Journal of Medicinal Chemistry
ARTICLE
6H, AdCH2), 2.10 (bs, 3H, AdCH), 2.18 (bs, 6H, AdCH2), 4.29 (q, J =
7.3 Hz, 2H, OCH2CH3), 5.32 (s, 1H, OH), 6.77 (d, J = 8.5 Hz, 1H, 50-
ArH), 6.97 (d, J = 15.9 Hz, 1H, CHdCHCO), 7.71 (d, J = 15.9 Hz, 1H,
CHdCHCO), 7.75 (dd, J = 8.5 Hz, 2.4 Hz, 1H, 60-ArH), 7.98 (d, J = 2.4
Hz, 1H, 20-ArH), 8.62 (d, J = 1.2 Hz, 1H, 6-ArH), 8.97 ppm (d, J = 1.2
Hz, 1H, 3-ArH). HRMS calcd C25H28N2O3 [M þ H]þ, 405.2173;
found, 405.2181.
treatment, workup, and chromatography (4% EtOAc/hexane) gave 26
mg (89%) of 72 as an off-white solid, mp 170ꢀ172 ꢀC. IR 3455, 2908,
1740, 1325, 1151 cmꢀ1. 1H NMR δ 1.29 (t, J = 7.2 Hz, 3H, OCH2CH3),
1.82 (bs, 6H, AdCH2), 2.13 (bs, 3H, AdCH), 2.18 (bs, 6H, AdCH2),
4.19 (s, 2H, S(O)2CH2), 4.24 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.09 (s,
1H, OH), 6.77 (d, J = 8.1 Hz, 1H, 50-ArH), 7.22 (dd, J = 8.1 Hz, 2.1 Hz,
1H, 60-ArH), 7.35 (d, J = 2.1 Hz, 1H, 20-ArH), 7.57 (d, J = 8.1 Hz,
3-ArH), 7.88 (dd, J = 8.1 Hz, 1.8 Hz, 1H, 5-ArH), 8.07 ppm (d, J = 1.8
Hz, 1H, 6-ArH). HRMS calcd C26H29ClO5S [M þ H]þ, 489.1497;
found, 489.1495.
Ethyl (E)-3-[2-(30-(1-Adamantyl)-40-hydroxyphenyl)-5-pyrimidinyl]-2-
propenoate (36). Compound 30 (2.30 g, 4.65 mmol) after treatment,
workup, and chromatography (16ꢀ20% EtOAc/hexane) gave 1.8 g (95%)
of 36 as a pale-yellow solid, mp 226ꢀ228 ꢀC. IR 3345, 2856, 1715,
1456 cmꢀ1. 1H NMR δ 1.39 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.83 (bs, 6H,
AdCH2), 2.13 (bs, 3H, AdCH), 2.24 (bs, 6H, AdCH2), 4.33 (q, J = 7.2 Hz,
2H, OCH2CH3), 5.38 (bs, 1H, OH), 6.59 (d, J = 16.2 Hz, 1H,
CHdCHCO), 6.79 (d, J = 8.1 Hz, 1H, 50-ArH), 7.65 (d, J = 16.2 Hz,
1H, CHdCHCO), 8.22 (dd, J = 8.1 Hz, 2.1 Hz, 1H, 60-ArH), 8.44 (d, J =
2.1 Hz, 1H, 20-ArH), 8.90 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd
C25H28N2O3 [M þ H]þ, 405.2173; found, 405.2191.
Ethyl 3-[4-(30-(1-Adamantyl)-40-hydroxy)-3-chlorophenyl]propanoate
(73). Compound 67 (322 mg, 0.61 mmol) after treatment, workup, and
chromatography (5% to 20% EtOAc/hexane) gave 250 mg (93%) of 73 as a
1
white solid, mp 46ꢀ47 ꢀC. IR 3380, 2903, 1710, 1251 cmꢀ1. H NMR
δ 1.29 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.81 (bs, 6H, AdCH2), 2.12
(bs, 3H, AdCH), 2.18 (bs, 6H, AdCH2), 2.68 (t, J = 7.8 Hz, 2H,
CH2CH2CO), 2.98 (t, J = 7.8 Hz, 2H, CH2CH2CO), 4.18 (q, J = 7.2 Hz,
2H, OCH2CH3), 5.03 (s, 1H, OH), 6.73 (d, J = 8.1 Hz, 1H, 50-ArH),
7.15 (dd, J = 1.2 Hz, 8.1 Hz, 1H, 6-ArH), 7.18 (dd, J = 1.8 Hz, 7.8 Hz, 1H,
60-ArH), 7.28 (d, J = 7.8 Hz, 1H, 5-ArH), 8.32 (d, J = 1.8 Hz, 1H, 20-
ArH), 8.33 ppm (d, J = 1.2 Hz, 1H, 2-ArH). HRMS calcd C27H31ClO3
[M þ H]þ, 439.2034; found, 439.2032.
Ethyl (E)-3-{6-[30-(1-Adamantyl)-40-hydroxyphenyl]-3-pyridazinyl}-2-
propenoate (37). Compound 31 (53 mg, 0.11 mmol) after treatment,
workup, and chromatography (14ꢀ33% EtOAc/hexane) gave 36 mg
(84%) of 37 as a yellow solid, mp 246ꢀ248 ꢀC. IR 3360, 2907, 1714,
1568, 1227 cmꢀ1 1H NMR (acetone-d6) 1.36 (t, J = 7.5 Hz, 3H,
.
Ethyl 6-[30-(1-Adamantyl)-40-hydroxyphenyl]-1H-indole-2-carbox-
ylate (82). Compound 81 (70.0 mg, 0.138 mmol) after treatment,
workup, and chromatography (20% EtOAc/hexane) gave 48 mg (84%)
of 82 as a pale-yellow solid, mp 216ꢀ217 ꢀC. IR 3367, 2902, 1681, 1514,
1274, 1208 cmꢀ1. 1H NMR δ 1.46 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.84
(bs, 6H, AdCH2), 2.14 (bs, 3H, AdCH), 2.23 (bs, 6H, AdCH2), 4.45 (q,
J = 7.2 Hz, 2H, OCH2CH3), 4.97 (bs, 1H, OH), 6.78 (d, J = 8.1 Hz, 1H,
50-ArH), 7.26 (d, J = 0.9 Hz, 1H, 7-InH), 7.36 (dd, J = 8.1 Hz, 2.1 Hz, 1H,
60-ArH), 7.41 (dd, J = 0.9 Hz, 8.4 Hz, 1H, 5-InH), 7.54 (d, J = 2.1 Hz, 1H,
20-ArH), 7.57 (s, 1H, 3-InH), 7.73 (d, J = 8.4 Hz, 1H, 4-InH), 8.91
ppm (bs, 1H, NH). HRMS calcd C27H29NO3 [M þ H]þ, 416.2220;
found, 416.2219.
OCH2CH3), 1.86 (bs, 6H, AdCH2), 2.13 (bs, 3H, AdCH), 2.30 (bs, 6H,
AdCH2), 4.30 (q, J = 7.5 Hz, 2H, OCH2CH3), 7.03 (d, J = 8.4 Hz, 1H, 50-
ArH), 7.06 (d, J = 15.9 Hz, 1H, CHdCHCO), 7.91 (d, J = 15.9 Hz, 1H,
CHdCHCO), 7.96 (dd, J = 8.4 Hz, 2.1 Hz, 1H, 60-ArH), 8.06 (d, J = 9.0
Hz, 1H, 4-ArH), 8.17 (d, J = 9.0 Hz, 1H, 5-ArH), 8.20 (d, J = 2.1 Hz, 1H, 20-
ArH), 8.96 ppm (s, 1H, OH). HRMS calcd C25H28N2O3 [M þ H]þ,
405.2173; found, 405.2174.
2-[30-(1-Adamantyl)-40-hydroxyphenyl]-5-(carbethoxymethylamino)-
pyrimidine (68). Compound 62 (51 mg, 0.10 mmol) after treatment,
workup, and chromatography (20% EtOAc/hexane) gave 41.6 mg (99%)
of 68 as a pale-tan solid, mp 190 ꢀC (dec.). IR 3432, 2904, 1708, 1211 cmꢀ1
.
Ethyl (E)-3-{1-[30-(1-Adamantyl)-40-hydroxyphenyl]piperidin-4-yl}
-2-propenoate (95). Compound 91 (59 mg, 0.12 mmol) after treat-
ment, workup, and chromatography (14ꢀ20% EtOAc/hexane) gave 37
mg (77%) of 95 as an off-white solid, mp 67ꢀ69 ꢀC. IR 3362, 2907,
1701, 1172 cmꢀ1. 1H NMR δ 1.33 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.68
(m, 2H, N(CH2CH2)2CH), 1.80 (bs, 6H, AdCH2), 1.87 (m, 2H,
N(CH2CH2)2CH), 2.11 (bs, 3H, AdCH), 2.14 (bs, 6H, AdCH2),
2.23 (m, 1H, N(CH2CH2)2CH), 2.69 (m, 2H, N(CH2CH2)2CH),
3.53 (m, 2H, N(CH2CH2)2CH), 4.23 (q, J = 7.2 Hz, 2H, OCH2CH3),
4.54 (bs, 1H, OH), 5.87 (d, J = 15.6 Hz, 1H, CHdCHCO), 6.59 (d, J =
7.8 Hz, 1H, 60-ArH), 6.69 (d, J = 7.8 Hz, 1H, 50-ArH), 6.92 (s, 1H, 20-
ArH), 7.0 ppm (dd, J = 15.6 Hz, 6.9 Hz, 1H, CHdCHCO). HRMS calcd
C26H35NO3 [M þ H]þ, 410.2690; found, 410.2686.
1H NMR δ 1.32 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.79 (bs, 6H, AdCH2),
2.09 (bs, 3H, AdCH), 2.21 (m, 6H, AdCH2), 4.30 (q, J = 7.2 Hz, 2H,
OCH2CH3), 4.60 (m, 1H, NH), 4.72 (s, 2H, NHCH2CO), 5.85 (s, 1H,
OH), 6.71 (d, J = 8.4 Hz, 1H, 50-ArH), 8.03 (dd, J = 8.4 Hz, 2.1 Hz, 1H, 60-
ArH), 8.27 (d, J = 2.1 Hz, 1H, 20-ArH), 8.45 ppm (s, 2H, 4-ArH, 6-ArH).
HRMS calcd C24H29N3O3 [M þ H]þ, 408.2287; found, 408.2291.
Ethyl 2-[30-(1-Adamantyl)-2-chloro-40-hydroxy-1,10-biphenyl-4-ylami-
no]acetate (69). Compound 63 (256 mg, 0.48 mmol) after treatment,
workup, and chromatography (25% EtOAc/hexane) gave 138 mg (65%) of
69 as a pale-tan solid, mp 184 ꢀC (dec.). IR 3342, 2903, 1712, 1210 cmꢀ1. 1H
NMR δ1.33 (t, J= 7.2 Hz, 3H, OCH2CH3), 1.78(m, 6H, AdCH2), 2.09(m,
3H, AdCH), 2.16 (m, 6H, AdCH2), 3.92 (d, J = 5.4 Hz, 2H, NHCH2CO),
4.28 (q, J = 7.2 Hz, 3H, OCH2CH3), 4.39 (t, J = 5.4 Hz, 1H, NHCH2CO),
4.80 (s, 1H, OH), 6.56 (dd, J = 8.4 Hz, 2.4 Hz, 1H, 5-ArH), 6.67 (d, J = 8.4
Hz, 1H, 50-ArH),6.69(d,J= 2.4 Hz, 1H, 3-ArH), 7.12 (dd, J= 8.1 Hz, 2.1 Hz,
1H, 60-ArH), 7.16 (J = 8.1 Hz, 1H, 6-ArH), 7.26 (d, J = 2.1 Hz, 1H, 20-ArH).
HRMS calcd C26H30ClNO3 [M þ H]þ, 440.1987; found, 440.1985.
Ethyl 2-[30-(1-Adamantyl)-2-chloro-40-hydroxy-1,10-biphenyl-4-ylthio]-
acetate (71). Compound 65 (54 mg, 0.10 mmol) after treatment, workup,
and chromatography (4% EtOAc/hexane) gave 45 mg (94%) of 71 as a pale-
Ethyl 3-[4-(30-(1-Adamantyl)-40-hydroxyphenyl)piperazinyl]propionate
(96). Compound 92 (206 mg, 0.410 mmol) after treatment, workup, and
chromatography (33ꢀ66% EtOAc/hexane) gave 111 mg (66%) of 96 as an
off-white solid, mp 162ꢀ163 ꢀC. IR 3356, 2903, 1732, 1501, 1175 cmꢀ1. 1H
NMR δ1.29(t,J= 7.2 Hz, 3H, OCH2CH3),1.79(bs, 6H, AdCH2),2.10(bs,
3H, AdCH), 2.13 (bs, 6H, AdCH2), 2.57 (t, J =7.5 Hz, 2H, NCH2CH2CO),
2.66 (bs, 4H, ArN(CH2CH2)2N), 2.79 (t, J = 7.5 Hz, 2H, NCH2CH2CO),
3.10 (bs, 4H, ArN(CH2CH2)2N), 4.18 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.74
(s, 1H, OH), 6.58 (d, J = 8.7 Hz, 1H, 50-ArH), 6.66 (d, J = 8.7 Hz, 1H, 60-
ArH), 6.90 ppm (s, 1H, 20-ArH). HRMS calcd C25H36N2O3 [M þ H]þ,
413.2799; found, 413.2802.
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yellow solid, mp 95ꢀ97 ꢀC. IR 3433, 2901, 1712, 1472, 1284 cmꢀ1. H
NMR δ1.29 (t, J= 7.2 Hz, 3H, OCH2CH3), 1.80 (bs, 6H, AdCH2), 2.10 (bs,
3H, AdCH), 2.16 (bs, 6H, AdCH2), 3.69 (s, 2H, SCH2), 4.23 (q, J = 7.2 Hz,
2H, OCH2CH3), 5.04 (bs, 1H, OH), 6.71 (d, J = 8.4 Hz, 1H, 50-ArH), 7.15
(dd,J= 8.1 Hz, 2.1 Hz, 1H, 6-ArH), 7.26 (d, J= 8.1 Hz, 1H, 5-ArH), 7.29 (d, J
= 2.1 Hz, 1H, 2-ArH), 7.34 (dd, J= 8.4 Hz, 1.8 Hz, 1H, 60-ArH), 7.52ppm(d,
J = 1.8 Hz, 1H, 20-ArH). HRMS calcd C26H29ClO3S [M þ H]þ, 457.1599;
found, 457.1596.
Ethyl 3-{4-[30-(1-Adamantyl)-40-hydroxyphenyl]-3-oxopiperazin-1-
yl}-3-oxopropionate (97). Compound 94 (91 mg, 0.17 mmol) after
treatment, workup, and chromatography (MeOH/EtOAc/hexane, 0:2.5:1ꢀ
1:9:0) gave 76 mg (100%) of 97 as a white solid, mp 217ꢀ219 ꢀC. IR 3319,
1
2903, 1737, 1647, 1423 cmꢀ1. H NMR δ 1.34 (t, J = 7.5 Hz, 3H,
Ethyl 2-[30-(1-Adamantyl)-2-chloro-40-hydroxy-1,10-biphenyl-4-yl-
sulfonyl]acetate (72). Compound 66 (35 mg, 0.060 mmol) after
OCH2CH3), 1.79 (bs, 6H, AdCH2), 2.11 (bs, 9H, AdCH, AdCH2), 3.56
3808
dx.doi.org/10.1021/jm200051z |J. Med. Chem. 2011, 54, 3793–3816