Phenyl Alkyl Ketones as Inhibitors
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7683
3.88-3.91 (1H, m), 4.54 (1H, d, J ) 6.8 Hz), 4.96 (1H, s),
6.83-6.85 (2H, dd, J ) 2.8,5.2 Hz), 6.70 (1H, d, J ) 7.6 Hz)
ppm. 13C NMR (100 MHz, CDCl3): 26.36, 26.65, 33.06, 33.35,
33.53, 36.43, 37.64, 56.06, 67.22, 73.01, 74.67, 78.84, 112.00,
113.60, 119.37, 137.67, 146.85, 149.66 ppm. HRMS (ESI+): calcd
for C20H31O4 - H2O, 317.2117; found, 317.2112. Anal. Calcd for
C20H30O4: C, 71.82; H, 9.04. Found: C, 71.92; H, 9.10.
1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-
-phenylpropan-1-ol (4p). Yield: 99%. 1H NMR (400 MHz,
CDCl3): 1.96-2.00 (1H, m), 2.09 (1H, s), 2.11-2.18 (2H, m),
2.63-2.72 (2H, m), 3.83 (3H, s), 3.82 (3H, m), 3.85-3.90 (1H,
m), 3.94-4.03 (3H, m), 4.59 (1H, t, J ) 7.2 Hz), 4.93-4.95 (1H,
m), 6.83 (1H, s), 6.85 (1H,s), 6.91 (1H, d, J ) 8.4 Hz), 7.17 (3H,
t, J ) 4.4 Hz), 7.25-7.00 (2H, dd, J ) 7.2, 7.6 Hz) ppm. 13C
NMR (100 MHz, CDCl3): 32.14, 33.07, 40.49, 56.07, 67.22, 73.00,
73.49, 78.86, 112.08, 113.63, 119.41, 125.89, 128.42, 128.44,
137.35, 141.79, 146.92, 149.76 ppm. HRMS (ESI+): calcd for
C20H25O4 - H2O, 311.1647; found, 311.1639. Anal. Calcd for
C20H24O4, C, 73.15; H, 7.37; found, C, 73.25; H, 7.56.
4-[5-(1-Hydroxypentyl)-2-methoxyphenoxy]piperidine-1-car-
boxylic Acid tert-Butyl Ester (4v). Yield: 84%. H NMR (400
1
MHz, CDCl3): 0.95 (3H, t, J ) 7.2 Hz), 1.44 (2H, q, J ) 7.2, 7.6
Hz), 1.47 (9H, s), 1.69 (4H, m), 1.73 (2H, s), 1.92-1.96 (2H, m),
2.91 (2H, t, J ) 7.2 Hz), 3.23-3.00 (2H, m), 3.80 (2H, m), 4.63
(1H, s), 3.91 (3H, s), 4.50-4.51 (1H, m), 4.70-4.72 (1H, s), 6.92
(1H, d, J ) 8.4 Hz), 7.57 (1H, d, J ) 2 Hz), 7.60-7.63 (1H, dd,
J ) 2, 6.4 Hz) ppm. 13C NMR (100 MHz, CDCl3): 14.03, 22.59,
28.06, 28.45, 30.83, 38.79, 56.04, 74.28, 74.53, 79.52, 112.13,
115.49, 119.75, 137.72, 146.47, 150.37, 154.84 ppm. HRMS
(ESI+): calcd for C18H25NO4 - (H2O + tert-butyl): 320.1862;
found, 320.1882.
1-[4-Difluoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-
3-methylbutan-1-ol (4w). Yield: 15%. 1H NMR (CDCl3): 7.13 (1H,
d, J ) 8.4 Hz), 6.95 (1H, s), 6.90 (1H, d, J ) 8.4 Hz), 6.51 (1H,
t, J ) 75.2 Hz), 5.00 (1H, m), 4.72 (1H, m), 4.03-3.90 (4H, m),
2.20 (2H, m), 1.94 (1H, s, br), 1.70 (2H, m), 1.47 (1H, m), 0.96
(6H, d, J ) 6.0 Hz). 13C NMR (CDCl3): 149.0, 144.3, 140.1, 122.9,
118.9, 116.3 (triplet, J ) 258 Hz), 112.8, 78.8, 72.8, 72.2, 67.1,
48.5, 33.0, 24.8, 23.1, 22.2. MS-EI: 316 (M+).
2-Cyclohexyl-1-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phe-
1
1-[4-Difluoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-
nyl]ethanol (4q). Yield: 55%. H NMR (400 MHz, CDCl3): 0.94
1
pentan-1-ol (4za). Yield: %. H NMR (CDCl3): 7.13 (1H, d, J )
(2H, m), 1.20 (2H, m), 1.36 (1H, m), 1.48 (1H, m), 1.69 (7H, m),
2.18 (2H, m), 3.84 (3H, s), 3.90 (1H, m), 4.00 (2H, m), 4.71 (1H,
s), 4.96 (1H, s), 6.83 (1H, s), 6.85 (1H, s), 6.92-6.89 (1H, q, J )
2.0, 6.0 Hz) ppm. 13C NMR (100 MHz, CDCl3): 26.17, 26., 26.56,
33.03, 33.07, 33.91, 34., 46.97, 56.07, 67.23, 71.79, 73.01, 78.86,
112.06, 113.59, 113.63, 119.27, 138.03, 146.88, 149.68 ppm.
HRMS (ESI+): calcd for C19H28O4 - H2O, 303.1960; found,
303.1975.
1-[4-Difluoromethoxy-3-(tetrahydrofuran-3-ylxoy)phenyl]-
2,2-dimethylpropan-1-ol (4r). Yield: 8.6%. 1H NMR (400 MHz,
CDCl3): 0.92 (9H, d, J ) 0.8 Hz), 1.95 (1H, s), 2.16-2.20 (2H,
m), 3.90-3.92 (1H, m), 3.98-4.00 (3H, m), 4.36 (1H, s), 4.96
(1H, d, J ) 2.0 Hz), 6.52 (1H, (d) t, J ) 75.2 Hz), 6.85-6.87 (1H,
dd, J ) 2.0, 6.0 Hz), 6.89-6.91 (1H, dd, J ) 2.0, 2.4 Hz), 7.11
(1H, d, J ) 8.0 Hz) ppm. 13C NMR (100 MHz, CDCl3): 25.88,
0.71, 32.98, 33.02, 35.71, 67.16, 72.80, 72.83, 78.72, 81.73, 114.69
(t, J ) 160 Hz), 120.96, 121.93, 140.05, 140.88, 148.17 ppm. MS
(EI+): calcd for C16H22F2O4, 316; found, 316.
1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-methyl-
butan-1-ol (4s). Yield: 34%. 1H NMR (400 MHz, CDCl3):
0.91-0.94 (6H, q, J ) 4.4, 2.0 Hz), 1.24 (1H, s), 1.44-1.49 (1H,
m), 1.64-1.72 (2H, m), 1.92 (1H, bs, O-H), 2.16-2.19 (2H, m),
3.83 (3H, s), 3.86-3.91 (1H, m), 3.97-4.02 (3H, m), 4.64-4.67
(1H, q, J ) 5.6, 2.0 Hz), 4.94-4.97 (1H, m), 6.84 (1H, d, J ) 8.4
Hz), 6.86 (1H, J ) 2 Hz), 6.91-6.89 (1H, dd, J ) 2, 6.4 Hz) ppm.
13C NMR (100 MHz, CDCl3): 22.34, 23.09, 24.84, 33.04, 48.28,
56.06, 67.21, 72.41, 72.99, 78.85, 112.04, 113.62, 119.32, 137.96,
146.89, 149.68 ppm. HRMS (ESI+): calcd for C16H22O3 - H2O,
263.1647; found, 263.1648.
3-[2-Difluoromethoxy-5-(1-hydroxypentyl)phenoxy]pyrrolidine-1-
carboxylic Acid tert-Butyl Ester (4t). Yield: 25%. 1H NMR
(400 MHz, CDCl3): 0.89 (3H, t, J ) 6.8 Hz), 1.36 (4H, m), 1.46
(9H, s), 1.73 (2H, m), 1.95 (1H, d, J ) 2.8 Hz), 2.20 (2H, m), 3.67
(4H, m), 4.63 (1H, s), 4.93 (1H, s), 6.65 (1H, t, J ) 75.2 Hz), 6.91
(1H, s), 6.96 (1H, d, J ) 1.6 Hz), 7.12 (1H, d, J ) 6.8 Hz) ppm.
13C NMR (100 MHz, CDCl3): 14.0, 22.55, 27.9, 28.47, 0.72, 30.82,
31.67, 39.02, 44.07, 51.08, 51.57, 74.02, 78.11, 79.61, 113.4, 119.4,
122.89 ppm. HRMS (ESI+): calcd for C21H31F2NO5, 416.2248;
found, 416.2247.
8.0 Hz), 6.94 (1H, s), 6.90 (1H, dd, J ) 2.0 and 8.4 Hz), 6.52 (1H,
t, J ) 75.2 Hz), 5.00 (1H, m), 4.64 (1H, m), 4.03-3.91 (4H, m),
2.18 (2H, m), 1.98 (1H, s, br), 1.75 (1H, m), 1.67 (1H, m),
1.42-1.24 (4H, m), 0.90 (3H, t, J ) 7.2 Hz). 13C NMR (CDCl3):
149.0 (s), 143.8 (s), 140.1 (s), 122.9 (d), 119.0 (d), 116.3 (triplet,
J ) 258 Hz, d), 112.8 (d), 78.7 (d), 74.0 (d), 72.8 (t), 67.1 (t), 39.0
(t), 33.0 (t), 27.8 (t), 22.5 (t), 14.0 (q). MS-EI: 316 (M+).
3-Cyclohexyl-1-[4-difluoromethoxy-3-(tetrahydrofuran-3-
yloxy)phenyl]propan-1-ol (4zb). Yield: 51%. 1H NMR (CDCl3):
7.11 (1H, d, J ) 8.0 Hz), 6.94 (1H, s), 6.89 (1H, d, J ) 8.4 Hz),
6.50 (1H, t, J ) 74.8 Hz), 4.97 (1H, m), 4.59 (1H, m), 4.01-3.87
(4H, m), 2.18 (2H, m), 1.94 (1H, s, br), 1.80-1.67 (7H, m),
1.34-1.12 (6H, m), 0.88 (2H, m). 13C NMR (CDCl3): 149.1, 143.9,
140.4, 122.8, 119.2, 116.4 (triplet, J ) 258 Hz), 113.4, 79.1, 74.4,
72.8, 67.1, 37.7, 36.7, 33.4, 33.3, 33.1, 26.6, 26.3.
2-Cyclohexyl-1-[4-difluoromethoxy-3-(tetrahydrofuran-3-
yloxy)phenyl]ethanol (4zc). Yield: 35%. 1H NMR (CDCl3): 7.14
(1H, d, J ) 8.4 Hz), 6.95 (1H, d, J ) 2.0 Hz), 6.91 (1H, dd, J )
2.0 and 8.0 Hz), 6.53 (1H, t, J ) 75.2 Hz), 5.01 (1H, m), 4.77
(1H, m), 4.03-3.91 (4H, m), 2.20 (2H, m), 2.00 (1H, s, br),
1.83-1.66 (6H, m), 1.52-1.39 (2H, m), 1.31-1.15 (3H, m), 0.98
(2H, m). 13C NMR (CDCl3): 149.0 (s), 144.3 (s), 140.0 (s), 122.9
(d), 118.91 (d), 118.89 (d), 116.3 (triplet, J ) 258 Hz, d), 112.8
(d), 78.7 (d), 72.8 (t), 71.5 (d), 67.1 (t), 47.2 (t), 34.2 (d), 33.9 (t),
33.0 (t), 32.8 (t), 26.5 (t), 26.2 (t), 26.1 (t).
1-[4-Difluoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-
phenylpropan-1-ol (4zd). Yield: 46%. 1H NMR (CDCl3): 7.30-7.25
(2H, m), 7.20-7.11 (4H, m), 6.92-6.88 (2H, m), 6.50 (1H, t, J )
74.8 Hz), 4.96 (1H, m), 4.64 (1H, m), 3.99-3.89 (4H, m), 2.72
(2H, m), 2.18-1.97 (5H, m). 13C NMR (CDCl3): 149.0 (s), 143.5
(s), 141.4 (s), 140.1 (s), 128.42 (d), 128.36 (d), 126.0 (d), 122.9
(d), 119.0 (d), 116.2 (triplet, J ) 258 Hz, d), 112.81 (d), 112.78
(d), 78.7 (d), 73.2 (d), 72.7 (t), 67.1 (t), 40.6 (t), 32.9 (t), 31.9 (t).
1-[4-Difluoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-
4-phenylbutan-1-ol (4ze). Yield: 56%. 1H NMR (CDCl3): 7.28-7.25
(2H, m), 7.19-7.10 (4H, m), 6.89-6.85 (2H, m), 6.50 (1H, t, J )
75.2 Hz), 4.95 (1H, m), 4.64 (1H, m), 3.99-3.89 (4H, m), 2.63
(2H, t, J ) 6.8 Hz), 2.15 (2H, m), 2.01 (1H, s, br), 1.78-1.61 (4H,
m). 13C NMR (CDCl3): 149.0 (s), 143.6 (s), 142.0 (s), 140.1 (s),
128.37 (d), 128.31 (d), 125.8(d), 122.9 (d), 119.0 (d), 116.2 (triplet,
J ) 258 Hz, d), 112.7 (d), 78.7 (d), 73.8 (d), 72.8 (t), 67.1 (t), 38.6
(t), 35.6 (t), 33.0 (t), 27.4 (t).
3[2-Difluoromethoxy-5-(1-hydroxy-3-methylbutyl)phenoxy]-
pyrrolidine-1-carboxylic Acid tert-Butyl Ester (4u). Yield: 14%.
1H NMR (400 MHz, CDCl3): 0.96 (6H, d, J ) 6.4 Hz), 1.46 (9H,
s), 1.69 (2H, m), 1.90 (1H, d, J ) 2.8 Hz), 2.20 (2H, m), 3.57 (4H,
m), 4.71 (1H, s), 4.94 (1H, s), 6.65 (1H, d (t), J ) 75.2 Hz), 6.92
(1H, d, J ) 6.8 Hz), 6.97 (1H, d, J ) 1.2 Hz), 7.12 (1H, d, J ) 6.4
Hz) ppm. 13C NMR (100 MHz, CDCl3): 14.1 (d), 22.6, 24.7, 28.4,
31.5, 43.6 (d), 48.5, 51.5 (d), 60.3, 72.1, 79.60, 113.5 (d, J ) 14
Hz), 119.4, 122.9, 140.3 ppm. HRMS (ESI+): calcd for
C17H21F2NO4 - (H2O + tert-butyl), 342.1515; found, 342.1159.
1-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-3-methyl-
butan-1-ol (4zf). Yield: 34%. 1H NMR (CDCl3): 7.09 (1H, d, J )
8.4 Hz), 6.97 (1H, d, J ) 1.6 Hz), 6.83 (1H, dd, J ) 1.6 and 8.4
Hz), 6.51 (1H, t, J ) 75.6 Hz), 4.82 (1H, m), 4.70 (1H, m),
1.92-1.79 (7H, m), 1.72-1.62 (4H, m), 1.46 (1H, m), 0.95 (6H,
d, J ) 6.0 Hz). 13C NMR (CDCl3): 149.6 (s), 144.0 (s), 140.0
(triplet, J ) 3.0 Hz, s), 122.7 (d), 117.9 (d), 116.4 (triplet, J ) 257