New Heterocyclic Hepatitis C Virus (HCV) Inhibitors
355
1-[(1-Methyl-1H-indol-2-yl)methyl]piperidine-4-carb-
oxylic acid (1.2.7). Yield 78%. GC-MS (ESI) [M + H]+ 273.
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-4-yl]-(4-
methylpiperazin-1-yl)ketone (27). Yield 56%. GC-MS
PMR (DMSO-d ), d, ppm: 7.46 (d, J 8.0 Hz, 1H), 7.38 (d, J
(M + H)+ 355. PMR (DMSO-d , 400 MHz), d, ppm: 11.41
6
6
8.4 Hz, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 6.31 (s, 1H), 3.74
(s, 3H), 3.60 (s, 2H), 2.80 (m, 2H), 2.20 (m, 1H), 2.03 (m,
2H), 1.78 (m, 2H), 1.52 (m, 2H).
(br.s, 1H), 10.93 (br.s, 1H), 7.60 (d, J 7.6 Hz, 1H), 7.51 (d,
J = 8.4 Hz, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 6.81 (s, 1H),
4.54 (br.s, 2H), 4.40 (br.m, 1H), 4.12 (br.m, 1H), 3.85 (s,
3H), 3.50 (br.m, 5H), 3.00 (br.m, 4H), 2.87 (br.m, 2H), 2.73
(s, 3H), 1.98 (br.m, 2H), 1.82 (br.m, 2H).
1-[(1-Methyl-1H-indol-2-yl)methyl]piperidine-3-carb-
oxylic acid (1.2.8). Yield 93%. GC-MS (ESI) [M + H]+ 273.
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-4-yl]-(4-
PMR (DMSO-d ), d, ppm: 7.46 (d, J 8.0 Hz, 1H), 7.38 (d, J
6
methylpiperazin-1-yl)ketone dihydrochloride (27•2HCl).
Yield 46%. GC-MS (M + H)+ 355. PMR (DMSO-d ,
8.0 Hz, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 6.32 (s, 1H), 3.73
(s, 3H), 3.62 (m, 2H), 2.84 (m, 1H), 2.64 (m, 1H), 2.39 (m,
1H), 2.20 (m, 1H), 2.08 (m, 1H), 1.77 (m, 1H), 1.63 (m, 1H),
1.41 (m, 2H).
6
400 MHz), d, ppm: 11.28 (br.s, 1H), 11.14 (br.s, 1H), 7.59 (d,
J 8.0 Hz, 1H), 7.50 (d, J 8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m,
1H), 6.83 (br.m, 1H), 4.57 (br.s, 2H), 4.37 (br.m, 1H), 4.07
(br.m, 1H), 3.87 (s, 3H), 3.55 (br.m, 1H), 3.42 (br.m, 4H),
3.14 (br.m, 2H), 3.02 (br.m, 3H), 2.89 (br.m, 1H), 2.72 (br.m,
3H), 1.98 (br.m, 1H), 1.86 (br.m, 2H), 1.44 (br.m, 1H).
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-4-yl]-(4-
propylpiperazin-1-yl)ketone dihydrochloride (28•2HCl).
1-{[1-(4-Chlorobenzyl)-1H-indol-2-yl]methyl}piperi-
dine-3-carboxylic acid (1.2.9). Yield 82%. GC-MS (ESI)
[M + H]+ 383, 385. PMR (DMSO-d ), d, ppm: 7.51 (d, J
6
7.6 Hz, 1H), 7.32 (d, J 8.4 Hz, 2H), 7.29 (d, J 8.4 Hz, 1H),
7.06 (m, 1H), 7.01 (m, 3H), 6.43 (s, 1H), 5.50 (s, 2H), 3.54
(m, 2H), 2.81 (m, 1H), 2.60 (m, 1H), 2.15 (m, 2H), 1.99 (m,
1H), 1.72 (m, 1H), 1.54 (m, 1H), 1.29 (m, 2H).
Yield 28%. GC-MS (M + H)+ 383. PMR (DMSO-d ,
6
1-[(1-Methyl-1H-benz[d]imidazol-2-yl)methyl]piperi-
400 MHz), d, ppm: 11.29 (br.s, 1H), 10.80 (br.s, 1H), 7.60 (d,
J 8.0 Hz, 1H), 7.51 (d, J 8.0 Hz, 1H), 7.23 (m, 1H), 7.09 (m,
1H), 6.80 (s, 1H), 4.55 (br.s, 2H), 4.39 (br.m, 1H), 4.11
(br.m, 1H), 3.85 (s, 3H), 3.59 (br.m, 1H), 3.51 (br.m, 2H),
3.43 (br.m, 2H), 3.12 (m, 1H), 2.98 (br.m, 5H), 2.86 (br.m,
2H), 2.73 (s, 3H), 1.96 (br.m, 2H), 1.82 (br.m, 2H), 1.72 (m,
2H), 0.90 (t, J 7.2 Hz, 3H).
dine-4-carboxylic acid (1.2.10). Yield 74%. GC-MS (ESI)
[M + H]+ 274. PMR (DMSO-d ), d, ppm: 7.76 (m, 2H), 7.42
6
(m, 2H), 4.74 (s, 2H), 3.98 (s, 3H), 3.63 (m, 2H), 3.28 (m,
2H), 2.57 (m, 1H), 2.05 (m, 2H), 1.99 (m, 2H).
Amides of 1-(hetarylmethyl)piperidinecarboxylic ac-
ids (25 – 28 and 58 – 62), general method. A solution of the
appropriate 1-(hetarylmethyl)piperidinecarboxylic acid
(1.2.8 – 1.2.11, 1 mmol) and carbodiimidazole (195 mg,
1.2 mmol) in DMF (4 mL) was stirred for 1 h at 65°C,
treated with the amine (1.1 mmol), stirred for another 12 h at
65°C, poured into K CO solution (10%), and extracted with
[1-(1-Methyl-1H-benzimidazol-2-ylmethyl)piperidin-
4-yl]-(4-propylpiperazin-1-yl)ketone
dihydrochloride
(58•2HCl). GC-MS (ESI) [M + H]+ 384. PMR (DMSO-d ),
6
d, ppm: 11.39 (br.s, 1H), 7.69 (d, J 7.6 Hz, 1H), 7.64 (d, J
8.0 Hz, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 4.62 (s, 2H), 4.40
(br.m, 1H), 4.13 (br.m, 1H), 3.91 (s, 3H), 3.61 (br.m, 4H),
3.15 (br.m, 3H), 2.98 (br.m, 4H), 2.86 (br.m, 2H), 1.95 (br.m,
2H), 1.88 (m, 2H), 1.73 (m, 2H), 0.90 (t, J 7.0 Hz, 3H).
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-3-yl]-(4-
methylpiperazin-1-yl)ketone dihydrochloride (59•2HCl).
2
3
CH Cl . The extract was dried over Na SO and evaporated
2
2
2
4
in vacuo. The solids were chromatographed over silica gel
(EtOAc:Et N eluent, 40:1). Yields of amides 25 – 28 and
3
58 – 62, ~80%. Dihydrochlorides of the amides were pre-
pared by adding a 5% excess of HCl solution (3 M) in
GC-MS (ESI) [M + H]+ 355. PMR (DMSO-d ), d, ppm:
dioxane to solutions of the bases in Me CO. The precipitates
2
6
were filtered off, rinsed with Et O, and dried in vacuo.
11.28 (m, 2H), 7.59 (d, J 8.0 Hz, 1H), 7.50 (d, J 8.0 Hz, 1H),
7.22 (m, 1H), 7.07 (m, 1H), 6.84 (s, 1H), 4.57 (s, 2H), 4.38
(m, 1H), 4.07 (m, 1H), 3.87 (s, 3H), 3.53 (m, 2H), 3.41 (m,
4H), 3.14 (m, 2H), 3.02 (br.m, 4H), 2.89 (br.m, 1H), 2.73
(br.s, 3H), 1.98 (m, 1H), 1.86 (m, 2H), 1.44 (m, 1H).
2
N-(2-Dimethylaminoethyl)-1-(1-methyl-1H-indol-2-yl-
methyl)piperidine-4-carboxamide
dihydrochloride
(25•2HCl). GC-MS (ESI) [M + H]+ 343. PMR (DMSO-d ),
6
d, ppm: 10.62 (m, 2H), 8.42 (t, J 5.0 Hz, 1H), 7.59 (d, J
7.2 Hz, 1H), 7.50 (d, J 8.0 Hz, 1H), 7.22 (m, 1H), 7.07 (m,
1H), 6.83 (s, 1H), 4.55 (m, 2H), 3.85 (s, 3H), 3.48 (br.m,
2H), 3.28 (m, 2H), 3.12 (m, 2H), 3.05 (br.m, 2H), 2.74 (d, J
3.2 Hz, 3H), 2.42 (m, 1H), 2.00 (m, 4H).
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-3-yl]-(4-
propylpiperazin-1-yl)ketone (60). Yield 47%. GC-MS
(M + H)+ 383. PMR (DMSO-d , 400 MHz), d, ppm: 11.19
6
(br.m, 2H), 7.59 (d, J 7.6 Hz, 1H), 7.50 (d, J 8.0 Hz, 1H),
7.22 (m, 1H), 7.07 (m, 1H), 6.83 (br.m, 1H), 4.56 (br.s, 2H),
4.37 (m, 1H), 4.05 (m, 1H), 3.87 (s, 3H), 3.61 (m, 1H), 3.44
(br.m, 5H), 3.14 (br.m, 2H), 2.98 (br.m, 4H), 2.86 (br.m, 1H),
1.98 (br.m, 1H), 1.86 (br.m, 2H), 1.70 (br.m, 2H), 1.44 (br.m,
1H), 0.89 (br.m, 3H).
N-(2-Dimethylaminopropyl)-1-(1-methyl-1H-indol-2-
ylmethyl)piperidine-4-carboxamide
dihydrochloride
(26•2HCl). GC-MS (ESI) [M + H]+ 357. PMR (DMSO-d ),
6
d, ppm: 10.51 (m, 2H), 8.23 (t, J 5.2 Hz, 1H), 7.59 (d, J
8.0 Hz, 1H), 7.50 (d, J 8.4 Hz, 1H), 7.22 (m, 1H), 7.08 (m,
1H), 6.82 (s, 1H), 4.54 (m, 2H), 3.85 (s, 3H), 3.48 (br.m,
2H), 3.25 (m, 2H), 3.09 (m, 2H), 2.99 (m, 2H), 2.70 (d, J
4.8 Hz, 3H), 2.38 (m, 1H), 1.96 (m, 4H), 1.78 (m, 2H).
[1-(1-Methyl-1H-indol-2-ylmethyl)piperidin-3-yl]-(4-
propylpiperazin-1-yl)ketone dihydrochloride (60•2HCl).
Yield 47%. GC-MS (M + H)+ 383. PMR (DMSO-d ,
6