D.P. Arama et al. / European Journal of Medicinal Chemistry 93 (2015) 202e213
209
(2C), 129.9, 130.1, 131.6, 132.0, 138.5, 141.5, 145.4, 152.6, 152.7, 156.8,
3.3.7. (4S)-4-benzyl-2-(3,4,5-trimethoxyphenyl)-3,4-dihydro-5H-
159.2, 181.6; FT-IR (cmꢂ1): 3027, 2956, 2923, 1732, 1645, 1633, 1556,
1523, 1480, 1421, 1335, 1299, 1247, 1122, 1094, 1073, 1044, 949, 898,
820, 761; HPLC, Tr ¼ 1.60 min; MS (ESIþ): m/z 395.1 [MþH]þ; HRMS
calcd for C25H23N4O 395.1872, found 395.1858.
pyrido[10,20:1,2] imidazo[4,5-d][1,3]diazepin-5-one (1p)
Yellow solid (m
¼
0.192 g, 59%); mp: 119.0e120.0 ꢀC;
20
[a
]
¼ þ22.98ꢀ (c 0.87, CHCl3); 1H NMR (CDCl3, 300 MHz):
d ppm
D
3.35 (bs, 1H), 3.70 (s, 6H), 3.82 (s, 4H),4.31 (bs, 1H), 6.82 (bs, 2H),
7.03 (td, 1H, J ¼ 14.5, 6.9 Hz), 7.33 (m, 8H), 9.58 (bs, 1H); 13C NMR
3.3.3. (4S)-4-benzyl-2-(2-methoxyphenyl)-3,4-dihydro-5H-pyrido
[10,20:1,2]imidazo[4,5-d][1,3]diazepin-5-one (1l)
(CDCl3, 100 MHz): d ppm 29.9, 36.5, 56.4 (2C), 61.0, 105.1, 106.8 (2C),
112.1, 114.2, 115.9, 127.1, 128.8 (2C), 128.9, 129.9 (2C), 130.9, 141.7,
146.2, 153.1 (2C), 159.7, 166.5, 182.3; FT-IR (cmꢂ1): 2937, 2836, 1719,
1625, 1559, 1462, 1409, 1333, 1232, 1122, 1000, 763, 700;
HPLC,Tr ¼ 1.50 min; MS (ESIþ): m/z 457.1 [MþH]þ; HRMS calcd for
Yellow solid (m
¼
0.255 g, 72%); mp: 104.0e105.0 ꢀC;
20
[
a]
¼ ꢂ24.86ꢀ (c 1.5, CHCl3); 1HNMR (CDCl3, 300 MHz):
d ppm
D
3.09 (m, 1H), 3.32 (m, 1H), 3.60 (s, 3H), 4.24 (dd, 1H, J ¼ 9.0, 6.0 Hz),
6.80 (d, 1H, J ¼ 9.0 Hz), 6.99 (m, 2H), 7.20e7.24 (m, 6H), 7.35e7.46
(m, 3H), 8.22 (bs, 1H), 9.50 (d, 1H, J ¼ 6.0 Hz); 13C NMR (CDCl3,
C25H25N4O4 457.1876, found 457.1874.
75 MHz):
d
ppm 36.5, 56.0, 66.4, 111.6, 112.6, 113.8, 116.0, 121.5,
3.3.8. (4S)-4-(1-naphthyl)methyl-2-(2-methylphenyl)-3,4-dihydro-
5H-pyrido[10,20:1,2] imidazo[4,5-d][1,3]diazepin-5-one (1q)
122.3, 126.7 (2C), 128.6, 128.7 (2C), 129.8, 129.9, 130.6, 133.1, 133.3,
138.1, 146.5, 156.3, 158.1, 181.9; FT-IR (cmꢂ1): 660, 680, 694, 722,
741, 842, 904, 921, 978, 1024, 1042, 1073, 1106, 1126, 1163, 1182,
1240, 1269, 1297, 1335, 1453, 1481, 1524, 1562, 1601, 1622, 1645,
2971; HPLC, Tr ¼ 1.34 min; MS (ESIþ): m/z 397.1 [MþH]þ; HRMS
calcd for C24H21N4O2 397.1665, found 397.1655.
Yellow solid (m
¼
0.105 g, 45%); mp: 134.4e135.4 ꢀC;
20
[a
]
¼ þ29.4ꢀ (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz):
d ppm 2.20
D
(s, 3H), 3.71 (bs, 1H), 4.18 (bs, 2H), 6.9 (t, 1H, J ¼ 9.0 Hz), 7.12e7.19
(m, 4H), 7.30e7.48 (m, 5H), 7.61 (bs,1H), 7.76 (d, 1H, J ¼ 9.0 Hz), 7.85
(dd, 2H, J ¼ 9.0, 3.0 Hz), 8.05 (dd, 1H, J ¼ 9.0, 3.0 Hz), 9.48 (d, 1H,
J ¼ 9.0 Hz); 13C NMR (CDCl3, 75 MHz):
d ppm 20.4, 33.9, 53.5 (from
3.3.4. (4S)-4-benzyl-2-(3-methoxyphenyl)-3,4-dihydro-5H-pyrido
[10,20:1,2]imidazo[4,5-d][1,3]diazepin-5-one (1m)
1He13C HSQC correlation), 113.7, 115.3, 120.2, 121.8, 124.0, 125.6,
126.0 (2C), 127.3, 128.4, 128.6, 128.9, 130.3, 130.7, 131.2, 132.3 (2C),
134.1, 135.6, 138.4, 145.6, 156.1, 157.4, 159.5, 181.2; FT-IR (cmꢂ1):
2927, 1691, 1632, 1556, 1523, 1480, 1421, 1335, 1301, 1247, 1162, 1124,
760; HPLC, Tr ¼ 1.69 min; MS (ESIþ): m/z 431.2 [MþH]þ; HRMS
calcd for C28H23N4O 431.1872, found 431.1873.
Brown dough (m
¼
0.130 g, 94%); mp: 66.0e67.0 ꢀC;
20
[
d
a
]
¼ þ3.2ꢀ (c 0.375, DMSO); 1H NMR (DMSO-d6, 400 MHz):
D
ppm 2.96 (dd, 1H, J ¼ 12.0, 8.0 Hz), 3.26 (dd, 1H, J ¼ 12.0, 4.0 Hz),
3.75 (s, 3H), 4.56 (dd, 1H, J ¼ 12.0, 4.0 Hz), 6.97e7.03 (m, 1H),
7.13e7.50 (m, 10H), 7.90e7.97 (m, 2H), 9.54 (d, 1H, J ¼ 8.0 Hz); 13C
NMR (DMSO-d6, 100 MHz):
d
ppm 34.7, 55.4, 63.7, 111.7, 114.8, 115.1,
3.3.9. (4S)-4-methyl-2-(2-methylphenyl)-3,4-dihydro-5H-pyrido
[10,20:1,2]-imidazo[4,5-d][1,3]diazepin-5-one (1r)
116.4, 120.2, 122.7, 127.0 (2C), 128.5, 128.6 (2C), 129.4, 129.8, 133.4,
136.1, 143.4, 150.1, 158.0, 158.3, 159.0, 180.3; FT-IR (cmꢂ1): 2963,
1648, 1596, 1580, 1519, 1488, 1466, 1454, 1417, 1332, 1292, 1259,
1177, 1129, 1029, 762; HPLC, Tr ¼ 1.42 min; MS (ESIþ): m/z 397.1
[MþH]þ; HRMS calcd for C24H21N4O2 397.1665, found 397.1654.
White solid (m
¼
0.023 g, 8%); mp: 124.0ꢀCe125.0 ꢀC;
20
[a
]
¼ ꢂ41.04ꢀ (c 0.57, CHCl3); 1H NMR (CDCl3, 400 MHz):
d ppm
D
1.68 (bs, 3H), 2.42 (s, 3H), 4.09e4.16 (m, 1H), 6.93 (t, 1H, J ¼ 8.0 Hz),
7.17e7.35 (m, 6H), 7.61 (d,1H, J ¼ 8.0 Hz), 9.48 (d,1H, J ¼ 8.0 Hz); 13
C
NMR (CDCl3, 100 MHz):
d ppm 16.6, 20.3, 63.4, 111.7, 113.4, 114.8,
3.3.5. (4S)-4-benzyl-2-(2,5-dimethoxyphenyl)-3,4-dihydro-5H-
126.0, 128.2, 130.0 (2C), 130.5, 131.0, 131.1, 135.6, 137.9, 145.4, 154.6,
182.5; FT-IR (cmꢂ1): 2929, 1645, 1627, 1558, 1523, 1482, 1419, 1337,
1300,1248, 757; HPLC, Tr ¼ 1.14 min; MS (ESIþ): m/z 305.3 [MþH]þ;
HRMS calcd for C18H17N4O 305.1402, found 305.1404.
pyrido[10,20:1,2]imidazo [4,5-d][1,3]diazepin-5-one (1n)
Yellow solid (m
¼
0.089 g, 39%); mp: 155.0e156.0 ꢀC;
20
[
a]
¼ ꢂ12.0ꢀ (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz):
d ppm 3.13
D
(m, 1H), 3.31 (m, 1H), 3.59 (s, 3H), 3.79 (s, 3H), 4.25 (m, 1H), 6.76 (d,
1H, J ¼ 9.0 Hz), 6.92e7.03 (m, 2H), 7.16e7.24 (m, 6H), 7.47 (t, 2H,
J ¼ 6.0 Hz), 7.80 (bs, 1H), 9.54 (d, 1H, J ¼ 6.0 Hz); 13C NMR (CDCl3,
3.3.10. (4S)-4-methyl-2-(3,4-dimethoxyphenyl)-3,4-dihydro-5H-
pyrido[10,20:1,2] imidazo[4,5-d][1,3]diazepin-5-one (1s)
75 MHz):
d
ppm 36.5, 54.2 (from 1He13C HSQC correlation), 56.2,
Brown solid (m
¼
0.006 g, 6%); mp: 102.0e103.0 ꢀC;
20
56.7, 112.6, 113.4, 113.9, 116.0, 120.3, 126.5, 126.7, 128.6, 128.7, 129.8,
129.9, 130.7, 134.2, 138.0, 143.2, 146.4, 152.5, 154.1, 182.0; FT-IR
(cmꢂ1): 3019, 2928, 2832, 1647, 1635, 1565, 1526, 1480, 1460,
1448, 1412, 1335, 1318, 1268, 1240, 1220, 1178, 1099, 1074, 1042,
1024, 961, 941, 902, 870, 813, 755, 740, 697, 676,; HPLC,
Tr ¼ 1.66 min; MS (ESIþ): m/z 427.1 [MþH]þ; HRMS calcd for
[
a
]
¼ ꢂ40.8ꢀ (c 0.25, CHCl3); 1H NMR (CDCl3, 300 MHz):
d ppm
D
1.61 (bs, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.66 (bs, 1H), 6.84 (d, 1H,
J ¼ 9.0 Hz), 6.97 (t, 1H, J ¼ 9.0 Hz), 7.45e7.48 (m, 3H), 7.67 (bs, 1H),
8.07 (bs, 1H), 9.53 (d, 1H, J ¼ 6.0 Hz); 13C NMR (CDCl3, 75 MHz):
d
ppm 16.4, 56.1, 56.2, 56.3, 109.7, 110.6, 112.3, 113.7, 115.9, 116.1,
117.6, 121.5, 128.0, 128.6, 129.9, 130.2, 149.3, 152.5, 183.1; HPLC,
C
25H23N4O3 427.1770, found 427.1778.
Tr ¼ 1.10 min; MS (ESIþ): m/z 351.2 [MþH]þ; HRMS calcd for
C19H19N4O3 351.1457, found 351.1458.
3.3.6. (4S)-4-benzyl-2-(3,4-dimethoxyphenyl)-3,4-dihydro-5H-
pyrido[10,20:1,2]imidazo [4,5-d][1,3]diazepin-5-one (1o)
3.3.11. (4S)-4-benzyloxymethyl-2-(2-methylphenyl)-3,4-dihydro-
Yellow solid (m
¼
0.115 g, 77%); mp: 136.0e137.0 ꢀC;
5H-pyrido[10,20:1,2] imidazo[4,5-d][1,3]diazepin-5-one (1t)
20
[
a]
¼ þ36.8ꢀ (c 1, DMSO); 1H NMR (DMSO-d6, 400 MHz):
d
ppm
Yellow solid (m
¼
0.036 g,31%); mp: 102.0e103.0 ꢀC;
D
¼ ꢂ8.25ꢀ (c 0.4, CHCl3); 1H NMR (CDCl3, 300 MHz):
d ppm 2.41
20
2.90e3.17 (m, 3H), 3.70 (s, 3H), 3.81 (s, 3H), 4.15 (bs,1H), 6.97 (d,1H,
J ¼ 8.0 Hz), 7.14 (bs, 1H), 7.17 (td, 1H, J ¼ 8.0, 4.0 Hz), 7.24e7.32 (m,
6H), 7.64e7.70 (m, 2H), 9.47 (d, 1H, J ¼ 8.0 Hz); 13C NMR (DMSO-d6,
[a
]
D
(bs, 3H), 4.10 (bs,1H), 4.25 (dd,1H, J ¼ 9.0, 6.0 Hz), 4.54 (m,1H), 4.71
(bs, 2H), 6.93 (t, 1H, J ¼ 6.0 Hz), 7.17 (dd, 3H, J ¼ 9.0, 6.0 Hz),
7.29e7.39 (m, 8H), 7.63 (d, 1H, J ¼ 6.0 Hz), 9.47 (d, 1H, J ¼ 6.0 Hz);
100 MHz):
d ppm 35.1, 54.9, 55.4, 55.6, 108.4, 110.8, 112.3, 113.6,
115.7, 122.6, 125.3, 126.5, 127.3 (2C), 127.8, 128.3 (2C), 129.5, 129.7,
130.5, 136.7, 146.1, 147.9, 151.8, 180.1; FT-IR (cmꢂ1): 2925, 2853, 699,
739, 764, 814, 840, 937, 973, 1021, 1080, 1140, 1173, 1231, 1261, 1335,
1435, 1462, 1496, 1510, 1557, 1599, 1623; HPLC, Tr ¼ 1.33 min; MS
(ESIþ): m/z 427.0 [MþH]þ; HRMS calcd for C25H23N4O3 427.1770,
found 427.1774.
13C NMR (CDCl3, 100 MHz):
d ppm 29.8, 69.9, 73.7, 73.8, 113.8, 115.3,
126.0, 126.1, 126.2, 127.8 (2C), 128.0, 128.5 (2C), 128.6, 130.4, 130.8,
130.9, 131.2, 131.3, 135.6, 138.3, 138.4, 145.7, 180.6; FT-IR (cmꢂ1):
3055, 3023, 2923, 2853, 2246, 1634, 1558, 1523, 1421, 1336, 1250,
1097, 907, 762, 729, 696; HPLC, Tr ¼ 1.55 min; MS (ESIþ): m/z 411.3
[MþH]þ; HRMS calcd for C25H23N4O2 411.1821, found 411.1825.