The de novo design and synthesis of cyclic urea inhibitors of factor Xa : Optimization of the S4 ligand

Abstract In this report refinements to the S4 ligand group leads to compound 19 Download high-res image (33KB) Download full-size image Scheme 1 . Synthesis of 2,4-diazepin-3-one analogues. Reagents: (i) 3-cyanophenylisocyanate, DMF, 18 h; (ii) 3 equiv NaH, 2 equiv BrCh 2 CH 2 CH 2 CH 2 Br, DMF, 70 °C, 3 h, then HCl:Et 2 O; (iii) R -Cl (see Table 1 ), Et 3 N, THF, then HCl(g), CH 3 CO 2 CH 3 :CH 3 OH (5:1), 0–10 °C, 18 h, then 5 equiv NH 4 CO 3 , CH 3 OH, 18 h; (iv) R -Cl (2-, 3-, 4-nitrophenylsulfonyl chlorides), Et 3 N, THF, then HCl(g), CH 3 CO 2 CH 3 :CH 3 OH (5:1), 0–10 °C, 18 h, then 5 equiv (NH 4 ) 2 CO 3 , CH 3 OH, 18 h, then H 2 , Pd-C, MeOH. , an inhibitor of fXa with good potency in vitro and an improved pharmacokinetic profile in rabbit. The X-ray crystallographic study of a representative analogue confirms our binding model for this series.