J. Pu et al. / Bioorg. Med. Chem. 17 (2009) 4708–4717
4713
StepD. To amine 7 (1.74 mmol) in CH2Cl2 (15 mL) was added tri-
ethylamine (0.29 mL, 2.1 mmol) and the appropriate sulfonyl chlo-
ride or carbonyl chloride (2.09 mmol). After 1 h to 2 days the
reaction mixture was diluted with EtOAc (30 mL), washed with
1 N HCl (30 mL), dried (Na2SO4) and concentrated. Column chro-
matography provided target compounds.
6.6.1.7.
4-Chloro-N-[2-ethyl-1-(2-phenyl-2H-pyrazol-3-yl)-
butyl]-benzenesulfonamide (14). 1H NMR (400 MHz, DMSO-d6):
d 8.34 (d, 1H, J = 6.86 Hz), 7.63–7.61 (m, 2H), 7.56–7.51 (m, 4H),
7.49–7.44 (d, 1H, J = 7.5 Hz), 7.38 (s, 1H), 7.24 (d, 2H, J = 7.47 Hz),
6.27 (s, 1H), 4.48 (m, 1H), 1.33 (m, 1H), 1.19 (m, 2H), 1.09–1.02 (m,
2H), 0.56 (t, 3H, J = 6.9 Hz), 0.46 (t, 3H, J = 7.01 Hz). MS (+ESI):
418.1 (M+H)+. Anal. Calcd for C21H24ClN3O2S: C, 60.35; H, 5.79; N,
10.05. Found: C, 60.11; H, 6.00; N, 10.11.
6.6.1.1. 5-Chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyra-
zol-5-yl]butyl}thiophene-2-sulfonamide (8). 1H NMR (400 MHz,
DMSO-d6): d 0.62 (t, 3H, J = 7.4 Hz), 0.70 (t, 3H, J = 7.3 Hz), 0.93–
1.04 (m, 2H), 1.16–1.40 (m, 3H), 3.71 (s, 3H), 4.46 (m, 1H), 5.20
(q, 2H, J = 15.8 Hz), 6.12 (d, 1H, J = 1.8 Hz), 6.84 (d, 1H, J = 4.1 Hz),
6.88 (d, 2H, J = 8.7 Hz), 6.95 (d, 1H, J = 4.0 Hz), 7.05 (d, 2H,
J = 8.7 Hz), 7.24 (d, 1H, J = 1.8 Hz), 8.46 (d, 1H, J = 9.5 Hz); MS
(ꢀESI): 466 (MꢀH)ꢀ. Anal. Calcd for C21H26ClN3O3S2: C, 53.89; H,
5.60; N, 8.98. Found: C, 53.96; H, 5.72; N, 8.66.
6.6.1.8.
4-Cyano-N-[2-ethyl-1-(2-phenyl-2H-pyrazol-3-yl)-
butyl]-benzenesulfonamide (15). 1H NMR (400 MHz, DMSO-
d6): d 8.51 (d, 1H, J = 9.61 Hz), 7.97 (d, 2H, J = 8.39 Hz), 7.75 (d,
2H, J = 8.08 Hz), 7.57 (d, 2H, J = 7.4 Hz), 7.55 (s, 1H), 7.35 (s,
1H), 7.25 (d, 2H, J = 6.2 Hz), 6.21 (s, 1H), 4.52 (m, 1H), 1.36 (m,
1H), 1.11 (m, 2H), 1.05–1.02 (m, 2H), 0.59 (t, 3H, J = 6.7 Hz)
0.48 (t, 3H, J = 7.05 Hz). MS (+ESI): 409.1 (M+H)+. Anal. Calcd for
C22H24N4O2S: C, 64.68; H, 5.92; N, 13.71. Found: C, 64.36; H,
5.86; N, 13.70.
6.6.1.2. N-[1-(1-Butyl-1H-pyrazol-5-yl)-2-ethylbutyl]-5-chloro-
thiophene-2-sulfonamide (9). 1H NMR (400 MHz, DMSO-d6): d
0.76 (t, 3H, J = 7.2 Hz), 0.82 (t, 3H, J = 7.4 Hz), 0.88 (t, 3H,
J = 7.4 Hz), 1.07–1.19 (m, 1H), 1.20–1.33 (m, 4H), 1.34–1.48 (m,
2H), 1.59–1.70 (m, 2H), 3.81–3.94 (m, 2H), 4.44 (m, 1H), 6.09 (d,
1H, J = 1.7 Hz), 7.02 (d, 1H, J = 4.1 Hz), 7.10 (d, 1H, J = 4.0 Hz),
7.19 (d, 1H, J = 1.7 Hz), 8.53 (d, 1H, J = 9.17 Hz); MS (ꢀESI): 402
(MꢀH)ꢀ. Anal. Calcd for C19H22ClN3O3S2: C, 50.54; H, 6.49; N,
10.40. Found: C, 50.58; H, 6.65; N, 10.31.
6.6.1.9. 3,4-Dichloro-N-[2-ethyl-1-(2-phenyl-2H-pyrazol-3-yl)-
butyl]-benzenesulfonamide (16). 1H NMR (400 MHz, DMSO-d6):
d 8.44 (d, 1H, J = 8.23 Hz), 7.75 (d, 1H, J = 8.4 Hz), 7.72 (1H, d,
J = 2.2 Hz), 7.58–7.48 (m, 4H), 7.38 (s, 1H), 7.25 (d, 2H, J = 7.6 Hz),
6.27 (s, 1H), 4.48 (m, 1H), 1.39–1.31 (m, 1H), 1.28–1.15 (m, 2H),
1.13–1.07 (m, 2H), 0.61 (t, 3H, J = 6.89 Hz), 0.51 (t, 3H,
J = 7.07 Hz). MS (+ESI): 452.1 (M+H)+. Anal. Calcd for C21H23N3O2S:
C, 55.75; H, 5.12; N, 9.29. Found: C, 55.72; H, 5.15; N, 9.08.
6.6.1.3. 5-Chloro-N-(2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-
1H-pyrazol-5-yl}butyl)thiophene-2-sulfonamide (10). 1H NMR
6.6.1.10. 4-Chloro-N-{2-ethyl-1-[2-(4-methoxy-benzyl)-2H-pyr-
azol-3-yl]-butyl}-benzamide (17). 1H NMR (400 MHz, DMSO-
d6): d 8.69 (1H, d, J = 9.01 Hz), 7.79 (2H, d, J = 8.56 Hz), 7.50
(2H, d, J = 8.55 Hz), 7.41 (1H, s), 7.08 (2H, d, J = 8.56 Hz), 6.83
(2H, d, J = 8.55 Hz), 6.29 (1H, s), 5.40 (2H, q, J = 15.5 Hz), 5.20
(1H, t, J = 9.4 Hz), 3.68 93H, s), 1.87 (1H, m), 1.55 (1H, m), 1.35
(1H, m), 0.99 (1H, m), 0.89 (1H, m), 0.75 (3H, t, J = 7.3 Hz),
0.58 (3H, t, J = 7.2 Hz). MS (+ESI): 426.3 (M+H)+. Calcd for
C24H28ClN3O2.
(400 MHz, DMSO-d6):
d 0.68 (t, 3H, J = 7.4 Hz), 0.94 (t, 3H,
J = 7.4 Hz), 1.10–1.30 (m, 4H), 1.42–1.57 (m, 1H), 2.41 (s, 3H),
5.28 (dd, 1H, J = 4.2, 10.0 Hz), 6.37 (s, 1H), 6.91 (d, 1H, J = 4.0 Hz),
6.95 (d, 1H, J = 4.0 Hz), 7.51 (d, 2H, J = 8.2 Hz), 7.61 (s, 1H), 7.81
(d, 2H, J = 8.2 Hz), 8.51 (d, 1H, J = 10.2 Hz). MS (ꢀESI): 500 (MꢀH)ꢀ.
Anal. Calcd for C20H24ClN3O4S3: C, 47.85; H, 4.82; N, 8.37. Found: C,
48.00; H, 4.75; N, 8.38.
6.6.1.4.
5-Chloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)-
(11). 1H
NMR (400 MHz,
butyl]thiophene-2-sulfonamide
6.6.1.11.
butyl]thiophene-2-sulfonamide
5-Bromo-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)-
(18). 1H
NMR (400 MHz,
DMSO-d6): d 8.60 (d, 1H, J = 9.3 Hz), 7.57 (t, 2H, J = 7.6 Hz), 7.51
(m, 1H), 7.47 (m, 1H), 7.34 (m, 2H), 7.22 (d, 1H, J = 4.0 Hz), 7.12
(d, 1H, J = 4.0 Hz), 6.36 (m, 1H), 4.57 (m, 1H), 1.31 (m, 1H), 1.16
(m, 2H), 1.04 (m, 2H), 0.58 (t, 3H, J = 7.3 Hz), 0.48 (t, 3H,
J = 7.3 Hz); MS (+ESI): 424 (MꢀH)ꢀ. Anal. Calcd for C19H22N3O2ClS2:
C, 53.82; H, 5.23; N, 9.91. Found: C, 54.07; H, 5.31; N, 9.87.
DMSO-d6): d 8.58 (d, 1H, J = 8.7 Hz), 7.59–7.52 (m, 2H), 7.50–7.49
(d, 1H, J = 7.2 Hz), 7.46 (s, 1H), 7.34 (d, 2H, J = 8.2 Hz), 7.21 (d,
1H, J = 5.02 Hz), 7.17 (d, 1H, J = 5.01 Hz), 6.35 (s, 1H), 4.56 (m,
1H), 1.34–1.32 (m, 1H), 1.19–1.11 (m, 2H), 1.10–1.01 (m, 2H),
0.55 (t, 3H, J = 7.05 Hz), 0.49 (t, 3H, J = 6.99 Hz). MS (+ESI): 468.1
(M+H)+. Anal. Calcd for C19H22BrN3O2S2: C, 48.72; H, 4.73; N,
8.97. Found: C, 48.72; H, 4.31; N, 8.84.
6.6.1.5. 4-Chloro-N-{2-ethyl-1-[2-(4-methoxy-benzyl)-2H-pyra-
zol-3-yl]-butyl}-benzenesulfonamide (12). 1H NMR (400 MHz,
DMSO-d6): d 0.61 (t, 3H, J = 7.2 Hz), 0.65 (t, 3H, J = 7.5 Hz), 0.79–
0.99 (m, 2H), 1.17–1.36 (m, 3H), 3.72 (s, 3H), 4.39 (t, 1H,
J = 7.6 Hz), 5.02 (q, 2H, J = 15.8 Hz), 6.01 (d, 1H, J = 1.4 Hz), 6.87
(d, 2H, J = 8.8 Hz), 6.99 (d, 2H, J = 8.8 Hz), 7.14 (d, 1H, J = 1.9 Hz),
7.39 (s, 4H), 8.19 (d, 1H, J = 8.6 Hz); MS (+ESI): 462.1 (M+H)+. Anal.
Calcd for C23H28ClN3O3S2: C, 59.79; H, 6.11; N, 9.10. Found: C,
54.69; H, 5.89; N, 8.95.
6.6.1.12. 4,5-Dichloro-N-[2-ethyl-1-(1-phenyl-1H-pyrazol-5-yl)-
butyl]thiophene-2-sulfonamide (19). 1H NMR (400 MHz, DMSO-
d6): d 8.76 (d, 1H, J = 9.4 Hz), 7.60–7.53 (m, 2H), 7.51–7.48 (m, 2H),
7.36 (d, 2H, J = 8.4 Hz), 7.29 (s, 1H), 6.35 (s, 1H), 4.55 (m, 1H), 1.37–
1.31 (m, 1H), 1.29–1.24 (m, 2H), 1.19–1.15 (m, 1H), 1.11–1.05 (m,
1H), 0.62 (t, 3H, J = 7.01 Hz), 0.52 (t, 3H, J = 6.93 Hz). MS (+ESI):
458.1 (M+H)+. Anal. Calcd for C19H21Cl2N3O2S2: C, 49.78; H, 4.62;
N, 9.17. Found: C, 51.52; H, 4.97; N, 8.56. 1H NMR is included in
the Supplementary data as an indication of purity.
6.6.1.6. 4-Bromo-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyra-
zol-5-yl]butyl}-benzene sulfonamide (13). 1H NMR (400 MHz,
DMSO-d6): d 0.61 (t, 3H, J = 7.3 Hz), 0.65 (t, 3H, J = 7.3 Hz), 0.84–
0.99 (m, 2H), 1.17–1.36 (m, 3H), 3.72 (s, 3H), 4.40 (t, 1H,
J = 7.5 Hz), 5.05 (q, 2H, J = 15.7 Hz), 6.01 (d, 1H, J = 1.5 Hz), 6.87
(d, 2H, J = 8.6 Hz), 6.99 (d, 2H, J = 8.6 Hz), 7.14 (d, 1H, J = 1.7 Hz),
7.32 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.4 Hz), 8.21 (d, 1H,
8.9 Hz); MS (+ESI): 506 (M+H)+. Anal. Calcd for C23H28BrN3O3S2C:
54.55; H, 5.57; N, 8.30. Found: C, 54.73; H, 5.56; N, 8.21.
6.6.1.13.
5-Chloro-N-{1-[1-(4-methoxybenzyl)-1H-pyrazol-5-
yl]ethyl}thiophene-2-sulfonamide (20). 1H NMR (400 MHz,
DMSO-d6): d 1.16 (d, 3H, J = 8.4 Hz) 3.71 (s, 3H), 4.59 (m, 1H),
5.23 (m, 2H), 6.15 (d, 1H, J = 1.7 Hz), 6.86 (d, 1H, J = 8.7) 7.05 (d,
2H, J = 8.7 Hz), 7.11 (d, 1H, J = 4.0 Hz), 7.21 (d, 1H, J = 4.1 Hz),
7.29 (d, 1H, J = 1.7 Hz), 8.64 (br s, 1H); MS (ꢀESI): 410 (MꢀH)ꢀ.
Anal. Calcd for C17H18ClN3O3S2: C, 49.47; H, 4.40; N, 10.20. Found:
C, 49.48; H, 4.38; N, 9.87.