Journal of Medicinal Chemistry
ARTICLE
solid (40 mg, 59%). 1H NMR (500 MHz, CD3OD) δ 8.51 (s, 2H), 6.74
(s, 2H), 5.80 (t, J = 3.7 Hz, 2H), 4.18 (m, 2H), 3.22 (d, 2H), 3.78 (s,
6H), 2.81 (m, 4H), 2.30 (m, 4H), 2.30 (s, 6H), 2.25 (s, 6H), 1.93 (m,
8H), 1.82 (4, 2H). 13C NMR (125 MHz, CD3OD) δ 170.3, 156.1,
150.2, 146.4, 140.6, 127.5, 124.8, 122.4, 121.1, 118.8, 115.0, 106.5,
55.9, 52.4, 45.3, 40.8, 30.8, 9.4. IR (KBR) νmax 3274, 2937, 2848, 1708,
1689, 1604, 1521, 1457, 1386, 1080, 772 cmꢀ1. HRMS (FAB) m/z:
[M + H+] for C40H49N4O10, calcd, 745.3449; found, 745.3418.
This material was determined to be ∼97.3% pure (retention time =
2.049) by HPLC analysis on autosampler (Agilent TOF/Agilen-
tA3B1C3.m method with 49% CHCl3, 49% MeOH, and 2% H2O,
flow rate 5.0 mL/min).
(E)-N1,N6-Bis(8-methoxy-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)hex-3-enediamide (28). Colorless amorphous solid (34
mg, 44%). 1H NMR (500 MHz, CDCl3) δ 8.62 (s, 2H), 8.13 (s, 2H),
7.16 (d, J = 8.8 Hz, 2H), 6.93 (dd, J = 8.7, 17.2 Hz, 2H), 5.93 (m, 2H),
4.48 (m, 2H), 3.98 (s, 6H), 3.29 (dd, J = 1.6, 3.9 Hz, 4H), 2.81 (m, 4H),
2.46 (m, 4H), 2.41 (s, 6H), 2.14 (m, 4H), 1.98 (m, 4H). 13C NMR (125
MHz, CDCl3) δ 169.7, 158.6, 151.9, 144.4, 137.8, 127.7, 124.3, 122.6,
121.9, 114.8, 113.6, 73.5, 61.7, 52.2, 45.9, 41.3, 30.4. IR (KBR) νmax
3377, 2943, 2881, 1701, 1691, 1604, 1518, 1460, 1357, 1205, 1059,
972 cmꢀ1. HRMS (FAB) m/z: [M + H+] for C38H45N4O10, calcd,
717.3136; found, 717.3135.
(E)-N1,N8-Bis(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)oct-4-enediamide (29). Colorless amorphous solid (87
mg, 53%). 1H NMR (500 MHz, CDCl3 + CD3OD) δ 8.46 (s, 2H), 7.16
(d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 5.49 (dd, J = 9.4, 12.9 Hz,
2H), 4.42 (m, 2H), 2.61 (m, 4H), 2.41 (m, 8H), 2.31 (m, 4H), 2.30 (s,
6H), 2.16 (s, 6H), 1.94 (m, 4H), 1.84 (m, 4H). 13C NMR (125 MHz,
CDCl3 + CD3OD) δ 172.2, 159.2, 156.6, 149.3, 129.8, 125.5, 125.2,
121.0, 114.8, 113.1, 110.3, 71.5, 51.7, 45.6, 36.8, 29.8, 27.9, 8.0. IR (KBR)
νmax 3335, 3085, 3043, 2923, 2852, 1703, 1681, 1604, 1523, 1377, 1097,
771 cmꢀ1. HRMS (FAB) m/z: [M + H+] for C40H49N4O8, calcd,
713.3550; found, 713.3564. This material was determined to be ∼100%
pure (retention time = 2.137) by HPLC analysis on autosampler (Agilent
TOF/AgilentA3B1C3.m method with 49% CHCl3, 49% MeOH, and 2%
H2O, flow rate 5.0 mL/min).
(E)-N1,N8-Bis(6-methoxy-8-methyl-7-(1-methylpiperidin-4-yloxy)-
2-oxo-2H-chromen-3-yl)oct-4-enediamide (30). Colorless amorphous
solid (45 mg, 61%). 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 2H), 6.76 (s,
2H), 5.59 (t, J = 3.5 Hz, 2H), 4.26 (m, 2H), 3.84 (s, 6H), 2.98 (m, 4H),
2.47 (m, 12H), 2.31 (s, 6H), 2.06 (m, 12H), 1.97 (m, 4H). 13C NMR
(125 MHz, CDCl3) δ 172.0, 159.1, 150.2, 146.8, 143.5, 130.0, 124.1,
122.6, 120.5, 115.3, 106.5, 56.0, 52.2, 45.3, 37.2, 37.1, 30.6, 28.1, 9.7. IR
(KBR) νmax 3323, 2933, 2850, 1716, 1685, 1533, 1465, 1389, 1220,
1190, 771 cmꢀ1. HRMS (FAB) m/z: [M + H+] for C42H53N4O10, calcd,
773.3762; found, 773.3774.
7.28 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.47 (t, J = 3.7 Hz, 2H),
4.47 (m, 2H), 2.68 (m, 4H), 2.42 (m, 8H), 2.35 (s, 6H), 2.32 (s, 6H),
2.12 (m, 4H), 2.05 (m, 4H), 1.93 (m, 4H), 1.82 (m, 4H). 13C NMR (125
MHz, CDCl3) δ 172.4, 159.4, 157.0, 149.5, 130.5, 125.6, 124.6, 121.4,
115.4, 113.4, 110.6, 72.2, 52.4, 46.3, 37.0, 32.0, 30.8, 25.1, 8.5. IR (KBR)
νmax 3328.9, 2935, 2786, 1708, 1676, 1604, 1527, 1371, 1265, 1099,
769 cmꢀ1. HRMS (FAB) m/z: [M + H+] for C42H53N4O8, calcd,
741.3863; found, 741.3863.
(E)-N1,N10-Bis(6-methoxy-8-methyl-7-(1-methylpiperidin-4-yloxy)-
2-oxo-2H-chromen-3-yl)dec-5-enediamide (33). Colorless amorphous
solid (54 mg, 70%). 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 8.07 (s,
2H), 6.79 (s, 2H), 5.46 (t, J = 3.7 Hz, 2H), 4.22 (m, 2H), 3.86 (s, 6H),
2.77 (m, 4H), 2.43 (t, J = 7.5 Hz, 4H), 2.35 (s, 6H), 2.29 (s, 6H), 2.11 (m,
8H), 1.93 (m, 8H), 1.84 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 172.5,
159.2, 150.5, 147.1, 143.6, 130.5, 124.0, 122.6, 120.8, 115.1, 106.5, 78.5,
56.1, 53.6, 46.2, 37.0, 32.1, 31.9, 25.1, 9.8. IR (KBR) νmax 3325, 2939, 2849,
1708, 1686, 1521, 1465, 1387, 1085, 1010, 772 cmꢀ1. HRMS (FAB) m/z:
[M + H+] for C44H57N4O10, calcd, 801.4075; found, 801.4058.
(E)-N1,N10-Bis(8-methoxy-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)dec-5-enediamide (34). Colorless amorphous solid (24
mg, 42%). 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 2H), 8.02 (s, 2H),
7.16 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.46 (tt, J = 1.4, 3.8 Hz,
2H), 4.47 (m, 2H), 3.99 (s, 6H), 2.78 (t, J = 10.1 Hz, 4H), 2.44 (m, 4H),
2.42(t, J = 7.4Hz, 4H), 2.38 (s, 6H), 2.11 (m, 8H), 1.96 (m, 4H), 1.81 (p,
J = 7.2, 14.5 Hz, 4H). 1H NMR (125 MHz, CDCl3) δ 172.5, 158.9, 151.9,
144.4, 137.8, 130.5, 124.1, 122.5, 122.0, 114.9, 113.5, 61.6, 52.3, 46.0,
37.0, 31.9, 30.6, 30.1, 25.1. IR (KBR) νmax 3379, 29439, 2864, 1718, 1697,
1647, 1607, 1521, 1460, 1369, 1280, 1034, 968, 767 cmꢀ1. HRMS (FAB)
m/z: [M + H+] for C42H53N4O10, calcd, 773.3762; found, 773.3757.
This material was determined to be ∼93.5% pure (retention time =
2.353) by HPLC analysis on autosampler (Agilent TOF/Agilen-
tA3B1C3.m method with 49% CHCl3, 49% MeOH, and 2% H2O, flow
rate 5.0 mL/min).
(E)-N1,N12-Bis(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)dodec-6-enediamide (35). Colorless amorphous solid
1
(54 mg, 68%). H NMR (500 MHz, CDCl3) δ 8.62 (s, 2H), 7.98 (s,
2H), 7.24 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.41 (t, J = 3.7 Hz,
2H), 4.45 (m, 2H), 2.65 (m, 4H), 2.42 (t, J = 7.5 Hz, 4H), 2.37 (m, 4H),
2.32 (s, 6H), 2.30 (s, 6H), 2.02 (m, 8H), 1.90 (m, 4H), 1.73 (m, 4H),
1.46 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 172.5, 159.4, 156.9,
149.5, 130.3, 125.5, 124.5, 121.4, 115.3, 113.3, 110.6, 52.4, 46.3, 37.7,
32.3, 30.8, 29.1, 25.0, 8.5. IR (KBR) νmax 3327, 2931, 2358, 1712, 1676,
1605, 1529, 1371, 1261, 1097, 1041, 771 cmꢀ1. HRMS (FAB) m/z:
[M + H+] for C44H57N4O8, calcd, 769.4176; found, 769.4193.
(E)-N1,N6-Bis(7-(3-(dimethylamino)propoxy)-8-methyl-2-oxo-2H-
chromen-3-yl)hex-3-enediamide (36). Colorless amorphous solid (24
mg, 34%). 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 2H), 7.15 (dd, J = 3.9,
8.5, 2H), 6.72 (d, J = 8.5 Hz, 2H), 5.77 (t, J = 4.6 Hz, 4H), 3.94 (t, J = 5.4
Hz, 4H), 3.14 (m, 4H), 2.40 (m, 4H), 2.15 (s, 6H), 2.14 (s, 6H), 2.13 (s,
6H), 1.89 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 170.3, 159.1, 158.3,
149.1, 127.3, 125.6, 120.7, 113.6, 112.9, 108.6, 66.6, 56.1, 44.8, 44.5, 40.6,
26.9, 7.7. IR (KBR) νmax 3312, 2939, 2857, 1707, 1682, 1608, 1521,
1365, 1269, 1172, 1039, 903 cmꢀ1. HRMS (FAB) m/z: [M + H+] for
C36H45N4O8, calcd, 661.3237; found, 661.3215.
(Z)-N1,N8-Bis(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)oct-4-enediamide (38). 1H NMR (400 MHz, CDCl3) δ
8.58 (s, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.43 (m,
2H), 4.63 (m, 2H), 2.94 (m, 8H), 2.57 (s, 6H), 2.45 (s, 6H), 2.31 (m,
12H), 2.07 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 178.3, 174.0,
160.9, 158.0, 151.3, 138.0, 132.2, 131.8, 130.3, 127.5, 125.7, 124.4, 123.6,
123.5, 116.6, 115.5, 112.3, 54.2, 52.6, 46.1, 39.2, 39.1, 36.3, 30.6, 30.0,
29.8, 26.7, 25.0, 24.9, 9.9. IR (KBR) νmax 3335, 3085, 3043, 2923, 2852,
1703, 1681, 1604, 1523, 1377, 1097, 771 cmꢀ1. HRMS (FAB) m/z:
[M + H+] for C40H49N4O8, calcd, 713.3550; found, 713.3564.
(E)-N1,N8-Bis(8-methoxy-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)oct-4-enediamide (31). Colorless amorphous solid (27
mg, 49%). 1H NMR (500 MHz, CDCl3) δ 8.61 (s, 2H), 8.06 (s, 2H),
7.13 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 5.61 (t, J = 3.4 Hz, 2H),
4.42 (m, 2H), 3.98 (s, 6H), 2.71 (m, 4H), 2.50 (t, J = 6.6 Hz, 4H), 2.45
(m, 4H), 2.31 (m, 4H), 2.31 (s, 6H), 2.04 (m, 4H), 1.91 (m, 4H). 13C
NMR (125 MHz, CDCl3) δ 171.8, 158.8, 152.1, 144.1, 137.5, 130.1,
124.3, 122.4, 121.9, 114.7, 113.4, 74.4, 61.6, 52.7, 46.3, 37.3, 31.1, 28.2.
IR (KBR) νmax 3374, 2948, 2880, 1704, 1690, 1604, 1522, 1465, 1362,
1227, 1067, 972, 773 cmꢀ1. HRMS (FAB) m/z: [M + H+] for C40H49-
N4O10, calcd, 745.3449; found, 745.3434. This material was determined
to be ∼93.3% pure (retention time = 2.180) by HPLC analysis on auto-
sampler (Agilent TOF/AgilentA3B1C3.m method with 49% CHCl3,
49% MeOH, and 2% H2O, flow rate 5.0 mL/min).
(E)-N1,N10-Bis(8-methyl-7-(1-methylpiperidin-4-yloxy)-2-oxo-2H-
chromen-3-yl)dec-5-enediamide (32). Colorless amorphous solid (47
mg, 77%). 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 2H), 7.99 (s, 2H),
6245
dx.doi.org/10.1021/jm200553w |J. Med. Chem. 2011, 54, 6234–6253