Evaluation of Hsp90 inhibitor 6BrCaQ
2.28 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=164.1, 160.6,
153.0 (2C), 145.8, 145.4, 141.6, 137.2, 133.9, 131.2, 129.8 (2C),
128.5, 128.1 (2C), 124.7, 123.4, 120.1, 118.0, 114.3, 105.4 (2C), 61.0,
56.4 (2C), 30.7, 21.6 ppm; IR (neat): n˜ =3276, 1650, 1623, 1596,
1523, 1487, 1416, 1367, 1333, 1230, 1193, 1182, 1122, 1078, 1015,
868, 834, 753, 734, 700, 665, 605, 559 cmÀ1; MS (APCI+): m/z: 539.1
[M+H]+; Anal. calcd for C27H26N2O8S (538.12): C 60.21, H 4.87, N
5.20; found: C 59.67, H 4.92, N 5.11.
7.73–7.70 (m, 1H), 7.63 (t, 1H, J=8.4 Hz), 7.43 (d, 1H, J=8.1 Hz),
7.33 (t, 1H, J=8.0 Hz), 7.15 (d, 2H, J=8.2 Hz), 7.09 (s, 2H), 3.84 (s,
6H), 3.76 (s, 3H), 2.16 ppm (s, 3H); 13C NMR (75 MHz, [D6]DMSO):
d=163.5, 160.0, 152.2 (2C), 148.8, 145.4, 140.3, 136.4, 133.1, 131.1,
129.8 (2C), 127.9, 127.4 (2C), 122.9, 122.6, 121.5, 116.1, 115.4, 105.5
(2C), 60.0, 56.0 (2C), 20.8 ppm; IR (neat): n˜ =2923, 1653, 1579,
1475, 1367, 1333, 1221, 1172, 1125, 1061, 1003, 919, 764, 745, 714,
667, 636, 614 cmÀ1; MS (APCI+): m/z: 525.1 [M+H]+.
Compound 9c: Yellow solid (42 mg, 98%); Rf =0.57 (CH2Cl2/EtOAc,
9:1); mp: 195–1978C; 1H NMR (300 MHz, CDCl3): d=8.13 (s, 1H),
7.82 (dd, 1H, J2 =8.1 Hz, J2 =1.2 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.67–
7.63 (m, 2H), 7.52 (ddd, 1H, J1 =8.6 Hz, J2 =7.2 Hz, J3 =1.5 Hz), 7.33
(d, 1H, J=8.4 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.02 (d, 2H, J=8.6 Hz),
6.97 (d, 2H, J=8.7 Hz), 3.70 (s, 3H), 2.18 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=166.5 (d, 1C, JCF =253.1 Hz), 163.2, 160.2,
145.5, 144.9, 136.9, 133.9, 131.0, 130.2 (d, 2C, JCF =9.0 Hz), 129.7
(2C), 129.2 (d, 1C, JCF =2.2 Hz), 127.9 (2C), 124.6, 123.3, 119.7,
117.8, 115.3 (d, 2C, JCF =21.9 Hz), 114.1, 30.5, 21.5 ppm; IR (neat):
n˜ =1686, 1644, 1624, 1596, 1487, 1365, 1221, 1193, 1177, 1081,
852, 812, 742, 696, 657, 623, 588 cmÀ1; MS (APCI+): m/z: 467.1
[M+H]+.
Compound 9h: White solid (66 mg, 79%); Rf =0.46 (CH2Cl2/EtOAc,
9:1); mp: 126–1288C; 1H NMR (300 MHz, CDCl3): d=7.92 (s, 1H),
7.88 (dd, 1H, J1 =8.1 Hz, J2 =1.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 7.50
(ddd, 1H, J1 =8.6 Hz, J2 =7.3 Hz, J3 =1.4 Hz), 7.42 (d, 1H, J=2.1 Hz),
7.32 (d, 1H, J=8.5 Hz), 7.31 (d, 1H, J=8.5 Hz), 7.24 (t, 1H, J=
7.3 Hz), 7.00 (d, 2H, J=8.3 Hz), 6.66 (d, 1H, J=8.5 Hz), 3.69 (s, 3H),
2.71 (t, 2H, J=6.7 Hz), 2.16 (s, 3H), 1.75 (t, 2H, J=6.7 Hz),
1.28 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=163.8, 160.3, 157.6,
145.3, 143.9, 136.6, 134.0, 130.6, 129.8, 129.7 (2C), 128.0 (2C),
127.2, 124.6, 124.3, 123.2, 120.6, 120.0, 118.2, 117.0, 114.0, 75.3,
32.5, 30.5, 26.9 (2C), 22.3, 21.6 ppm; IR (neat): n˜ =3265, 1646, 1628,
1603, 1482, 1364, 1320, 1256, 1236, 1194, 1180, 1152, 1119, 1078,
1016, 949, 911, 866, 839, 814, 732, 700, 660, 608, 561 cmÀ1; MS
(APCI+): m/z: 533.1 [M+H]+.
Compound 9d: White solid (223 mg, 95%); Rf =0.34 (CH2Cl2/
1
EtOAc, 9:1); mp: 109–1118C; H NMR (300 MHz, CDCl3): d=8.06 (s,
Compound 9i: Yellow oil (19 mg, 87%); Rf =0.59 (CH2Cl2/EtOAc,
1
1H), 8.01 (dd, 1H, J1 =8.1 Hz, J2 =1.2 Hz), 7.80 (d, 2H, J=8.3 Hz),
7.62 (ddd, 1H, J1 =8.6 Hz, J2 =7.3 Hz, J3 =1.4 Hz), 7.49 (dd, 1H, J1 =
5.0 Hz, J2 =1.0 Hz), 7.44–7.40 (m, 2H), 7.35 (t, 1H, J=7.3 Hz), 7.09
(d, 2H, J=8.1 Hz), 7.04 (dd, 1H, J1 =5.0 Hz, J2 =3.8 Hz), 3.79 (s, 3H),
2.25 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=160.2, 158.6, 145.5,
144.6, 138.0, 136.9, 133.9, 131.3, 131.0, 129.6 (3C), 128.0 (2C),
127.5, 124.8, 123.4, 119.2, 118.1, 114.1, 30.5, 21.6 ppm; IR (neat): n˜ =
1645, 1623, 1596, 1496, 1418, 1362, 1277, 1191, 1175, 1078, 850,
815, 758, 734, 700, 655, 604 cmÀ1; MS (APCI+): m/z: 455.0 [M+H]+.
8:2); H NMR (300 MHz, CDCl3): d=7.92 (d, 1H, J=1.1 Hz), 7.90 (s,
1H), 7.69 (d, 2H, J=8.3 Hz), 7.53 (t, 1H, J=8.4 Hz), 7.38–7.24 (m,
4H), 7.00 (d, 2H, J=8.4 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.25 (d, 1H, J=
9.9 Hz), 5.61 (d, 1H, J=9.9 Hz), 3.71 (s, 3H), 2.17 (s, 3H), 1.40 (s,
6H); 13C NMR (75 MHz, CDCl3): d=163.5, 160.3, 156.5, 145.4, 143.9,
136.6, 134.0, 131.3, 130.7, 129.7 (2C), 129.1, 128.0 (2C), 126.3,
125.3, 124.6, 123.3, 121.6, 120.6, 119.8, 118.2, 116.0, 114.1, 77.4,
30.5, 28.3 (2C), 21.6 ppm; IR (neat): n˜ =3249, 2975, 1643, 1600,
1575, 1478, 1361, 1317, 1268, 1213, 1190, 1177, 1122, 1075, 1013,
960, 912, 870, 814, 741, 697, 671, 659, 636, 621, 608, 595, 584,
578 cmÀ1; MS (APCI+): m/z: 531.1 [M+H]+.
Compound 9e: White solid (32 mg, 73%); Rf =0.59 (CH2Cl2/EtOAc,
8:2); mp: 257–2598C; 1H NMR (400 MHz, [D6]DMSO): d=11.41 (s,
1H), 9.59 (s, 1H), 7.87 (d, 1H. J=7.9 Hz), 7.76 (td, 1H, J1 =8.4 Hz,
J2 =1.1 Hz), 7.73 (d, 2H, J=8.4 Hz), 7.69 (d, 1H, J=8.6 Hz), 7.66 (d,
1H, J=8.0 Hz), 7.47–7.43 (m, 2H), 7.23 (t, 1H, J=7.4 Hz), 7.11 (d,
1H, J=1.1 Hz), 7.08 (t, 1H, J=7.2 Hz), 7.02 (d, 2H, J=8.1 Hz), 3.74
(s, 3H), 1.77 ppm (s, 3H); 13C NMR (100 MHz, [D6]DMSO): d=159.6,
158.9, 147.6, 145.4, 137.4, 136.6, 132.9, 131.5, 130.3, 129.8 (2C),
127.3 (2C), 126.8, 123.8, 123.5, 123.0, 121.8, 120.1, 119.8, 116.7,
115.2, 112.3, 104.9, 30.2, 20.5 ppm; IR (neat): n˜ =3255, 1645, 1626,
1599, 1538, 1366, 1252, 1192, 1177, 1074, 855, 734, 700, 653,
608 cmÀ1; MS (APCI+): m/z: 488.1 [M+H]+.
Compound 9j: The reaction was carried out using pyridine as sol-
vent to afford compound 9j without purification from 3b as a
yellow solid (20 mg, 15% over three steps); Rf =0.25 (CH2Cl2/EtOAc,
1
5:5); mp: 214–2168C; H NMR (300 MHz, [D6]DMSO): d=12.21 (s,
1H), 9.16 (s, 1H), 7.74 (d, 2H, J=8.3 Hz), 7.59 (d, 1H, J=9.0 Hz),
7.53 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J1 =8.6 Hz, J2 =2.1 Hz), 7.18
(d, 2H, J=8.3 Hz), 6.95 (dd, 1H, J1 =9.0 Hz, J2 =2.4 Hz), 6.89 (d, 1H,
J=2.4 Hz), 6.69 (d, 1H, J=8.6 Hz), 3.85 (s, 3H), 2.78 (t, 2H, J=
6.5 Hz), 2.18 (s, 3H), 1.82 (t, 2H, J=6.5 Hz), 1.32 ppm (s, 6H);
13C NMR (75 MHz, [D6]DMSO): d=163.9, 161.4, 160.4, 156.4, 149.0,
145.2, 138.2, 133.0, 129.8 (3C), 127.4, (2C), 127.1, 124.5, 124.1,
119.9, 118.8, 115.9, 111.6, 109.9, 98.0, 74.9, 55.5, 31.9, 26.5 (2C),
21.7, 20.9 ppm; IR (neat): n˜ =1655, 1516, 1482, 1358, 1259, 1175,
1119, 1061, 946, 837, 736, 675 cmÀ1; MS (APCI+): m/z: 549.0
[M+H]+.
Compound 9 f: Yellow solid; (28 mg, 70%); Rf =0.13 (cyclohexane/
1
EtOAc, 5:5); mp: 163–1658C; H NMR (300 MHz, CDCl3): d=7.78 (d,
2H, J=8.3 Hz), 7.65 (dd, 1H, J1 =8.1 Hz, J2 =0.9 Hz), 7.49 (t, 1H, J=
8.5 Hz), 7.29 (d, 1H, J=8.6 Hz), 7.28 (d, 2H, J=8.0 Hz), 7.22 (bs,
1H), 7.16 (t, 1H, J1 =8.1 Hz), 3.68 (s, 3H), 2.40 (s, 3H), 2.06 (t, 2H,
J=7.8 Hz), 1.55 (sext, 2H, J=7.4 Hz), 0.89 ppm (t, 3H, J=7.4 Hz);
13C NMR (75 MHz, CDCl3): d=170.5, 160.2, 145.8, 144.8, 137.0,
133.9, 130.8, 129.9 (2C), 128.3 (2C), 124.4, 123.0, 119.7, 117.6, 114.0,
38.4, 30.4, 21.7, 18.5, 13.7 ppm; IR (neat): n˜ =3239, 2925, 1681,
1629, 1597, 1499, 1462, 1359, 1289, 1231, 1191, 1173, 1062, 1010,
865, 811, 745, 711, 650, 613, 590, 568, 559 cmÀ1; MS (APCI+): m/z:
415.1 [M+H]+; Anal. calcd for C21H22N2O5S (414.19): C 60.85, H 5.35,
N 6.76; found: C 60.22, H 5.58, N 6.70.
Compound 9k: White solid (40 mg, 96%); Rf =0.27 (CH2Cl2/EtOAc,
8:2); mp: 144–1468C; 1H NMR (300 MHz, CDCl3): d=8.34 (s, 1H),
7.78 (dd, 1H, J1 =8.1 Hz, J2 =1.0 Hz), 7.73 (dd, 1H, J1 =3.8 Hz, J2 =
1.2 Hz), 7.61–7.56 (m, 2H), 7.41 (d, 1H, J=8.4 Hz), 7.27 (t, 1H, J=
7.6 Hz), 7.13 (s, 2H), 6.97 (dd, 1H, J1 =4.9 Hz, J2 =4.0 Hz), 3.91 (s,
3H), 3.90 (s, 6H), 3.79 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
164.3, 160.2, 153.0 (2C), 144.4, 141.5, 137.0, 135.6, 135.5, 134.9,
131.0, 128.6, 127.7, 124.2, 123.2, 120.4, 117.4, 114.2, 105.2 (2C),
61.0, 56.3 (2C), 30.6 ppm; IR (neat): n˜ =3268, 1641, 1621, 1596,
1486, 1415, 1363, 1333, 1287, 1223, 1180, 1126, 1097, 1073, 1005,
920, 864, 827, 753, 727, 698, 669, 610, 584 cmÀ1; MS (APCI+): m/z:
531.0 [M+H]+.
Compound 9g: The reaction was carried out using a mixture of
THF/pyridine (1:1) as solvent to give a beige solid (66 mg, 32%);
Rf =0.44 (CH2Cl2/EtOAc, 8:2); mp: 218–2208C; 1H NMR (300 MHz,
[D6]DMSO): d=12.41 (s, 1H), 9.60 (s, 1H), 7.75 (d, 2H, J=8.2 Hz),
ChemMedChem 2011, 6, 804 – 815
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