Design, synthesis, and biological evaluation of quinoxalinyl and quinolinyl derivatives as ALK5 inhibitors

Six series of ether (14a-i and 15a-i), ester (17a-f and 18a-f) and amine derivatives (21a and 22a-g) containing quinoxalinyl and quinolinyl moieties were synthesized and evaluated for their inhibitory activities against activin receptor-like kinase 5 (ALK5). Among all the compounds, compound 22f (IC₅₀ = 0.267 μM) exhibited the highest ALK5 inhibitory activity, comparable to that of the positive control LY-2157299. This study revealed that introducing amino groups into the side chains of quinoxalinyl and quinolinyl derivatives is more effective in enhancing ALK5 inhibition than ether or ester groups. These findings provide new insights and a theoretical foundation for the development of pyrazole-based ALK5 inhibitors.

ALK5 inhibitor; Amine; Pyrazole; Quinoline; Quinoxaline.