Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.

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Additions of the -alkoxy allylic stannanes (S)-l and (fZ)-l and the racemate (RS)-l to the threose and erythrose aldehyde derivatives 6 and 15 in the presence of BFg-OEl^o r MgBr2OEt2 were examined in order to establish stereochemical preferences. It was found that (S)-l and aldehyde 6 afforded the syn,anti,syn adduct 7 in the BFs-promoted reaction, while (R)-1 and 6 gave the syn,syn,syn adduct 8 under MgBr2 conditions. Likewise, (S)-l and aldehyde 15 yielded the syn,anti,anti adduct 16 with BF3, whereas (fí)-l and 15 led to the syn,syn,anti adduct 17 with MgBr2. The MgBr2promoted reactions showed sufficient rate differences between the matched and mismatched stannanes to allow the use of racemic stannane (fiS)-l in just over 2-fold excess, whereupon the matched adducts 8 and 17 were favored by greater than 9:1 over the mismatched adducts. The major adducts

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