General Information. Aniline, p-trifluoromethyl aniline and commercially available ketones were distilled prior to use. Commercially available p-anisidine was purified by vacuum sublimation followed by recrystallization from water. All solvents were purified according to the method of Grubbs.

General Information. Aniline, p-trifluoromethyl aniline and commercially available ketones were distilled prior to use. Commercially available p-anisidine was purified by vacuum sublimation followed by recrystallization from water. All solvents were purified according to the method of Grubbs.

In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ's Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile.

A highly diastereoselective α-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl•LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles.

The acid promoted addition of organotrifluoroborate salts to imine and enamine electrophiles is reported. Use of the trifluoroborate bypasses the need for α-hetero substitution on the electrophile, greatly expanding the scope of the Petasis borono–Mannich reaction. A variety of vinyl, aromatic and heteroaromatic trifluoroborate salts undergo addition with good efficiency under mild conditions.