Benzimidazole DeriVatiVes as HCV NS5B Inhibitors
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4731
2-[4-(4-Carbamoyl-4′-chlorobiphenyl-2-ylmethoxy)phenyl]-1-
cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3j). Mp 280-
Hz, 1H), 8.16 (s, 1H), 8.30 (s, 1H), 8.37 (d, J ) 7.3 Hz, 1H); MS
(FAB) m/z 640 (M + H)+. Anal. (C37H35ClFN3O4‚HCl) C, H, N.
2-{4-[4′-Chloro-4-(2-hydroxyethylcarbamoyl)biphenyl-2-yl-
methoxy]-2-fluorophenyl}-1-cyclohexyl-1H-benzimidazole-5-
carboxylic Acid (10d). Mp 270-271 °C; 1H NMR (DMSO-d6) δ
1.17-1.48 (m, 3H), 1.58-1.70 (m, 1H), 1.76-2.00 (m, 4H), 2.12-
2.37 (m, 2H), 3.37 (m, 2H), 3.55 (t, J ) 6.3 Hz, 2H), 3.60 (s, 1H),
4.11 (m, 1H), 5.14 (s, 2H), 7.07 (d, J ) 8.7 Hz, 1H), 7.19 (d, J )
12.6 Hz, 1H), 7.47 (d, J ) 7.5 Hz, 1H), 7.49 (d, J ) 8.7 Hz, 2H),
7.53 (d, J ) 8.7 Hz, 2H), 7.66 (t, J ) 7.7 Hz, 1H), 7.98-8.02 (m,
2H), 8.17 (d, J ) 9 Hz, 1H), 8.19 (s, 1H), 8.31 (s, 1H), 8.62 (t, J
) 6 Hz, 1H); HRMS calcd for C36H34ClFN3O5 (M + H)+ 642.2171,
found 642.2159; HPLC method A, 99% (10.36 min); HPLC method
B, 99% (6.50 min).
1
281 °C; H NMR (DMSO-d6) δ 1.20-1.52 (m, 3H), 1.58-1.73
(m, 1H), 1.80-1.93 (m, 2H), 1.97-2.12 (m, 2H), 2.18-2.38 (m,
2H), 4.36 (m, 1H), 5.14 (s, 2H), 7.24 (d, J ) 9 Hz, 2H), 7.43-
7.57 (m, 6H), 7.73 (d, J ) 9 Hz, 2H), 7.99 (dd, J ) 1.7, 8 Hz,
1H), 8.04 (d, J ) 9 Hz, 1H), 8.13 (brs, 1H), 8.19 (d, J ) 1.8 Hz,
1H), 8.26 (d, J ) 9 Hz, 1H), 8.30 (d, J ) 1.5 Hz, 1H); MS (FAB)
m/z 580 (M + H)+. Anal. (C34H30ClN3O4‚HCl‚0.5H2O) C, H, N.
2-[4-(4′-Chloro-4-methylcarbamoylbiphenyl-2-ylmethoxy)-
phenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3k).
Mp 268-269 °C; 1H NMR (DMSO-d6) δ 1.18-1.50 (m, 3H),
1.55-1.72 (m, 1H), 1.75-2.10 (m, 4H), 2.18-2.40 (m, 2H), 2.82
(d, J ) 4.4 Hz, 3H), 4.34 (m, 1H), 5.14 (s, 2H), 7.22 (d, J ) 8.7
Hz, 2H), 7.47 (d, J ) 8.1 Hz, 1H), 7.52 (s, 4H), 7.71 (d, J ) 8.7
Hz, 2H), 7.95 (d, J ) 8.1 Hz, 1H), 8.01 (d, J ) 8.7 Hz, 1H), 8.15
(s, 1H), 8.22 (d, J ) 8.7 Hz, 1H), 8.28 (s, 1H), 8.61 (q, J ) 4.4
Hz, 1H); MS (FAB) m/z 594 (M + H)+. Anal. (C35H32ClN3O4‚
HCl‚0.8H2O) C, H, N.
2-[4-(4′-Chloro-4-dimethylcarbamoylbiphenyl-2-ylmethoxy)-
phenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3l).
Mp 266-267 °C; 1H NMR (DMSO-d6) δ 1.21-1.50 (m, 3H),
1.60-1.72 (m, 1H), 1.81-1.94 (m, 2H), 1.97-2.09 (m, 2H), 2.20-
2.37 (m, 2H), 2.97 (brs, 3H), 3.01 (brs, 3H), 4.35 (m, 1H), 5.15 (s,
2H), 7.23 (d, J ) 8.7 Hz, 2H), 7.42 (d, J ) 7.6 Hz, 1H), 7.49-
7.55 (m, 5H), 7.71 (s, 1H), 7.72 (d, J ) 8.7 Hz, 2H), 8.03 (dd, J
) 1.5, 8.7 Hz, 1H), 8.25 (d, J ) 9.1 Hz, 1H), 8.30 (d, J ) 1.5 Hz,
1H); MS (FAB) m/z 608 (M + H)+. Anal. (C36H34ClN3O4‚HCl) C,
H, N.
2-[4-(4′-Chloro-4-dimethylcarbamoylbiphenyl-2-ylmethoxy)-
2-fluorophenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid
1
(10e). Mp 240-241 °C; H NMR (DMSO-d6) δ 1.21-1.45 (m,
3H), 1.59-1.72 (m, 1H), 1.79-1.95 (m, 4H), 2.13-2.32 (m, 2H),
2.98 (s, 3H), 3.01 (s, 3H), 4.06 (m, 1H), 5.14 (s, 2H), 7.03 (dd, J
) 1.8, 8.2 Hz, 1H), 7.17 (dd, J ) 2.2, 12 Hz, 1H), 7.43 (d, J ) 7.9
Hz, 1H), 7.44-7.56 (m, 5H), 7.63 (t, J ) 8.2 Hz, 1H), 7.71 (d, J
) 1.8 Hz, 1H), 7.97 (dd, J ) 1.5, 8.6 Hz, 1H), 8.13 (d, J ) 9 Hz,
1H), 8.29 (s, 1H); MS (FAB) m/z 626 (M + H)+. Anal. (C36H33-
ClFN3O4‚HCl) C, H, N.
2-{4-[4′-Chloro-4-(piperidine-1-carbonyl)biphenyl-2-yl-
methoxy]-2-fluorophenyl}-1-cyclohexyl-1H-benzimidazole-5-
1
carboxylic Acid (10f). Mp 223-224 °C; H NMR (DMSO-d6) δ
1.18-1.71 (m, 10H), 1.71-1.98 (m, 4H), 2.10-2.35 (m, 2H),
3.23-3.71 (m, 2H), 4.07 (m, 1H), 5.15 (s, 2H), 7.02 (dd, J ) 2.2,
8.4 Hz, 1H), 7.16 (dd, J ) 2.2, 12 Hz, 1H), 7.43 (d, J ) 7.5 Hz,
1H), 7.47-7.51 (m, 5H), 7.63 (t, J ) 8.4 Hz, 1H), 7.67 (s, 1H),
7.97 (dd, J ) 1.4, 8.7 Hz, 1H), 8.13 (d, J ) 8.7 Hz, 1H), 8.29 (s,
1H); MS (FAB) m/z 666 (M + H)+. Anal. (C39H37ClFN3O4‚HCl)
C, H, N.
2-[4-(4-Benzylcarbamoyl-4′-chlorobiphenyl-2-ylmethoxy)phe-
nyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3m). Mp
1
231-233 °C; H NMR (DMSO-d6) δ 1.19-1.47 (m, 3H), 1.59-
1.72 (m, 1H), 1.79-1.91 (m, 2H), 1.95-2.08 (m, 2H), 2.18-2.37
(m, 2H), 4.35 (m, 1H), 4.52 (d, J ) 5.9 Hz, 2H), 5.15 (s, 2H),
7.22-7.28 (m, 3H), 7.34 (d, J ) 4.4 Hz, 4H), 7.48-7.55 (m, 5H),
7.72 (d, J ) 8.6 Hz, 2H), 8.03 (d, J ) 7.9 Hz, 2H), 8.22 (s, 1H),
8.24 (d, J ) 8.9 Hz, 1H), 8.29 (s, 1H), 9.23 (t, J ) 6.2 Hz, 1H);
MS (FAB) m/z 670 (M + H)+. Anal. (C41H36ClN3O4‚HCl‚CH3-
CH2OH) C, H, N.
2-{4-[4′-Chloro-4-(morpholine-4-carbonyl)biphenyl-2-yl-
methoxy]-2-fluorophenyl}-1-cyclohexyl-1H-benzimidazole-5-
carboxylic Acid (10g). Mp 248-249 °C; 1H NMR (DMSO-d6) δ
1.21-1.47 (m, 3H), 1.58-1.70 (m, 1H), 1.78-1.96 (m, 4H), 2.14-
2.31 (m, 2H), 3.33-3.75 (m, 6H), 4.05 (m, 1H), 4.00-4.40 (m,
2H), 5.12 (s, 2H), 7.03 (d, J ) 8.4 Hz, 1H), 7.18 (dd, J ) 2.1, 12.1
Hz, 1H), 7.43-7.57 (m, 6H), 7.64 (t, J ) 8.8 Hz, 1H), 7.72 (s,
1H), 7.98 (d, J ) 8.8 Hz, 1H), 8.15 (d, J ) 8.6 Hz, 1H), 8.29 (s,
1H); MS (FAB) m/z 668 (M + H)+. Anal. (C38H35ClFN3O5‚0.3H2O)
C, H, N.
2-{4-[4′-Chloro-4-(4-hydroxypiperidine-1-carbonyl)biphenyl-
2-ylmethoxy]-2-fluorophenyl}-1-cyclohexyl-1H-benzimidazole-
5-carboxylic Acid (10h). Mp 182-185 °C; 1H NMR (DMSO-d6)
δ 1.19-1.55 (m, 5H), 1.60-1.95 (m, 7H), 2.10-2.30 (m, 2H),
3.10-3.35 (m, 2H), 3.45-4.40 (m, 5H), 5.14 (s, 2H), 7.02 (d, J )
8.4 Hz, 1H), 7.15 (d, J ) 11.7 Hz, 1H), 7.43 (d, J ) 7.5 Hz, 1H),
7.45-7.55 (m, 5H), 7.62 (t, J ) 8.2 Hz, 1H), 7.68 (s, 1H), 7.96 (d,
J ) 8.9 Hz, 1H), 8.11 (d, J ) 8.9 Hz, 1H), 8.28 (s, 1H); MS (FAB)
m/z 682 (M + H)+. Anal. (C39H37ClFN3O5‚HCl‚0.5H2O) C, H, N.
2-[4-(4′-Chloro-4-dimethylaminobiphenyl-2-ylmethoxy)phe-
nyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3f). Steps
1-3: Preparationof2-[4-(4′-Chloro-4-nitrobiphenyl-2-ylmethoxy)-
phenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid Meth-
yl Ester (20a). Compound 20a was prepared from 2-bromo-5-
nitrotoluene 14e and the phenol 11a using the procedure described
above for 2b (steps 1-3) in 51% yield: 1H NMR (CDCl3) δ 1.15-
1.39 (m, 3H), 1.60-1.77 (m, 1H), 1.78-1.95 (m, 4H), 2.10-2.32
(m, 2H), 3.87 (s, 3H), 4.26 (m, 1H), 4.97 (s, 2H), 6.94 (d, J ) 8.5
Hz, 2H), 7.27 (d, J ) 8.3 Hz, 2H), 7.39 (d, J ) 8.6 Hz, 2H), 7.42
(d, J ) 8.6 Hz, 1H), 7.49 (d, J ) 8.5 Hz, 2H), 7.57 (d, J ) 8.7 Hz,
1H), 7.88 (d, J ) 8.6 Hz, 1H), 8.26 (d, J ) 8.4 Hz, 1H), 8.39 (s,
1H), 8.49 (s, 1H).
2-[4-(4′-Chloro-5-dimethylcarbamoylbiphenyl-2-ylmethoxy)-
phenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid (3n).
Compound 3n was prepared from 3-bromo-4-methylbenzoic acid
using the procedure described for 3h (steps 1-5) and 10a (steps
1-3) in 39% yield. In this case, dimethylamine was used instead
of methylamine: mp 261-262 °C; 1H NMR (DMSO-d6) δ 1.21-
1.50 (m, 3H), 1.60-1.70 (m, 1H), 1.81-2.08 (m, 4H), 2.20-2.37
(m, 2H), 2.98 (brs, 6H), 4.36 (m, 1H), 5.14 (s, 2H), 7.23 (d, J )
9 Hz, 2H), 7.37 (d, J ) 1.8 Hz, 1H), 7.51-7.54 (m, 5H), 7.73 (d,
J ) 9 Hz, 2H), 7.74 (d, J ) 8.1 Hz, 1H), 8.03 (dd, J ) 1.5, 8.4
Hz, 1H), 8.43 (d, J ) 8.4 Hz, 1H), 8.31 (d, J ) 1.5 Hz, 1H); MS
(FAB) m/z 608 (M + H)+. Anal. (C36H34ClN3O4‚HCl‚H2O) C, H,
N.
2-[4-(4′-Chloro-4-propylcarbamoylbiphenyl-2-ylmethoxy)-2-
fluorophenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid
1
(10b). Mp 263-264 °C; H NMR (DMSO-d6) δ 0.91 (t, J ) 7.5
Hz, 3H), 1.05-1.45 (m, 3H), 1.47-1.70 (m, 3H), 1.75-2.00 (m,
4H), 2.05-2.30 (m, 2H), 3.26 (m, 2H), 4.08 (m, 1H), 5.13 (s, 2H),
7.04 (d, J ) 8.7 Hz, 1H), 7.17 (d, J ) 12 Hz, 1H), 7.47 (d, J ) 7.2
Hz, 1H), 7.48 (d, J ) 9 Hz, 2H), 7.53 (d, J ) 9 Hz, 2H), 7.64 (t,
J ) 9 Hz, 1H), 7.95-8.00 (m, 2H), 8.14 (d, J ) 8.4 Hz, 1H), 8.16
(s, 1H), 8.29 (s, 1H), 8.60 (t, J ) 6.3 Hz, 1H); MS (FAB) m/z 640
(M + H)+. Anal. (C37H35ClFN3O4‚HCl‚0.5H2O) C, H, N.
2-[4-(4′-Chloro-4-isopropylcarbamoylbiphenyl-2-ylmethoxy)-
2-fluorophenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic Acid
1
(10c). Mp 272-273 °C; H NMR (DMSO-d6) δ 1.19 (d, J ) 6.3
Hz, 6H), 1.14-1.44 (m, 3H), 1.57-1.72 (m, 1H), 1.78-1.99 (m,
4H), 2.13-2.34 (m, 2H), 4.03-4.22 (m, 2H), 5.13 (s, 2H), 7.06
(dd, J ) 2.1, 8.4 Hz, 1H), 7.18 (dd, J ) 1.8, 12 Hz, 1H), 7.46 (d,
J ) 7.8 Hz, 1H), 7.48 (d, J ) 8.7 Hz, 2H), 7.53 (d, J ) 8.4 Hz,
2H), 7.65 (t, J ) 8.4 Hz, 1H), 7.95-8.02 (m, 2H), 8.15 (d, J ) 7.8
Step 4: Preparation of 2-[4-(4-Amino-4′-chlorobiphenyl-2-
ylmethoxy)phenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxy-
lic Acid Methyl Ester (21a). To a solution of 20a (1.70 g, 2.85
mmol) obtained above in EtOH (20 mL) and THF (15 mL) was
added tin(II) chloride dihydrate (3.20 g, 14.2 mmol). The mixture