W. J. Flosi et al. / Bioorg. Med. Chem. 14 (2006) 6695–6712
6711
5.9.38. (2S,3S)-2-[3-(2-Methoxymethyl-thiazol-4-ylmeth-
yl)-2,4-dioxo-imidazolidin-1-yl]-3-methyl-pentanoic acid
{(1S,2R)-1-benzyl-3-[cyclopentylmethyl-(4-methoxy-ben-
zenesulfonyl)-amino]-2-hydroxy-propyl}-amide (15). The
carboxylic acid core 42 and the amine core 27 were cou-
2H), 3.02–3.22 (m, 3H), 3.39–3.79 (m, 3H), 3.81–3.90
(m, 1H), 3.96 (d, J = 10.85 Hz, 1H), 4.20–4.33 (m,
1H), 4.40 (br s, 1H), 4.88–5.08 (m, 2H), 6.26 (d,
J = 9.16 Hz, 1H), 7.03 (dd, J = 8.31, 2.20 Hz, 1H),
7.10–7.20 (m, 5H), 7.34 (t, J = 8.14 Hz, 2H), 7.44–7.54
(m, 1H), 7.59–7.69 (m, 1H), 7.76 (d, J = 7.80 Hz, 1H),
7.94 (d, J = 8.48 Hz, 1H), 8.12 (d, J = 8.48 Hz, 1H);
MS (ESI) m/z 730.9 [M+H]+.
1
pled using method 3 to produce 15 in 48% yield. H
NMR (300 MHz, MeOH) d ppm 0.75 (d, J = 6.44 Hz,
3H), 0.83 (t, J = 7.29 Hz, 3H), 1.22–1.35 (m, 2H),
1.49–1.62 (m, 4H), 1.60–1.76 (m, 4H), 1.77–1.90 (m,
1H), 2.19–2.32 (m, 1H), 2.47 (dd, J = 13.56, 11.87 Hz,
1H), 2.89–3.08 (m, 4H), 3.13–3.27 (m, 3H), 3.39–3.48
(m, 1H), 3.43 (s, 3H), 3.66 (d, J = 17.97 Hz, 1H), 3.75–
3.84 (m, 1H), 3.87 (s, 3H), 4.11 (d, J = 11.19 Hz, 1H),
4.12–4.23 (m, 1H), 4.66 (s, 2H), 4.70–4.84 (m, 2H),
6.95–7.02 (m, 3H), 7.05–7.10 (m, 2H), 7.11–7.16 (m,
2H), 7.23 (s, 1H), 7.71–7.80 (m, 2H); MS (ESI) m/z
771.2 [M+H]+.
5.9.42. (S)-N-{(1S,2R)-3-[(3-Amino-4-chloro-benzenesulfo-
nyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-3-meth-
yl-2-[3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-
imidazolidin-1-yl]-butyramide (19). The carboxylic acid
core 45 and the amine core 29 were coupled using method
3, substituting PyBOP for EDC, to produce 19 in 70%
1
yield. H NMR (300 MHz, DMSO-D6) d ppm 0.68 (d,
J = 6.78 Hz, 3H), 0.75 (d, J = 6.78 Hz, 3H), 0.82 (d,
J = 6.10 Hz, 6 H), 1.86–2.06 (m, 2H), 2.38 (dd,
J = 13.05, 11.70 Hz, 1H), 2.77–2.90 (m, 1H), 2.94 (dd,
J = 8.99, 4.24 Hz, 1H), 2.97–3.12 (m, 2H), 3.17–3.27 (m,
1H), 3.59 (br s, 1H), 3.80 (m, 1H), 3.88 (s, 3H), 3.91–
3.99 (m, 1H), 4.02 (d, J = 10.85 Hz, 1H), 4.95–5.05 (m,
2H), 5.81 (br s, 2H), 6.88 (dd, J = 8.48, 2.03 Hz, 1H),
6.93–7.02 (m, 1H), 7.08–7.18 (m, 5H), 7.17–7.28 (m,
4H), 7.32–7.38 (m, 1H), 7.48 (d, J = 8.14 Hz, 1H), 7.55
(d, J = 7.80 Hz, 1H), 8.23 (d, J = 9.83 Hz, 1H); MS
(ESI) m/z 753.6 [M+H]+.
5.9.39. (S)-2-(3-Benzyl-2,4-dioxo-imidazolidin-1-yl)-N-
{(1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl-(4-methoxy-ben-
zenesulfonyl)-amino]-propyl}-3-methyl-butyramide (16).
The carboxylic acid core 43 and the amine core 25 were
1
coupled using method 3 to produce 16 in 43% yield. H
NMR (300 MHz, chloroform-D) d ppm 0.75 (d,
J = 6.78 Hz, 3H), 0.82 (d, J = 6.44 Hz, 3H), 0.87 (d,
J = 6.78 Hz, 3H), 0.94 (d, J = 6.78 Hz, 3H), 1.75–1.89
(m, 1H), 1.99–2.10 (m, 1H), 2.63 (dd, J = 14.07,
10.68 Hz, 1H), 2.77 (dd, J = 13.56, 6.44 Hz, 1H), 2.89–
2.99 (m, 1H), 2.99–3.09 (m, 2H), 3.12–3.25 (m, 2H),
3.53 (d, J = 17.97 Hz, 1H), 3.76–3.85 (m, 2H), 3.88 (s,
3H), 4.17–4.28 (m, 1H), 4.53–4.69 (m, 2H), 6.05 (d,
J = 9.49 Hz, 1H), 6.91–7.01 (m, 4H), 7.02–7.11 (m,
4H), 7.27–7.38 (m, 3H), 7.39–7.46 (m, 2H), 7.69–7.76
(m, 2H); MS (ESI) m/z 680.0 [M+H]+.
5.9.43. (S)-N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-
(4-methoxy-benzenesulfonyl)-amino]-propyl}-3-methyl-2-
[3-(1-methyl-1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-
imidazolidin-1-yl]-butyramide (20). The carboxylic acid
core 45 and the amine core 25 were coupled using meth-
od 3, substituting PyBOP for EDC, to produce 20 in
1
69% yield: H NMR (300 MHz, chloroform-D) d ppm
5.9.40. (S)-N-{(1S,2R)-3-[(3-Amino-4-chloro-benzenesulfo-
nyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-2-(2,4-
dioxo-3-quinolin-2-ylmethyl-imidazolidin-1-yl)-3-meth-
yl-butyramide (17). The carboxylic acid core 44 and the
amine core 29 were coupled using method 3, substituting
0.77 (d, J = 6.44 Hz, 3H), 0.80 (d, J = 6.78 Hz, 3H),
0.86 (d, J = 6.44 Hz, 3H), 0.91 (d, J = 6.44 Hz, 3H),
1.74–1.92 (m, 1H), 1.97–2.17 (m, 1H), 2.71 (dd,
J = 13.90, 10.85 Hz, 1H), 2.77–2.86 (m, 1H), 2.92–3.02
(m, 1H), 3.06 (dd, J = 8.31, 3.56 Hz, 1H), 3.11–3.25
(m, 1H), 3.36 (d, J = 17.97 Hz, 1H), 3.66 (d,
J = 17.97 Hz, 1H), 3.84–3.87 (m, 4H), 3.88 (s, 3H),
3.96 (d, J = 10.85 Hz, 1H), 4.10–4.19 (m, 1H),
4.22–4.35 (m, 1H), 4.80–4.97 (m, 2H), 6.39 (d,
J = 9.49 Hz, 1H), 6.93–7.01 (m, 2H), 7.03–7.11 (m, m,
2H), 7.19–7.23 (m, 1H), 7.23–7.28 (m, 2H), 7.29–7.36
(m, 1H), 7.66–7.77 (m, 3H), 7.13–7.18 (H); MS (ESI)
m/z 733.8 [M+H]+.
1
PyBOP for EDC, to produce 17 in 65% yield. H NMR
(300 MHz, chloroform-D) d ppm 0.77–0.98 (m, 12H),
1.74–1.90 (m, 1H), 2.08–2.25 (m, 1H), 2.69 (dd,
J = 14.24, 10.51 Hz, 1H), 2.78 (dd, J = 13.39, 6.61 Hz,
1H), 2.92–3.01 (m, 2H), 3.06 (dd, J = 13.73, 9.32 Hz,
1H), 3.11–3.26 (m, 1H), 3.57 (dd, J = 101.73, 17.97 Hz,
2H), 3.79–3.86 (m, 2H), 3.88 (s, 3H), 3.92 (d,
J = 10.85 Hz, 1H), 4.18–4.32 (m, 1H), 4.89–5.10 (m,
2H), 6.17 (d, J = 9.49 Hz, 1H), 6.94–7.02 (m, 2H),
7.12–7.20 (m, 5H), 7.33 (d, J = 8.48 Hz, 1H), 7.44–7.54
(m, 1H), 7.62–7.68 (m, 1H), 7.70–7.74 (m, 2H), 7.77
(d, J = 7.80 Hz, 1H), 7.95 (d, J = 8.48 Hz, 1H), 8.13
(d, J = 8.48 Hz, 1H); MS (ESI) m/z 750.6 [M+H]+.
References and notes
1. Randolph, J. T.; DeGoey, D. A. Curr. Top. Med. Chem.
2004, 4, 1079.
2. Molla, A.; Vasavanonda, S.; Kumar, G.; Sham, H. L.;
Johnson, M.; Grabowski, B.; Denissen, J. F.; Kohlbren-
ner, W.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W.;
Kempf, D. J. Virology 1998, 250, 255.
3. Sham, H. L.; Kempf, D. J.; Molla, A.; Marsh, K. C.;
Kumar, G. N.; Chen, C.; Kati, W.; Stewart, K.; Lal, R.;
Hsu, A.; Betebenner, D.; Korneyeva, M.; Vasavanonda,
S.; McDonald, E.; Saldivar, A.; Wideburg, N.; Chen, X.;
Niu, P.; Park, C.; Jayanti, V.; Grabowski, B.; Granneman,
G. R.; Sun, E.; Japour, A. J.; Leonard, J. M.; Plattner, J.
5.9.41. (S)-N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[isobutyl-
(4-methoxy-benzenesulfonyl)-amino]-propyl}-2-(2,4-dioxo-
3-quinolin-2-ylmethyl-imidazolidin-1-yl)-3-methyl-butyra-
mide (18). The carboxylic acid core 44 and the amine
core 25 were coupled using method 3, substituting Py-
1
BOP for EDC, to produce 18 in 96% yield. H NMR
(300 MHz, chloroform-D) d ppm 0.80 (d, J = 6.44 Hz,
3H), 0.90 (m, 9H), 1.76–1.91 (m, 1H), 2.08–2.27 (m,
1H), 2.72 (dd, J = 14.07, 10.68 Hz, 1H), 2.79–3.00 (m,