and the solvent removed under reduced pressure. The purity of
the corresponding sulfonamide was determined by LC-MS and
1H NMR (see Table 3).
2-[4-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-[1,4]diazepan-1-
yl]nicotinonitrile (13e). Yellow oil, LC retention time = 2.75
(m/z 325.1, M + H); mmax(neat)/cm−1 2924, 1613, 1587, 1549,
1496, 1427, 1220, 1160, 1113, 939, 759, 730; dH(500 MHz;
CDCl3) 8.18 (1H, d, J 5 Hz, py H-6), 7.62 (1H, d, J 5 Hz, py
H-4), 6.53 (1H, t, J 5 Hz, py H-5), 6.32 (1H, s, pyrazole H-4),
3.94, 3.92 (4H, t, J 6 Hz, diazepine H-2, H-3), 3.89, 3.83 (4H, t, J
6 Hz, diazepine H-5, H-7), 3.75 (3H, s, pyrazole N-1 CH3), 2.22
(3H, s, pyrazole C-5 CH3), 2.05 (2H, quintet, J 6 Hz, diazepine
2-[4-(6-Morpholin-4-ylpyridine-3-sulfonyl)-[1,4]diazepam-1-
yl]nicotinonitrile (13a). Off-white solid, mp 168 ◦C, LC
retention time = 2.94 (m/z 428.2, M+); mmax(neat)/cm−1 2859,
1585, 1551, 1504, 1308, 1143, 1104, 1042, 997, 941, 837, 758,
702; dH(500 MHz; CDCl3) 8.45 (1H, d, J 5 Hz, py H-6ꢀ), 8.19
(1H, d, J 5 Hz, py H-5), 7.68 (2H, d, J 8 Hz, py H-4), 7.63
(2H, d, J 8 Hz, py H-3ꢀ), 6.57 (1H, t, J 5 Hz, py H-5), 6.48
(1H, d, py H-5ꢀ), 3.94 (4H, t, J 6.5 Hz, diazepine H-3, H-5),
3.72 (4H, t, J 6.5 Hz, morpholine H-2, H-6), 3.56 (4H, t, J
6.5 Hz, morpholine H-3, H-5), 3.43 (2H, t, J 6.5 Hz, diazepine
H-2), 3.19 (2H, t, J 6.5 Hz, diazepine H-7), 2.02 (2H, t, J
6.5 Hz, diazepine H-6); dC(125 MHz; CDCl3) 160.2 (C), 157.6
(C), 152.2 (CH), 147.9 (CH), 144.8 (CH), 136.2 (CH), 123.7
(C), 119.0 (CN), 112.5 (CH), 105.3 (CH), 90.4 (C), 66.5 (CH2),
51.3 (CH2), 49.3 (CH2), 48.6 (CH2), 47.6 (CH2), 44.9 (CH2),
28.5 (CH2); m/z (EI+) 428.16426 (M+, C20H24N6O3S requires
428.16306); 428.2 (100%) (M+).
=
H-6); dC(125 MHz; CDCl3) 164.0 (C O), 157.6 (C), 152.2 (C),
144.8 (CH), 141.8 (C), 138.9 (C), 119.2 (CN), 112.16 (CH), 108.0
(CH), 90.2 (C), 52.5 (CH2), 50.1 (CH2), 48.8 (CH2), 46.2 (CH2),
36.5 (CH3), 25.7 (CH2), 11.0 (CH3); m/z (EI+) 324.16858 (M+,
C17H20N6O requires 324.16986); 324.2 (45%) (M+).
2-[4-(1-Methyl-1H -imidazole-4-sulfonyl)-[1,4]diazepan-1-
yl]nicotinonitrile (13f). Yellow crystals, mp 151–152 ◦C, LC
retention time = 2.73 (m/z 347.1); mmax(neat)/cm−1 2211, 1585,
1552, 1486, 1454, 1443, 1327, 1218, 1156, 1117, 1039, 958, 868,
857, 759, 691; dH(500 MHz; CDCl3) 8.19 (1H, d, J 6 Hz, py
H-6), 7.34 (1H, d, J 6 Hz, py H-4), 7.33 (2H, m, imidazole H-2,
py H-5), 6.55 (1H, t, J 6 Hz, py H-5), 3.94 (4H, m, diazepine
H-2, H-3), 3.66 (3H, imidazole N-1 CH3), 3.54, 3.34 (4H, t,
J 6 Hz, diazepine H-5, H-7), 2.03 (2H, m, diazepine H-6);
dC(125 MHz; CDCl3) 157.7 (C), 152.2 (CH), 144.8 (CH), 140.3
(C), 138.9 (CH), 123.7 (CH), 119.1 (CN), 112.3 (CH), 90.3 (C),
51.6 (CH2), 49.6 (CH2), 48.5 (CH2), 48.1 (CH2), 33.9 (CH3),
28.5 (CH2); m/z (EI+) 346.12050 (M+, C15H18N6O2S requires
346.12119); 346.1 (45%) (M+), 264.1 (45%).
2-[4-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-
[1,4]diazepan-1-yl]nicotinonitrile (13b). LC retention time =
3.42 (m/z 413.2); mmax(neat)/cm−1 1649, 1598, 1336, 1209, 1182,
1089, 1039, 928, 751; dH(500 MHz; CDCl3) 8.30 (1H, d, J 6 Hz,
py H-6), 7.45 (2H, d, J 6 Hz, py H-4), 6.95 (1H, m, benzooxazine
H-8), 6.75 (1H, d, J 7.2 Hz, benzooxazine H-5), 6.63 (2H, t,
J 6 Hz, py H-5), 4.24 (2H, t, J 7 Hz, benzooxazine H-2), 4.08
(2H, br t, diazepine H-3), 4.02 (2H, br t, diazepine H-2), 3.74
(2H, br t, diazepine H-7), 3.65 (2H, br t, diazepine H-5), 3.28
(2H, t, J 6 Hz, benzooxazine H-3), 2.85 (3H, s, benzooxazine
N-4 CH3), 2.17 (2H, br t, diazepine H-6); dC(100 MHz; CDCl3)
157.2 (sat. carbon), 152.4 (CH), 148.2 (sat. carbon), 144.9
(CH), 133.5 (sat. carbon), 128.6 (sat. carbon), 118.9 (CN), 118.1
(CH), 116.1 (CH), 112.9 (CH), 111.0 (CH), 91.3 (sat. carbon),
65.1 (CH2), 51.4 (CH2), 50.1 (CH2), 48.1 (CH2), 47.6 (CH2),
45.2 (CH2), 38.8 (CH3), 26.4 (CH2); m/z (EI+) 413.15425 (M+,
C20H23N5O3S requires 413.15216); 413.2 (43%) (M+).
2-[4-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-[1,4]diazepan-1-
yl]nicotinonitrile (13g). Colourless crystals, mp 105 ◦C, LC
retention time = 2.54 (m/z 361.0); mmax(neat)/cm−1 1586, 1547,
1460, 1329, 1148, 1123, 1034, 903, 759, 707, 672; dH(500 MHz;
CDCl3) 8.20 (1H, d, J 5 Hz, py H-6), 7.62 (1H, d, J 5 Hz, py
H-4), 7.21 (1H, s, imidazole H-5), 6.57 (1H, t, J 5 Hz, py H-5),
3.93 (4H, t, J 6 Hz, diazepine H-2, H-3), 3.55 (2H, t, J 6 Hz,
diazepine H-7), 3.50 (3H, s, imidazole N-1 CH3), 3.35 (2H, t,
J 6 Hz, diazepine H-5), 2.27 (3H, s, imidazole C-2 CH3), 2.07
(2H, t, J 6 Hz, diazepine H-6); dC(125 MHz; CDCl3) 157.6 (C),
152.2 (CH), 146.9 (C), 144.7 (CH), 137.5 (CH), 124.2 (CH),
119.1 (CN), 112.3 (CH), 90.2 (C), 51.5 (CH2), 49.5 (CH2), 49.5
(CH2), 48.0 (CH2), 33.3 (CH3), 28.5 (CH2), 13.0 (CH3); m/z
(EI+) 360.13838 (M+, C16H20N6O2S requires 360.13684); 360.1
(25%) (M+), 201.1 (36%).
2-[4-(Quinoxaline-6-carbonyl)-[1,4]diazepan-1-yl]-nicotinonitrile
(13c). Yellow oil, LC retention time = 2.74 (m/z 359.10);
mmax(neat)/cm−1 2208, 1627, 1587, 1549, 1445, 1424, 1363, 1234,
1174, 1021, 906, 757, 743, 731; dH(500 MHz; CDCl3) 8.86 (2H, s,
quinoxaline H-2, H-3), 8.30 (1H, d, J 6 Hz, py H-6), 8.12 (1H, s,
quinoxaline H-5), 8.02 (4H, d, J 5.5 Hz, quinoxaline H-8), 7.45
(2H, d, J 6 Hz, py H-4), 6.63 (2H, t, J 6 Hz, py H-5), 4.08 (2H,
br t, diazepine H-3), 4.02 (2H, br t, diazepine H-2), 3.74 (2H,
br t, diazepine H-7), 3.65 (2H, br t, diazepine H-5), 2.17 (2H,
4-{5-[4-(2-Nitro-4-(trifluoromethyl)phenyl)piperazine-1-sulfonyl]-
pyridin-2-yl}morpholine (14a). Yellow solid, mp 202–203 ◦C,
LC retention time = 2.78 (m/z 502.1, M + H); mmax(neat)/cm−1
1621, 1512, 1317, 1225, 1178, 1128, 935, 856, 767; dH(500 MHz;
CDCl3) 8.52 (1H, s, py H-6), 7.92 (1H, s, Ph H-3), 7.78 (1H,
m, J 7 Hz, py H-4), 7.71 (1H, m, py H-3), 7.05 (1H, d, J
8.2 Hz, Ph H-5), 6.48 (1H, d, J 8.2 Hz, Ph H-6), 3.65 (4H, br
t, morpholine H-3, H-5), 3.57 (4H, br t, piperazine H-2, H-6),
3.07 (4H, br t, morpholine H-2, H-6), 2.98 (4H, br t piperazine
H-3, H-5); dC(125 MHz; CDCl3) 160.3 (C), 148.6 (CH), 147.6
(C), 141.5 (CH), 139.4 (C), 136.7 (CH), 130.3 (CH), 125.1 (C),
123.7 (CH), 121.6 (CH), 120.3 (JC–F 48 Hz, CF3), 119.0 (C),
105.4 (CH), 66.3 (CH2), 50.6 (CH2), 45.6 (CH2), 44.7 (CH2);
m/z (EI+) 501.12867 (M+, C20H22F3N5O5S requires 501.12937);
501.1 (48%) (M+).
=
br t, diazepine H-6); dC(125 MHz; CDCl3) 168.2 (C O), 157.3
(C), 152.2 (CH), 145.9 (CH × 2), 144.8 (CH), 143.1 (C), 142.4
(C), 129.9 (CH), 128.2 (CH), 127.4 (CH), 118.8 (CN), 112.8
(CH), 91.1 (C), 51.2 (CH2), 50.4 (CH2), 49.6 (CH2), 48.4 (CH2),
47.0 (CH2), 45.1 (CH2), 26.3 (CH2); m/z (EI+) 358.15410 (M+,
C20H18N6O requires 358.15421); 358.2 (35%) (M+).
2-[4-(3,5-Dimethylisoxazole-4-carbonyl)-[1,4]diazepan-1-
yl]nicotinonitrile (13d). Off-white solid, mp 103 ◦C, LC
retention time = 3.22 (m/z 326.0); mmax(neat)/cm−1 2920,
1587, 1503, 1439, 1333, 1171, 1120, 977, 902, 839, 755, 690;
dH(500 MHz; CDCl3) 8.22 (1H, d, J 5 Hz, py H-6), 7.65 (1H, d, J
5 Hz, py H-4), 6.65 (1H, s, py H-5), 3.95 (4H, t, J 6 Hz, diazepine
H-2, H-3), 3.48 (2H, t, J 6 Hz, diazepine H-5), 3.29 (2H, t,
J 6 Hz, diazepine H-7), 2.61 (3H, s, isoxazole C-5 CH3), 2.28
(3H, s, isoxazole C-3 CH3), 2.08 (2H, t, J 6 Hz, diazepine H-6);
4-Methyl-7-[4-(2-nitro-4-(trifluoromethyl)phenyl)piperazine-
1-sulfonyl]-3,4-dihydro-2H-benzo[1,4]oxazine
(14b). Pale
yellow gum, LC retention time 3.34 (m/z 486.1);
=
mmax(neat)/cm−1 1638, 1581, 1310, 1292, 1192, 1122, 1074,
1045, 928, 756, 769; dH(400 MHz; CDCl3) 8.12 (1H, s, Ph
H-3), 7.72 (1H, d, J 7.1 Hz, Ph H-5), 7.18 (1H, d, J 7.5 Hz,
benzooxazine H-6), 7.07 (1H, d, J 7.1 Hz, Ph H-6), 6.95
(1H, s, benzooxazine H-8), 6.85 (1H, d, J 7.5 Hz, benzooxazine
H-5), 4.38 (4H, br d, benzooxazine H-2, H-3), 3.35 (4H, br d,
piperazine H-3, H-5), 3.25 (3H, s, N-1 CH3), 2.95 (4H, br d,
=
dC(125 MHz; CDCl3) 173.2 (C O), 166.4 (C), 157.4, 157.4 (C),
152.2 (CH), 144.8 (CH), 118.0 (CN), 116.0 (C), 112.8 (CH), 90.5
(C), 51.4 (CH2), 48.9 (CH2), 48.8 (CH2), 47.1 (CH2), 28.6 (CH2),
12.8 (CH3), 11.1 (CH3); m/z (EI+) 325.15745 (M+, C17H19N5O2
requires 325.15387); 202.1 (55%) (M + H), 124.1 (36%).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 1 4 0 – 3 1 6 0
3 1 5 3