Synthesis and Evaluation of Imidazopyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

• Published in: Chemistry, an Asian journal Vol. 14; no. 8; pp. 1249 - 1261
• Main Authors: Gamage, Swarna A, Spicer, Julie A, Tsang, Kit Y, O'Connor, Patrick D, Flanagan, Jack U, Woo‐Jeong Lee, Dickson, James M J, Shepherd, Peter R, Denny, William A, Rewcastle, Gordon W
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 01-04-2019
• Subjects: Chemistry; Inhibitors; Kinases; Palladium; Pyridines; Pyrimidines; Selectivity
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201801762

Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐catalysed coupling of 2‐(difluoromethyl)imidazo[1,2‐a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5‐triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.