Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.

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.

[reaction: see text] By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from ethyl 2-chlorooxazole-4-carboxylate (2) was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles.

[reaction: see text] Novel and highly efficient syntheses of oxazolo[4,5-c]quinoline-4(5H)-ones (1) and thiazolo[4,5-c]quinoline-4(5H)-ones (2) from ethyl 2-chlorooxazole-4-carboxylate (4) and ethyl 2-bromo-5-chlorothiazole-4-carboxylate (13), respectively, are described.

The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described. [reaction: see text]