Synthesis and evaluation of non-dimeric HCV NS5A inhibitors

Abstract

Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).

Figure 1

Structures of BMS-790052 and targeted monodentate compounds.

Scheme 1

Reagents and conditions: (a) Br₂, CH₂Cl₂, rt, overnight, 70-95%; (b) Boc-Pro-OH, DIPEA, CH₃CN, rt, 5 h; (c) NH₄OAc, toluene, 95 °C, 15-20 h, 62-72% 2 steps; (d) 6N HCl, CH₃OH, 50 °C; (e) R⁴-(CO)NH-CHR³-COOH, DIPEA, HOBt, EDC, CH₃CN, 0 °C to rt, 15 h, 45-65% 2 steps; (f) NXS, CH₂Cl₂, rt, 0.5-15 h, 42-65% (X = Br, Cl, I).

Scheme 2

Reagents and conditions: a) R⁵-Ph-B(OH)₂, PdCl₂(PPh₃)₂, Na₂CO₃, THF, rt, 50-77%; (b) NCS, CH₂Cl₂, rt, 15 h, 58%.

Scheme 3

Reagents and conditions: (a) H₂, Pd/C, MeOH, rt, 15 h, 91%; (b) MeOC(O)Cl, pyridine, rt or MeSO₂Cl, pyridine, rt, 15 h, 60-75%.