3150 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 8
Penning et al.
7.98 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 2H). MS (DCI):
m/z 321 (M þ H)þ.
general procedure B, using acetone in place of formaldehyde
(9 mg, 13%). H NMR (DMSO-d6): δ 0.76 (s, 2H), 0.95 (s,
1
2-(4-(1-Methylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-4-
carboxamide (8). The title compound was prepared from 6 and
formaldehyde using general procedure B (80 mg, 69%). 1H
NMR (CD3OD): δ 2.29 (m, 1H), 2.61 (m, 1H), 3.06 (s, 3H),
3.29 (m, 1H), 3.71 (m, 2H), 3.96 (m, 2H), 7.52 (t, J = 7.9 Hz,
1H), 7.62 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.98 (d,
J = 7.6 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H). MS (DCI): m/z 321
(M þ H)þ.
2H), 1.11 (m, 1H), 1.26 (d, J = 6.1 Hz, 2H), 1.48 (s, 2H), 1.73
(s, 3H), 2.16 (s, 1H), 2.93 (s, 1H), 7.33 (m, 1H), 7.52 (s, 1H),
7.73 (s, 3H), 7.86 (d, J = 7.7 Hz 1H), 8.17 (m, 2H), 9.35 (s, 1H).
MS (ESI): m/z 363 (M þ H)þ.
2-(4-(1-Isopropyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-
carboxamide (18). The title compound was prepared from 12
and acetone using general procedure B (41 mg, 72%). 1H NMR
(DMSO-d6): δ 1.27 (d, J = 4.6 Hz, 6H), 1.84 (m, 1H), 1.98 (m,
2H), 2.98 (m, 1H), 3.16 (d, J = 5.2 Hz, 2H), 3.43 (m, 4H), 7.34 (t,
J = 7.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.7 Hz,
2H), 7.87 (d, J = 7.4 Hz, 1H), 8.21 (d, J = 8.3 Hz, 2H), 9.32 (s,
1H). MS (ESI): m/z 363 (M þ H)þ.
2-(4-(1-Isopropylpyrrolidin-2-yl)phenyl)-1H-benzimidazole-
4-carboxamide (9). The title compound was prepared from 5
and acetone using general procedure B (34 mg, 30%). 1H
NMR (CD3OD): δ 1.34 (dd, J = 6.6, 2.0 Hz, 6H), 2.30 (m,
3H), 2.60 (m, 1H), 3.51 (m, 2H), 3.70 (m, 1H), 4.74 (m, 1H),
7.49 (t, J = 7.9 Hz, 1H), 7.83 (m, 3H), 7.99 (d, J = 7.6 Hz, 1H),
8.32 (d, J = 8.5 Hz, 2H). MS (DCI): m/z 349 (M þ H)þ.
2-(4-(1-Isopropylpyrrolidin-3-yl)phenyl)-1H-benzimidazole-
4-carboxamide (10). To a solution of 5 (100 mg, 0.33 mmol) in
MeOH (10 mL) was added acetone (38 mg, 0.54 mmol), and the
mixture was stirred at ambient temperature for 40 min. Sodium
triacetoxyborohydride (253 mg, 1.2 mmol) and AcOH (100 μL)
were added, and the mixture was stirred at ambient temperature
for 18 h. Dichloromethaneandwater wereadded, and the organic
layer was washed with dilute NaOH and water and concentrated.
Purification by HPLC provided the title compound (30 mg,
2-(4-(1-Isopropyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-
carboxamide (19). The title compound was prepared from 13
and acetone using general procedure B (86 mg, 76%). 1H NMR
(DMSO-d6): δ 1.30 (d, J = 6.7 Hz, 6H), 1.95 (m, 2H), 2.11 (d,
J = 13.7 Hz, 2H), 8.97 (s, 1H), 3.00 (ddd, J = 12.1, 8.8, 3.8 Hz,
1H), 3.26 (s, 1H), 3.13 (m, 3H), 3.53 (d, J = 9.5 Hz, 1H), 7.36 (t,
J = 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.77 (m, 2H), 7.87 (d,
J = 7.6 Hz, 1H), 8.23 (d, J = 8.2 Hz, 2H). MS (DCI): m/z 363
(M þ H)þ.
6-Fluoro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-car-
boxamide (20). The title compound was prepared as described
for the synthesis of 21, using 2,3-diamino-5-fluorobenzamide12
in place of 2,3-diamino-5-chlorobenzamide (120 mg, 57%). 1H
NMR (DMSO-d6): δ 2.12 (m, 3H), 2.47 (m, 1H), 3.41 (m, 2H),
4.69 (s, 1H), 7.62 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.99 (s, 1H),
8.33 (d, J = 8.2 Hz, 2H), 8.96 (s, 1H), 9.21 (s, 1H), 9.77 (s, 1H).
1
27%). H NMR (CD3OD): δ 1.44 (d, J = 6.7 Hz, 6H), 2.25
(m, 1H), 2.59 (m, 1H), 3.30 (m, 1H), 3.57 (m, 2H), 3.69 (m, 1H),
3.77-3.88 (m, 2H), 4.02 (dd, J = 10.7, 7.0 Hz, 1H), 7.54 (t, J =
7.9 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H),
7.99 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 7.9 Hz, 2H). Anal.
Anal. (C18H17FN4O 2.2TFA) C, H, N.
3
6-Chloro-2-(4-pyrrolidin-2-ylphenyl)-1H-benzimidazole-4-carbox-
amide (21). Step 1. Preparation of tert-Butyl 2-(4-(4-Carbamoyl-6-
chloro-1H-benzimidazol-2-yl)phenyl)pyrrolidine-1-carboxylate. To a
solution of tert-butyl 2-(4-carboxyphenyl)-pyrrolidine-1-carboxy-
late (500 mg, 1.7 mmol) in dichloromethane (10 mL) were added
oxalyl chloride (0.15 mL, 1.7 mmol) and DMF (1 drop), and the
mixture was stirred at ambient temperature for 1 h. After concen-
tration, the residue was dissolved in dichloromethane (20 mL), and
the solution was added to a solution of 2,3-diamino-5-chlorobenza-
mide12 (316 mg, 1.7 mmol) in THF (10 mL), followed by triethy-
lamine (2 mL). The mixture was stirred at ambient temperature for
18 h and concentrated. The residue was dissolved in AcOH (10 mL),
heated at 80 °C for 2 h, and concentrated. The residue was dissolved
in EtOAc, washed with sodium bicarbonate solution and brine, and
concentrated. Purification by flash chromatography on silica gel
using EtOAc afforded the title compound (370 mg, 55%).
(C21H24N4O 2.5TFA) C, H, N.
3
2-(4-Piperidin-2-ylphenyl)-1H-benzimidazole-4-carboxamide (11).
A mixture of 4a (0.905 g, 2.9 mmol) and PtO2 (180 mg) in AcOH
(20 mL) under hydrogen (60 psi) was stirred at ambient temperature
for 4.5 h, filtered through a nylon membrane, and concentrated.
The residue was purified by flash chromatography on silica gel using
10% MeOH/dichloromethane to provide the title compound
1
(0.56 g, 55%). H NMR (DMSO-d6): δ 1.64 (m, 1H), 1.89 (m,
6H), 3.03 (td, J = 12.2, 4.2 Hz, 2H), 3.17 (s, 1H), 4.27 (dd, J = 11.7,
3.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.77 (m, 4H), 7.89 (d, J =
7.5 Hz, 1H), 8.33 (d, J = 8.1 Hz, 2H), 9.33 (s, 1H). MS (ESI): m/z
321 (M þ H)þ.
2-(4-Piperidin-3-ylphenyl)-1H-benzimidazole-4-carboxamide (12).
The title compound was prepared from 3 using the procedure
described for 11 (0.96 g, 95%). 1H NMR (DMSO-d6): δ 1.52 (d,
J= 12.2 Hz, 1H), 1.63 (dd, J= 12.2, 3.0 Hz, 1H), 1.68 (m, 1H), 1.91
(s, 1H), 2.57 (m, 2H), 2.67-2.75 (m, 1H), 2.97 (d, J = 12.2 Hz, 1H),
3.03 (d, J = 11.3 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2
Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 7.6 Hz 1H), 8.16 (d,
J = 7.9 Hz, 1H), 9.33 (s, 1H). MS (ESI): m/z 321 (M þ H)þ.
2-(4-(1-Methyl-piperidin-3-yl)phenyl)-1H-benzimidazole-4-
carboxamide (15). The title compound was prepared from 12
and formaldehyde using general procedure B (10 mg, 22%).
1H NMR (DMSO-d6): δ 1.43 (dd, J = 12.0, 4.0 Hz, 1H), 1.62
(m, 1H), 1.71 (m, 1H), 1.85 (s, 2H), 1.96 (m, 1H), 1.99 (m, 1H),
2.20 (s, 3H), 2.82 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 7.48 (t, J =
7.3 Hz, 2H), 7.71 (d, J = 7.1 Hz, 2H), 7.85 (d, J = 7.4 Hz 1H),
Step 2. Preparation of 6-Chloro-2-(4-pyrrolidin-2-ylphenyl)-
1H-benzimidazole-4-carboxamide (21). To a solution of the
product of step 1 (410 mg, 0.93 mmol) in dichloromethane
(20 mL) was added TFA (4 mL), and the mixture was stirred
at ambient temperature for 1 h. After concentration, the residue
was purified by HPLC to provide the title compound (40 mg,
32%). 1H NMR (DMSO-d6): δ 2.12 (m, 3H), 2.46 (m, 2H), 3.39
(m, 2H), 4.68 (m, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.82 (m, 1H),
7.95 (s, 1H), 8.34 (d, J = 8.3 Hz, 2H), 8.94 (s, 1H), 9.14 (s, 1H),
9.73 (s, 1H). Anal. (C18H17ClN4O 2TFA) C, H, N, Cl.
3
2-(4-(1-Ethylpyrrolidin-2-yl)-2-fluorophenyl)-1H-benzimida-
zole-4-carboxamide (22). Step 1. Preparation of tert-Butyl 2-
(3-fluoro-4-methoxycarbonylphenyl)pyrrole-1-carboxylate. A
mixture of methyl 4-bromo-2-fluorobenzoate (4 g, 17.2 mmol),
1-(Boc)pyrrole-2-boronic acid (5.44 g, 25.8 mmol), and di-
chlorobis(triphenylphosphine)palladium(II) (1.2 g, 1.72 mmol)
in 7:3:2 DME/water/EtOH (300 mL) and 2 M aqueous sodium
carbonate (17.2 mL) was stirred for 140 min at 80 °C. The
mixture was cooled and concentrated, and the residue was
dissolved in EtOAc. The solution was washed with brine and
concentrated, and the residue was purified by flash chromatog-
raphy on silica gel using 1:4 EtOAc/hexane to afford the title
8.15 (d, J = 8.0 Hz, 2H), 9.32 (s, 1H). Anal. (C20H22N4O
4.35TFA) C, H, N.
3
2-(4-(1-Methyl-piperidin-4-yl)phenyl)-1H-benzimidazole-4-
carboxamide (16). The title compound was prepared from 13
and formaldehyde using general procedure B (7 mg, 8%). MS
(ESI): m/z 335 (M þ H)þ. 1H NMR (DMSO-d6): δ 1.23 (s, 1H),
1.95 (m, 2H), 2.07 (m, 2H), 2.83 (s, 3H), 2.92 (m, 1H), 3.11 (m,
1H), 3.51 (s, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.9 Hz,
2H), 7.76 (m, 2H), 7.87 (d, J = 7.3 Hz, 1H), 8.22 (d, J =
8.2 Hz, 2H), 9.35 (d, J = 2.7 Hz, 1H).
2-(4-(1-Isopropyl-piperidin-2-yl)phenyl)-1H-benzimidazole-
4-carboxamide (17). The title compound was prepared using
1
compound (5.51 g, 100%). H NMR (CDCl3): δ 1.41 (s, 9H),