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F. Areias et al. / European Journal of Medicinal Chemistry 54 (2012) 303e310
4.1.2.2. N-(4-Cyano-1-phenyl-1H-imidazol-5-yl)-2-imino-8-methoxy-
2H-chromene-3-carboxamide (3b). Compound 3b was isolated as
a yellow solid in 94% yield. Mp 208e210 ꢂC. 1H NMR (300 MHz,
4.1.2.8. 6-Bromo-N-(1-hydroxybutan-2-yl)-2-imino-2H-chromene-
3-carboxamide (3y). Compound 3y was isolated as a yellow solid
in 95% yield. Mp 134e136 ꢂC. 1H NMR (400 MHz, DMSO-d6)
DMSO-d6)
7.32 (d, J ¼ 7.5 Hz, 1H), 7.44e7.58 (m, 5H), 8.09 (s, 1H), 8.50 (s, 1H),
9.26 (s, 1H), 13.16 (s, 1H). 13C NMR (75 MHz, DMSO-d6)
56.00,
106.00, 115.04, 116.33, 118.34, 118.72, 121.51, 124.27, 125.47 (2C),
129.38, 129.78 (2C), 133.51, 134.57, 136.82, 142.73, 143.32, 145.85,
155.26, 160.34. Anal. Calcd for C21H15N5O3.0.6H2O: C, 63.67; H, 4.09;
N, 17.69. Found: C, 63.67; H, 3.98; N, 17.62.
d
3.86 (s, 3H), 7.18 (t, J ¼ 7.8 Hz,1H), 7.28 (d, J ¼ 7.8 Hz,1H),
d
1.42e1.60 (m, 5H), 3.27e3.32 (m, 1H), 3.40 (t, J ¼ 6.0 Hz, 2H),
4.41 (s, 1H), 7.15 (d, J ¼ 8.8 Hz, 1H), 7.66 (dd, J ¼ 7.6 Hz, 2.4 Hz, 1H),
8.01 (d, J ¼ 2.4 Hz, 1H), 8.37 (s, 1H), 9.10 (s, 1H), 10.22 (t, J ¼ 5.2 Hz,
d
1H). 13C NMR (100 MHz, DMSO-d6)
d 25.62, 29.98, 39.64, 60.12,
115.33, 117.10, 120.55, 121.42, 131.76, 134.94, 139.33, 152.48,
154.85, 160.94. Anal. Calcd for C14H15N2O3Br.0.1H2O: C, 49.40; H,
4.46; N, 8.22. Found: C, 49.17; H, 4.54; N, 8.05.
4.1.2.3. N-(4-Cyano-1-(4-methoxyphenyl)-1H-imidazol-5-yl)-2-imino-
8-methoxy-2H-chromene-3-carboxamide (3c). Compound 3c was
isolated as a yellow solid in 97% yield. Mp 184e187 ꢂC. 1H NMR
4.1.2.9. 6-Bromo-N-cyclopentyl-2-imino-2H-chromene-3-carboxamide
(3z). Compound 3z was isolated as an off-white solid in 96%
yield. Mp 180e182 ꢂC. 1H NMR (400 MHz, DMSO-d6)
d 1.36e1.48 (m,
(300 MHz, DMSO-d6)
d
3.80 (s, 3H), 3.86 (s, 3H), 7.07 (d, J ¼ 9.0 Hz,
2H), 1.49e1.72 (m, 4H), 1.84e1.95 (m, 2H), 4.08e4.21 (m, 1H), 7.15
(d, J ¼ 8.8 Hz, 1H), 7.65 (dd, J ¼ 8.8 Hz, 2.4 Hz, 1H), 8.01 (d, J ¼ 2.0 Hz,
1H), 8.36 (s, 1H), 9.06 (s, 1H), 10.30 (d, J ¼ 7.2 Hz, 1H). 13C NMR
1H), 7.19 (t, J ¼ 8.1 Hz,1H), 7.26e7.36 (m, 2H), 7.44 (s,1H), 7.99 (s,1H),
8.52 (s, 1H), 9.28 (s, 1H), 13.19 (s, 1H). 13C NMR (75 MHz, DMSO-d6)
d
55.52, 56.03, 105.18, 114.89 (2C), 115.24, 116.36, 118.38, 118.76,
(100 MHz, DMSO-d6) d 23.26 (2 C), 32.55 (2 C), 50.72, 115.33, 117.04,
121.54, 124.30, 126.05, 127.18 (2C), 134.77, 136.85, 142.76, 143.28,
145.88, 155.23, 159.78, 160.14. Anal. Calcd for C22H17N5O4.1.5H2O: C,
59.73; H, 4.52; N, 15.84. Found: C, 59.48; H, 4.49; N, 15.81.
120.55, 121.33, 131.75, 134.91, 139.58, 152.46, 154.94, 160.35. Anal.
Calcd for C15H15N2O2Br: C, 53.73; H, 4.48; N, 8.36. Found: C, 53.74;
H, 4.32; N, 8.28.
4.1.2.4. N-(4-Cyano-1-(4-cyanophenyl)-1H-imidazol-5-yl)-2-imino-
8-methoxy-2H-chromene-3-carboxamide (3d). Compound 3d was
isolated as an off-white solid in 86% yield. Mp 213e216 ꢂC. 1H NMR
4.1.2.10. 6-Bromo-N-cyclohexyl-2-imino-2H-chromene-3-carboxamide
(3aa). Compound 3aa was isolated as a white solid in 100% yield.
Mp 207e209 ꢂC. 1H NMR (400 MHz, DMSO-d6)
d 1.20e1.40 (m,
(400 MHz, DMSO-d6)
d
3.88 (s, 3H), 7.23 (t, J ¼ 6.0 Hz, 1H), 7.31e7.37
5H), 1.45e2.00 (m, 5H), 3.76e3.78 (m, 1H), 7.16 (d, J ¼ 8.8 Hz, 1H),
7.67 (dd, J ¼ 8.8 Hz, 2.4 Hz, 1H), 8.02 (d, J ¼ 2.4 Hz, 1H), 8.38 (s, 1H),
9.10 (s, 1H), 10.31 (d, J ¼ 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
(m, 2H), 7.79 (dd, J ¼ 8.8, 2.0 Hz, 1H), 8.04 (dd, J ¼ 6.8, 2.0 Hz, 1H),
8.15 (s, 1H), 9.45 (s, 1H), 13.35 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
d
56.06, 105.76, 111.97, 114.97, 116.44, 118.04, 118.44, 118.82, 121.54,
d 23.90 (2 C), 25.14, 32.00 (2 C), 115.34, 117.05, 120.58, 121.40,
124.41, 126.37 (2C), 133.94 (2C), 135.32, 136.42, 137.46, 142.64,
143.42, 145.92, 155.76, 160.37. Anal. Calcd for C22H14N6O3.1.5H2O: C,
60.41; H, 3.89; N, 19.22. Found: C, 60.66; H, 5.90; N, 19.30.
131.78, 134.95, 139.43, 152.48, 154.96, 159.92. Anal. Calcd for
C16H17N2O2Br: C, 55.01; H, 4.87; N, 8.02. Found: C, 53.03; H, 4.78;
N, 7.94.
4.1.2.5. 6-Bromo-N-(3-hydroxypropyl)-2-imino-8-methoxy-2H-chro-
mene-3-carboxamide (3v). Compound 3v was isolated as a yellow
solid in 99% yield. Mp 173e175 ꢂC. 1H NMR (300 MHz, DMSO-d6)
4.1.2.11. 6-Bromo-N-(2,3-dihydroxypropyl)-2-imino-2H-chromene-
3-carboxamide (3ab). Compound 3ab was isolated as a yellow
solid in 88% yield. Mp 166e168 ꢂC. 1H NMR (400 MHz, DMSO-d6)
d
1.64 (q, J ¼ 7.2 Hz, 2H), 3.32e3.34 (m, 2H), 3.44 (t, J ¼ 6.0 Hz, 2H),
d 3.10e3.22 (m, 1H), 3.24e3.39 (m, 2H), 3.46e3.68 (m, 1H), 4.62
3.88 (s, 3H), 4.51 (s, 1H), 7.38 (d, J ¼ 2.0 Hz, 1H), 7.55 (d, J ¼ 2.0 Hz,
(d, J ¼ 5.2 Hz, 1H), 4.89 (d, J ¼ 4.8 Hz, 1H), 7.15 (d, J ¼ 8.8 Hz, 1H),
7.66 (dd, J ¼ 8.8 Hz, 2.4 Hz, 1H), 8.01 (d, J ¼ 2.4 Hz, 1H), 8.38 (d,
J ¼ 2.4 Hz, 1H), 9.10 (d, J ¼ 1.2 Hz, 1H), 10.31 (t, J ¼ 5.6 Hz, 1H). 13C
1H), 8.31 (d, J ¼ 1.2 Hz, 1H), 9.16 (s, 1H), 10.24 (t, J ¼ 5.7 Hz, 1H). 13C
NMR (75 MHz, DMSO-d6)
d 32.12, 36.16, 56.42, 58.31, 115.13, 117.78,
120.36, 121.53, 122.87, 139.46, 142.00, 146.66, 154.39, 161.07. Anal.
Calcd for C14H15N2O4Br.0.5H2O: C, 46.15; H, 4.40; N, 7.69. Found: C,
46.15; H, 4.44; N, 7.63.
NMR (100 MHz, DMSO-d6) d 42.16, 63.71, 70.01, 115.31, 117.04,
120.56, 121.44, 131.78, 134.94, 139.39, 152.53, 154.60, 161.18. Anal.
Calcd for C13H13N2O4Br: C, 45.75; H, 3.81; N, 8.21. Found: C, 45.53;
H, 3.84; N, 8.34.
4.1.2.6. 6-Bromo-N-(2-hydroxyethyl)-2-imino-2H-chromene-3-carbo-
xamide (3w). Compound 3w was isolated as a yellow solid in
81% yield. Mp 160e162 ꢂC. 1H NMR (400 MHz, DMSO-d6)
4.1.2.12. 8-Methoxy-N-(2-methoxyethyl)-2-oxo-2H-chromene-3-carbo-
xamide (4a). Compound 4a was isolated as a yellow solid in 88%
d
3.30e3.40 (m, 2H), 3.48e3.51 (m, 2H), 4.70e4.80 (brs, 1H), 7.15 (d,
yield. Mp 151e153 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 3.28 (s, 3H),
J ¼ 8.8 Hz, 1H), 7.66 (dd, J ¼ 8.8 Hz, 2.4 Hz, 1H), 8.01 (d, J ¼ 2.0 Hz,
3.47e3.48 (m, 4H), 3.91 (s, 3H), 7.33 (t, J ¼ 7.8 Hz, 1H), 7.40 (dd,
1H), 8.38 (s, 1H), 9.10 (s, 1H), 10.33 (t, J ¼ 5.2 Hz, 1H). 13C NMR
J ¼ 8.1 Hz, 1.5 Hz, 1H), 7.49 (dd, J ¼ 7.5 Hz, 1.5 Hz, 1H), 8.81 (d,
(100 MHz, DMSO-d6)
d
41.91, 59.58, 115.32, 117.05, 120.55, 121.43,
J ¼ 1.2 Hz, 1H), 8.79 (brs, 1H). 13C NMR (75 MHz, DMSO-d6)
d 38.87,
131.78, 134.94, 139.39, 152.52, 154.61, 161.11. Anal. Calcd for
C12H11N2O3Br.0.5H2O: C, 45.00; H, 3.75; N, 8.75. Found: C, 44.90; H,
3.74; N, 8.73.
58.02, 70.29, 116.00, 118.99, 121.16, 125.07, 143.18, 146.23, 147.85,
160.20, 161.02. Anal. Calcd for C14H15NO5: C, 60.65; H, 5.42; N, 5.05.
Found: C, 60.61; H, 5.34; N, 5.30.
4.1.2.7. 6-Bromo-N-(3-hydroxypropyl)-2-imino-2H-chromene-3-carbo-
4.1.2.13. N-(2-Hydroxyethyl)-8-methoxy-2-oxo-2H-chromene-3-carbo-
xamide (3x). Compound 3x was isolated as a yellow solid in 94%
xamide (4b). Compound 4b was isolated as an off-white solid in
yield. Mp 161e163 ꢂC. 1H NMR (400 MHz, DMSO-d6)
d
1.64 (q,
55% yield. Mp 194e196 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 3.39
J ¼ 6.9 Hz, 2H), 3.25e3.39 (m, 2H), 3.40e3.49 (m, 2H), 4.20e4.80
(brs, 1H), 7.15 (d, J ¼ 9.0 Hz, 1H), 7.66 (dd, J ¼ 8.7 Hz, 2.4 Hz, 1H),
8.01 (d, J ¼ 2.4 Hz, 1H), 8.37 (s, 1H), 9.11 (s, 1H), 10.22 (t, J ¼ 5.7 Hz,
(q, J ¼ 5.4 Hz, 2H), 3.53 (q, J ¼ 5.4 Hz, 2H), 3.92 (s, 3H), 4.86
(t, J ¼ 4.8 Hz, 1H), 7.34 (t, J ¼ 7.5 Hz, 1H), 7.40 (dd, J ¼ 8.2 Hz, 1.8 Hz,
1H), 7.49 (dd, J ¼ 7.6 Hz, 1.5 Hz, 1H), 8.83 (m, 2H). 13C NMR
1H). 13C NMR (100 MHz, DMSO-d6)
d
32.12, 36.17, 58.31, 115.34,
(75 MHz, DMSO-d6) d 41.84, 56.14, 59.43, 115.95, 118.76, 121.15,
117.06, 120.56, 121.42, 131.78, 134.95, 139.33, 152.50, 154.79, 161.07.
HRMS-FAB (m/z): [M þ H]þ calcd. for C13H13N2O3Br: 327.01682,
found: 327.01573.
125.05, 143.15, 146.22, 147.77, 160.18, 160.97. Anal. Calcd
for C13H13NO5: C, 59.32; H, 4.94; N, 5.32. Found: C, 59.15; H, 4.83;
N, 5.41.