Synthesis and biological evaluation of new potent and selective HCV NS5A inhibitors

Abstract

NS5A inhibitors are a new class of direct-acting antiviral agents which display very potent anti-HCV activity in vitro and in humans. Rationally designed modifications to the central biphenyl linkage of a known NS5A series led to selection of several compounds that were synthesized and evaluated in a HCV genotype 1b replicon. The straight triphenyl linked compound 11a showed similar anti-HCV activity to the clinical compound BMS-790052 and a superior cytotoxicity profile in three different cell lines, with an EC(50) value of 26 pM and a therapeutic index of over four million in an HCV replicon assay. This triphenyl analog warrants further preclinical evaluation as an anti-HCV agent.

Figure 1.

Chemical structure of BMS-790052.

Figure 2.

Chemical structures for 6a–c, 7a–d and 12.

Scheme 1.

Synthesis of 5a–d. Reagents and conditions: (a) N-Boc-l-proline, MeCN, Et₃N, rt, 2 h, 51–100%; (b) NH₄OAc, toluene, 95–100 °C, 14 h, 51–73%; (c) 6 N HCl, MeOH, 50 °C, 4 h, 85–99%; (d) HOBt, EDAC, N-(methoxycarbonyl)-l-valine, MeCN, DIPEA, rt, 14 h, 64–95%.

Scheme 2.

Synthesis of 11a–e. Reagents and conditions: (a) Pd(PPh₃)₄, bis(pinacolato) diboron, KOAc, 1,4-dioxane, 80 °C, 16 h, 84%; (b) Pd(PPh₃)₄, NaHCO₃, 1,2-dimethoxyethane, H₂O, dihalide (1,4-diiodobenzene, 2,5-dibromopyridine, 1,3-dibromobenzene, 2,5-dibromothiophene, or 4,4′-diiodobiphenyl), 80 °C, 14 h, 80–99%; (c) 6 N HCl, MeOH, 50 °C, 4 h, 86–95%; (d) HOBt, EDAC, N-(methoxycarbonyl)-l-valine, MeCN, DIPEA, rt, 14 h, 28–59%.

Scheme 3.

Synthesis of triazole 17. Reagents and conditions: (a) (i) trimethylsilyl-acetylene, CuI, Pd(PPh₃)₄, Et₃N, THF, rt, 2 h; (ii) K₂CO₃, THF, MeOH, rt, 3 h, 72%; (b) 7c, CuSO₄, sodium ascorbate, t-BuOH, H₂O, 95–100 °C, 14 h, 67%; (c) 6 N HCl, MeOH, 50 °C, 4 h, 85%; (d) HOBt, EDAC, N-(methoxycarbonyl)-l-valine, MeCN, DIPEA, rt, 14 h, 80%.