Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel
series of 3-quinoline carboxamides has been discovered
and optimized as selective inhibitors of the ataxia telangiectasia
mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide
(72) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide
(74) as potent and highly selective ATM inhibitors with
overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM
inhibition in vivo. Efficacy in combination with the DSB-inducing
agent irinotecan was observed in a disease relevant model.