7260 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Zhou et al.
using method C. The pyrrolidinylbenzimidazoles were prepared
using method E (see compound 7ab).
2-yl]-1H-imidazole was prepared from 1-(tert-butoxycarbonyl)-
4,4-difluoro-L-proline and 2-bromo-1-(3-bromophenyl)ethanone
using method B followed by HCl de-Boc. This was then coupled
with 3-(20,30-dichlorobiphenyl-4-yl)propanoic acid using method
A to give the titled compound. 1H NMR (500 MHz, MeOH-d4) δ
7.92 (br, 1H), 7.68 (br, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 7.32 (m,
2H), 7.29 (m, 4H), 7.22 (m, 1H), 7.12 (d, 1H), 5.40 (m, 1H), 4.10
(m, 2H), 3.00 (t, 2H), 2.58 (m, 1H), 2.55 (t, 2H), 2.53 (m, 1H). MS:
calcd, 603.03; obsd, 604.01.
3-(Biphenyl-4-yl)-1-[2-(6-fluoro-1H-benzimidazol-2-yl)pyr-
rolidin-1-yl]propan-1-one (7w). MS: calcd, 413.19; obsd, 414.31.
3-(Biphenyl-4-yl)-1-[2-(6-chloro-1H-benzimidazol-2-yl)pyr-
rolidin-1-yl]propan-1-one (7x). MS: calcd, 429.16; obsd, 430.26.
3-(Biphenyl-4-yl)-1-{2-[6-(trifluoromethyl)-1H-benzimidazol-
2-yl]pyrrolidin-1-yl}propan-1-one (7y). MS: calcd, 463.19; obsd,
464.30.
3-(Biphenyl-4-yl)-1-[2-(5,6-difluoro-1H-benzimidazol-2-yl)pyr-
rolidin-1-yl]propan-1-one (7z). MS: calcd, 431.18; obsd, 432.30.
3-(Biphenyl-4-yl)-1-[2-(6-chloro-5-fluoro-1H-benzimidazol-2-
yl)pyrrolidin-1-yl]propan-1-one (7aa). 1H NMR (500 MHz,
DMSO-d6) δ 7.75 (d, 1H, JF-H), 7.60 (d, 2H), 7.53 (d, 2H),
7.43 (t, 2H), 7.42 (d, 1H, JF-H), 7.33 (t, 1H), 7.31 (d, 2H), 5.16 (d,
1H), 3.72 (m, 1H), 3.55 (m, 1H), 2.84 (t, 2H), 2.68 (t, 2H), 2.23
(m, 1H), 2.08 (m, 2H), 1.96 (m, 1H). MS: calcd, 447.15; obsd,
448.46.
3-(Biphenyl-4-yl)-1-[2-(5,6-dichloro-1H-benzimidazol-2-yl)pyr-
rolidin-1-yl]propan-1-one (7ab). Step 1. Preparation of 5,6-Di-
chloro-2-(pyrrolidin-2-yl)-1H-benzimidazole (Method E). To a DMF
(50 mL) of 4,5-dichlorobenzene-1,2-diamine (6.29 g, 35.5 mmol), N-
Boc-S-proline (7.64 g, 35.5 mmol), and DIEA (7.56 mL, 43.4 mmol)
was added HATU (15 g, 39.4 mmol). The solution was stirred for 5 h,
poured into water, and extracted with ethyl acetate. The organic layer
was dried over sodium sulfate and evaporated. The crude residue was
mixed with 30 mL of acetic acid and heated at 60 °Covernight.Acetic
acid was removed under reduced pressure, and the residue was
treated with 50 mL of 5N NaOH. The resulting solid was filtered
and washed with water and dried in air. Purification on comb-flash
gave a brown solid, which was further crystallized in ethyl acetate/
hexane to give a light-brown solid. Weight: 8.5 g. LC-MS: calcd,
355.09; obsd, 356.21.
The Boc-protected product was treated with 4N HCl in THF
for 2 h. Evaporation and vacuum drying left 7.85 g solid of 5,6-
dichloro-2-(pyrrolidin-2-yl)-1H-benzimidazole as the HCl salt.
MS: calcd, 255.03; obsd, 256.45.
Step 2. The pyrrolidinylbenzimidazole from above was
coupled with 3-(biphenyl-4-yl)proprionic acid using method C
to give compound 7ab. 1H NMR (500 MHz, MeOH-d4) δ 7.86
(s, 2H), 7.55 (d, 2H), 7.48 (d, 2H), 7.40 (t, 2H), 7.30 (t, 1H), 7.27
(d, 2H), 5.31 (m, 1H), 3.81 (m, 1H), 3.62 (m, 1H), 2.94 (t, 2H),
2.80 (t, 2H), 2.48 (m, 1H), 2.16 (m, 1H), 2.10 (m, 2H). MS: calcd,
463.12; obsd, 463.93.
2-(Biphenyl-4-yloxy)-1-[(1R,2S,5S)-2-(4-methyl-1H-benzimid-
azol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]ethanone (8e). MS: calcd,
423.19; obsd, 424.15. 1H NMR (500 MHz, DMSO-d6) δ 7.58 (d,
2H), 7.53 (d, 3H), 7.43 (t, 2H), 7.32 (t, 1H), 7.34 (br, 1H), 7.31 (t,
1H), 7.25 (br, 1H), 7.03 (d, 2H), 5.45 (d, 1H), 4.92 (d, 1H), 4.82
(d, 1H), 3.99 (m, 1H), 3.85 (d, 1H), 2.52 (s, 3H), 2.10 (m, 1H),
2.04 (m, 1H), 0.80 (m, 2H).
40-(3-{(2S,4R)-2-[5-(3-Chlorophenyl)-1H-imidazol-2-yl]-4-hy-
droxypyrrolidin-1-yl}-3-oxopropyl)biphenyl-3-carbonitrile (8f ). Step 1.
N-Boc-4(R)-hydroxy-L-proline was reacted with 2-bromo-
1-(3-chlorophenyl)ethanone using method B to give tert-butyl
(2S,4R)-2-[5-(3-chlorophenyl)-1H-imidazol-2-yl]-4-hydro-
xypyrrolidine-1-carboxylate in 70% yield. MS: calcd, 363.13; obsd,
364.17. The Boc group was removed with 4N HCl in dioxane to
give (3R,5S)-5-[5-(3-chlorophenyl)-1H-imidazol-2-yl]pyrrolidin-
3-ol as a solid. MS: calcd, 263.08; obsd, 264.28. 1H NMR (500
MHz, MeOH-d4) δ 7.96 (s, 1H), 7.89 (t, 1H), 7.76 (d, 1H), 7.50 (t,
1H), 7.45 (d, 1H), 5.29 (t, 1H), 4.56 (d, 1H), 3.70 (dd, 1H), 3.48
(d, 1H), 2.64 (d, 2H).
Step 2. The imidazole from above was coupled with cyano-
biphenylpropionic acid using method A to give 8f. MS: calcd,
1
496.17; obsd, 497.23. H NMR (500 MHz, DMSO-d6) δ 8.08
(br, 2H), 7.95 (d, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.74 (d, 1H),
7.65 (t, 1H), 7.62 (d, 2H), 7.54 (t, 1H), 7.47 (d, 1H), 7.34 (d, 2H),
5.15 (m, 1H), 4.50 (m, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 2.85 (m,
2H), 2.72 (m, 1H), 2.64 (m, 1H), 2.31 (m, 1H), 2.19 (m, 1H).
2-Amino-N-{(2S)-3-(biphenyl-4-yl)-1-[(2S)-2-(5,6-dichloro-1H-
benzimidazol-2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-2-methyl-
propanamide (8g). MS: calcd, 563.19; obsd, 564.29.
5,6-Dichloro-2-[(2S)-1-(2-methylalanyl-4-chloro-L-phenylala-
nyl)pyrrolidin-2-yl]-1H-benzimidazole (8h). MS: calcd, 521.12;
obsd, 522.13.
5,6-Dichloro-2-[(2S)-1-(2-methylalanyl-O-methyl-L-tyrosyl)-
azetidin-2-yl]-1H-benzimidazole (8i). MS: calcd, 503.15; obsd,
504.20.
N-{(2S)-3-(Biphenyl-4-yl)-1-[(2S)-2-(5,6-difluoro-1H-benz-
imidazol-2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-2-hydroxy-2-
methylpropanamide (8j). MS: calcd, 532.23; obsd, 533.20.
3-Amino-N-{(2S)-3-(biphenyl-4-yl)-1-[(2S)-2-(5,6-dichloro-
1H-benzimidazol-2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-2,2-
dimethylpropanamide (8k). MS: calcd, 577.20; obsd, 578.20
3-Amino-N-{(2S)-3-(biphenyl-4-yl)-1-[(2S)-2-(5,6-dichloro-
1H-benzimidazol-2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-3-met-
hylbutanamide (8l). MS: calcd, 577.20; obsd, 578.20.
2-Amino-N-{(2S)-3-(biphenyl-4-yl)-1-[(2S)-2-(5-tert-butyl-1H-
imidazol-2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-2-methylpro-
panamide (8m). MS: calcd, 501.31; obsd, 502.24.
N-{(2S)-3-(Biphenyl-4-yl)-1-[(2S)-2-(5-tert-butyl-1H-imidazol-
2-yl)pyrrolidin-1-yl]-1-oxopropan-2-yl}-2-hydroxy-2-methylpro-
panamide (8n). MS: calcd, 502.29; obsd, 503.23.
2-Amino-N-{(2S,3S)-3-(biphenyl-4-yl)-1-[(2S)-2-(5,6-dichloro-
1H-benzimidazol-2-yl)pyrrolidin-1-yl]-1-oxobutan-2-yl}-2-meth-
ylpropanamide (Nonpreferred Name) (8o). Step 1: Preparation
of (E)-Methyl 2-Acetamido-3-bromobut-2-enoate. Into a 1000 mL
four-necked round-bottom flask was placed a solution of (Z)-
methyl 2-acetamidobut-2-enoate16 (36 g, 229.30 mmol, 1.00 equiv)
in DCM (400 mL). To the above was added NBS (48.75 g, 273.91
mmol, 1.20 equiv) in several batches. The reaction mixture was
stirred overnight at room temperature. The resulting solution was
diluted with 500 mL of H2O qand extracted with 3 ꢀ 200 mL of
DCM. The combined organic layer was washed with 3 ꢀ 200 mL
3-(Biphenyl-4-yl)-1-[2-(4,5-dimethyl-1H-benzimidazol-2-yl)-
pyrrolidin-1-yl]propan-1-one (7ac). MS: calcd, 423.23; obsd,
424.35.
3-(Biphenyl-4-yl)-1-[2-(3H-imidazo[4,5-c]pyridin-2-yl)pyr-
rolidin-1-yl]propan-1-one (7ad). 1H NMR (500 MHz, DMSO-d6)
δ 9.36 (br, 1H), 8.58 (br, 1H), 8.10 (br, 1H), 7.61 (d, 2H), 7.54 (d,
2H), 7.44 (t, 2H), 7.33 (t, 1H), 7.32 (d, 2H), 5.25 (d, 1H), 3.76 (m,
1H), 3.62 (m, 1H), 2.78 (t, 2H), 2.61 (t, 2H), 2.34 (m, 1H), 2.08
(m, 2H), 2.01 (m, 1H). MS: calcd, 396.20; obsd, 397.22.
3-(Biphenyl-4-yl)-1-{2-[5-(3-fluorophenyl)-1H-imidazol-2-yl]-
pyrrolidin-1-yl}propan-1-one (8a). The intermediate pyrrolidinyl-
benzimidazole, prepared from the corresponding bromo ketone
using method B, was coupled with 3-(biphen-4-yl)propionic acid
using method A. 1H NMR (500 MHz, DMSO-d6) δ 8.02 (br, 1H),
7.7 (br, 2H), 7.62 (d, 2H), 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H),
7.33 (d, 2H), 7.22 (t, br, 1H), 5.18 (m,1H), 3.80 (m, 1H), 3.51 (m,
1H), 2.85 (t, 2H), 2.70 (t, 2H), 2.30 (m 1H), 2.05 (m, 3H). MS:
calcd, 439.21; obsd, 440.13.
3-(Biphenyl-4-yl)-1-{2-[5-(3-fluorophenyl)-1H-imidazol-2-yl]-
pyrrolidin-1-yl}-2,2-dimethylpropan-1-one (8b). MS: calcd, 467.24;
obsd, 468.39.
2-(Biphenyl-4-yloxy)-1-[(2S)-2-(4-methyl-1H-benzimidazol-2-
yl)pyrrolidin-1-yl]ethanone (8c). MS: calcd, 411.19; obsd, 412.11.
1-{2-[5-(3-Bromophenyl)-1H-imidazol-2-yl]-4,4-difluoropyr-
rolidin-1-yl}-3-(20,30-dichlorobiphenyl-4-yl)propan-1-one (8d). The
intermediate 5-(3-bromophenyl)-2-[(2S)-4,4-difluoropyrrolidin-