N2-aroylanthranilamide inhibitors of human factor Xa

Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K ass = 0.81 x 10 6 L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N 2 -aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B. and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N 2 -aroylanthranilamide 4 series with hfXa K ass = 58 x 10 6 L/mol (K i = 11.5 nM).