SKP2 Inhibitors
673
(7H, m, Alk–H), 1.72–1.79 (1H, m, NH), 2.37–2.47 (1H, dd,
PhCH2–Alk, J 8.3 and 13.7), 2.52–2.63 (2H, m, Alk–CH2–NH),
2.64–2.72 (1H, dd, PhCH2–Alk, J 5.5 and 13.8), 2.94 (6H, s,
ArN(CH3)2), 3.57–3.63 (1H, m, CH2–O), 3.67–3.69 (2H, s, HN–
CH2–Ar), 3.71–3.78 (1H, m, CH2–O), 6.61–6.67 (3H, m, Ar–H),
7.11–7.13 (2H, m, Ar–H), 7.16–7.19 (2H, m, Ar–H), 7.24–7.27
(2H, m, Ar–H). dC (125 MHz, CDCl3) 21.8, 29.4, 29.7, 30.3,
31.9, 32.9, 33.1, 37.2, 37.3, 39.4, 39.8, 40.7, 42.8, 43.0, 47.3,
47.4, 54.3, 61.9, 71.8, 111.4, 112.4, 116.5, 125.8, 128.3, 129.1,
141.5, 150.8. m/z (LC-MS ESIþ) 395.5 [M þ H]þ. Analytical
HPLC: 95.4 %.
(82 mg, 64 %); Rf 0.17 (silica, 50 % EtOAc/DCM). lmax/nm
(EtOH) 279.0, 268.0. nmax/cmꢀ1 2926 (C–H), 2857 (C–H), 2228
(CꢄN), 1608, 1494, 1453, 1365, 1204, 1084, 1041, 857, 817,
738, 699. dH (500 MHz, CDCl3) 1.12 (3H, s, Alk-CH3), 1.21
(3H, s, Alk-CH3), 1.26–1.29 (1H, m, Alk–H), 1.35–1.59 (8H, m,
Alk–H), 1.73–1.80 (1H, m, NH), 2.39 (1H, dd, Alk–H, J 8.7 and
13.7), 2.46–2.57 (2H, m, CH2CH2NH), 2.70 (1H, dd, Alk–H,
J 5.5 and 13.7), 3.61 (1H, t, Alk–H, J 12.1), 3.73 (2H, s,
NHCH2Ar), 3.76–3.79 (1H, m, Alk–H), 7.11 (2H, d, Ar–H, J
7.2), 7.16–7.19 (1H, m, Ar–H), 7.24–7.27 (2H, m, Ar–H), 7.35–
7.38 (2H, m, Ar–H), 7.58 (2H, d, Ar–H, J 8.2). dC (125 MHz,
CDCl3) 21.8, 29.4, 29.7, 30.5, 31.9, 33.1, 33.4, 37.4, 39.5, 39.9,
42.8, 42.9, 47.7, 53.4, 61.8, 71.8, 110.7, 119.0, 125.9, 128.3,
128.6, 129.0, 132.2, 141.4, 146.1. m/z (LC-MS ESIþ) 377.4
[M þ H]þ. Analytical HPLC: 95.8 %.
3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-(4-
isopropylbenzyl)-4-phenylbutan-1-amine 1d[21]
General procedure H: using amine 18 (200 mg, 0.77 mmol)
and 4-isopropylbenzaldehyde (0.139 mL, 0.161 g, 0.918 mmol),
chromatography (silica, 20 % EtOAc/DCM followed by 5 %
NH3(aq)/MeOH/DCM) eluted 1d as a yellow oil (47 mg, 16 %);
Rf 0.37 (silica, 5 % NH3(aq)/MeOH/DCM). nmax/cmꢀ1 3026 (C–
H), 2960 (C–H), 2927 (C–H), 2865 (C–H), 2818 (C–H), 1602,
1495, 1454, 1364, 1203, 1086, 818, 737, 699. dH (500 MHz,
CDCl3) 1.12 (3H, s, Alk-CH3), 1.21–1.22 (3H, s, Alk-CH3), 1.25
(3H, s, ArCH(CH3)2), 1.26 (3H, s, ArCH(CH3)2), 1.25–1.28
(2H, m, Alk–H), 1.36–1.62 (7H, m, Alk–H), 1.72–1.79 (1H, m,
NH), 2.35–2.46 (1H, dd, Alk–H, J 8.5 and 13.7), 2.50–2.61 (2H,
m, CH2CH2NH), 2.67 (1H, dd, Alk–H, J 5.6 and 13.6), 2.89 (1H,
septet, J 6.9, ArCH(CH3)2)), 3.58–3.63 (1H, m, Alk–H), 3.66–
3.68 (2H, s, NHCH2Ar), 3.72–3.78 (1H, m, Alk–H), 7.11 (2H, d,
Ar–H, J 7.4), 7.16–7.18 (5H, m, Ar–H), 7.24–7.27 (2H, m, Ar–
H). dC (125 MHz, CDCl3) 21.8, 24.0, 29.4, 29.7, 30.3, 31.9, 32.9,
33.1, 33.8, 37.2, 39.5, 39.8, 42.8, 43.0, 47.4, 53.7, 61.9, 71.8,
125.8, 126.4, 128.1, 128.3, 129.1, 137.7, 141.5, 147.6. m/z (LC-
MS ESIþ) 394.2 [M þ H]þ; m/z (HRMS) 394.3091; calc. for
C27H40NO [M þ H]þ 394.3104. Analytical HPLC: 99.8 %.
3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-(4-
methoxybenzyl)-4-phenylbutan-1-amine 1g[21]
General procedure H: using amine 18 (100 mg, 0.38 mmol)
and 4-anisaldehyde (56 mL, 62.7 mg, 0.46 mmol), chromato-
graphy (silica, 10–20 % EtOAc/DCM followed by 10 % MeOH/
Et2O) afforded 1g as a colourless oil (69 mg, 53 %); Rf 0.39
(silica, 10 % MeOH/Et2O). lmax/nm (EtOH) 275.0. nmax/cmꢀ1
2930 (C–H), 2856 (C–H), 1584, 1511, 1453, 1379, 1243, 1179,
1084, 1037, 822, 737, 699. dH (500 MHz, CDCl3) 1.12 (3H, s,
Alk-CH3), 1.21 (3H, s, Alk-CH3), 1.23–1.29 (1H, m, Alk–H),
1.33–1.60 (8H, m, Alk–H), 1.73–1.76 (1H, m, NH), 2.40 (1H,
dd, Alk–H, J 8.5 and 13.7), 2.48–2.59 (2H, m, CH2CH2NH),
2.66 (1H, dd, Alk–H, J 5.7 and 13.6), 3.58–3.65 (3H, m, Alk–H
and NHCH2Ar), 3.72–3.79 (4H, m, Alk–H and OCH3), 6.85
(2H, d, Ar–H, J 8.6), 7.11 (2H, d, Ar–H, J 7.3), 7.16–7.19 (3H,
m, Ar–H), 7.25–7.28 (2H, m, Ar–H). dC (125 MHz, CDCl3)
21.8, 29.4, 29.7, 30.3, 30.4, 31.9, 32.9, 33.1, 37.2, 37.3, 39.5,
39.8, 42.9, 43.0, 47.4, 53.3, 55.3, 61.9, 71.8, 113.8, 125.8, 128.3,
129.1, 129.2, 132.5, 141.5, 158.6. m/z (LC-MS ESIþ) 382.5
[M þ H]þ. Analytical HPLC: 98.8 %.
N-(4-Chlorobenzyl-3-(2,2-dimethyltetrahydro-2H-pyran-
4-yl)-4-phenylbutan-1-amine 1e[21]
5-(((3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-4-
phenylbutyl)amino)methyl)-N,N-dimethylpyridin-
2-amine 1h
General procedure H: using amine 18 (212 mg, 0.81 mmol) and
4-chlorobenzaldehyde (137 mg, 0.97 mmol), chromatography
(silica, 20 % EtOAc/DCM followed by 5 % NH3(aq)/MeOH/
DCM) afforded 1e as a yellow oil (80 mg, 26 %); Rf 0.34 (silica,
5 % NH3(aq)/MeOH/DCM). nmax/cmꢀ1 2970 (C–H), 2929 (C–
H), 2857 (C–H), 1601, 1491, 1453, 1365, 1285, 1202, 1086,
1015, 962, 801, 738, 699. dH (500 MHz, CDCl3) 1.13 (3H, s Alk-
CH3), 1.22 (3H, s Alk-CH3), 1.23–1.29 (2H, m, Alk–H), 1.34–
1.61 (6H, m, Alk–H), 1.73–1.80 (1H, m, NH), 2.40 (1H, dd,
Alk–H, J 8.6 and 13.7), 2.46–2.60 (2H, m, CH2CH2NH), 2.68
(1H, dd, Alk–H, J 5.9 and 13.7), 3.58–3.64 (1H, m, Alk–H), 3.66
(2H, s, NHCH2Ar), 3.71–3.79 (1H, m, Alk–H), 7.11 (2H, d, Ar–
H, J 8.2), 7.17–7.20 (3H, m, Ar–H), 7.25–7.28 (4H, m, Ar–H).
dC (125 MHz, CDCl3) 21.8, 29.4, 29.7, 30.4, 31.9, 33.0, 33.3,
37.3, 39.5, 39.8, 42.8, 43.0, 47.5, 53.2, 53.4, 61.9, 71.8, 125.8,
128.3, 128.5, 129.0, 129.4, 132.6, 138.9, 141.5. m/z (LC-MS
ESIþ) 386.2 [M þ H]þ; m/z (HRMS) 386.2236; calc. for
C24H33ClNO [M þ H]þ 386.2245. Analytical HPLC: 97.4 %.
General procedure H: using amine 18 (100 mg, 0.38 mmol) and
6-(N,N-dimethylamino)nicotinaldehyde (69 mg, 0.46 mmol),
chromatography (silica, 5 % MeOH/Et2O followed by 20 %
MeOH/EtOAc) afforded 1h as a dark-yellow oil (63 mg, 47 %);
Rf 0.33 (silica, 10 % MeOH/DCM). lmax/nm (EtOH) 253.5.
n
max/cmꢀ1 2926 (C–H), 2856 (C–H), 1608, 1559, 1511, 1453,
1398, 1364, 1318, 1208, 1178, 1085, 1015, 958, 858, 806, 738,
700. dH (500 MHz, CDCl3) 1.11–1.12 (3H, s, Alk-CH3), 1.20–
1.22 (3H, s, Alk-CH3), 1.25–1.27 (1H, m, Alk–H), 1.34–1.59
(7H, m, Alk–H), 1.71–1.77 (1H, m, NH), 2.34–2.44 (1H, dd,
PhCH2–Alk, J 8.4 and 13.7), 2.46–2.58 (2H, m, AlkCH2–NH),
2.62–2.72 (1H, dd, PhCH2–Alk, J 5.3 and 13.7), 3.07 (6H, s, Ar–
N(CH3)2), 3.56–3.62 (3H, m, HN–CH2Ar and CH2–O), 3.71–
3.77 (1H, m, CH2–O), 6.47–6.49 (1H, m, Ar–H), 7.10–7.12 (2H,
m, Ar–H), 7.15–7.18 (1H, m, Ar–H), 7.24–7.27 (2H, m, Ar–H),
7.41–7.44 (1H, m, Ar–H), 8.01–8.03 (1H, m, Ar–H).
dC (125 MHz, CDCl3) 21.8, 29.4, 29.6, 29.9, 31.9, 33.0, 33.2,
37.2, 37.3, 38.2, 39.4, 39.8, 42.8, 43.0, 46.7, 50.3, 61.8, 71.8,
105.7, 125.8, 128.3, 129.0, 129.1, 137.8, 141.3, 147.8, 158.9.
m/z (LC-MS ESIþ) 396.5 [M þ H]þ; m/z (HRMS) 396.3011;
calc. for C26H39N2O [M þ H]þ 396.3009. Analytical HPLC:
97.6 %.
4-(((3-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-4-
phenylbutyl)amino)methyl)benzonitrile 1f
General procedure H: using amine 18 (100 mg, 0.38 mmol)
and 4-formylbenzonitrile (61 mg, 0.46 mmol), chromatography
(silica, 10–50 % EtOAc/DCM) afforded 1f as a yellow oil