene precursors with dimethylformamide dimethylacetal. The inhibitory potency of the final products against five protein kinases (CDK5/p25, CK1δ/ɛ, GSK3α/β, DYRK1A and CLK1) was estimated. N-arylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine series of compounds (4a–j) turned out to be particularly promising for the development of new pharmacological inhibitors of CK1 and CLK1 kinases.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Synthesis of 40 novel tricyclic thieno[3,2-d]pyrimidin-4-amines. ► The inhibitory potency of the final products against five kinases was evaluated. ► Three compounds are promising as new inhibitors of CK1 and CLK1 kinases.