Synthesis and evaluation of imidazo[1,2-a]pyridine analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474

Abstract

Background: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in cancers, although several small molecule inhibitors of the pathway have now been identified. Our earlier work showed that replacement of one of the morpholine groups of the PI3K inhibitor 2-(difluoromethyl)-1-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)-1H-benzimidazole (ZSTK474) with sulfonamide-containing substituents, coupled with the addition of a methoxy group at the 4-position of the benzimidazole group, produced an active class of potent PI3Kα and dual PI3Kα/mTOR inhibitors. This work culminated in the clinical trial of our lead candidate PWT33597 in 2011. Here we describe our investigation of analogues of this class of inhibitors where the benzimidazole portion of the molecule is replaced by an imidazo[1,2-a]pyridine group. Material and methods: Compounds were prepared using a heteroaryl Heck reaction procedure that involved the palladium-catalysed coupling of 2-(difluoro¬methyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines. Compounds prepared included imidazo[1,2-a]pyridine analogues of the known inhibitors ZSTK474, PWT33597, SN32976, MIPS-9922 and AS2541019. The compounds were tested for their inhibitory activity against the p110α, p110β, and p110δ isoforms of PI3K using Homogeneous Time Resolved Fluorescence (HTRF) assays. Results: The imidazo[1,2-a]pyridine compounds followed their benzimidazole analogues in terms of selectivity for the PI3K isoforms, but in general showed less potency in the HTRF assays. Conclusions: Using a scaffold-hopping approach we have investigated imidazo[1,2-a]pyridine analogues of the ZSTK474 class of PI3K inhibitors. The new compounds maintain the isoform selectivity of their benzimidazole analogues, but in general show less potency.