Molecular Modeling-Guided Synthesis of Piperazine-Modified GW830263A Analogues as STK10 Inhibitors

Serine/Threonine Kinase 10 (STK10) is a chemically underexplored kinase that activates ERM proteins.¹ Molecular modeling performed herein on piperazine-modified GW830263A identified promising hits at the STK10 back-pocket. This work aims to synthesize these analogues via a convergent route comprising Fragments I and II (Fig. 1).² Fragment I synthesis starts with bromide 1 substitution by sodium thiomethoxide (quant.). The thioether was oxidized to sulfone (87%) using mCPBA, and the nitro group was reduced to aniline 4 (quant.) employing iron powder and ammonium chloride. Intermediate 7 was prepared in two steps (37% overall), starting from the monoacetylation of p-phenylenediamine 5 with acetic anhydride, followed by substitution on 2,4-dichloropyrimidine by the aniline. 7 was methylated with iodomethane (66%). Two steps are under development to furnish deacetylated common precursor 9. Analogue-specific Fragment II synthesis is ongoing. GW830263A first amidation step between a and 11 with N,N'-dicyclohexylcarbodiimide was accomplished (quant.), along with TFA-mediated hydrolysis (quant.).