Z.-Z. Zhou et al. / European Journal of Medicinal Chemistry 124 (2016) 372e379
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4.1.1.2. N-methyl-N-(pyridin-2-yl)-3-cyclopentyloxy-4-
CDCl3)
d
8.45 (dd, J ¼ 4.8, 1.2 Hz, 1H), 7.52e7.47 (m, 1H), 7.10e7.06
methoxybenzamide (7c). Yield: 57%. 1H NMR (400 MHz, CDCl3)
(m, 1H), 7.00e6.96 (m, 2H), 6.87e6.78 (m, 2H), 6.59 (t, J ¼ 75.0 Hz,
1H), 3.71 (d, J ¼ 6.8 Hz, 2H), 3.57 (s, 3H), 1.18e1.14 (m, 1H),
0.63e0.58 (m, 2H), 0.31e0.27 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
8.48 (dd, J ¼ 4.8, 1.2 Hz, 1H), 7.51e7.46 (m, 1H), 7.08e7.05 (m, 1H),
7.01 (dd, J ¼ 8.4, 2.0 Hz, 1H), 6.86 (d, J ¼ 2.0 Hz, 1H), 6.81 (d,
J ¼ 8.0 Hz, 1H), 6.71 (d, J ¼ 8.4 Hz, 1H), 4.56e4.51 (m, 1H), 3.81 (s,
3H), 3.61 (s, 3H), 1.85e1.66 (m, 6H), 1.59e1.53 (m, 2H). 13C NMR
d
169.8, 156.8, 149.9, 148.7, 141.7 (t, J ¼ 3.1 Hz), 137.8, 134.1, 121.7,
121.6, 121.2, 118.5 (-CHF2), 115.9 (-CHF2) 114.9, 113.3 (-CHF2), 73.9,
36.2, 9.9, 3.2. ESI-MS (m/z): 371.5 ([MþNa]þ), 349.5 ([MþH]þ). and
Anal. Calcd. for C18H18F2N2O3: C, 62.06; H, 5.21; N, 8.04; Found: C,
61.87; H, 5.33; N, 8.23.
(100 MHz, CDCl3)
d 170.8, 157.4, 151.8, 148.6, 146.8, 137.4, 127.9,
122.3, 121.8, 120.6, 115.3, 110.8, 80.3, 55.9, 36.1, 32.7. ESI-MS (m/z):
349.9. ([MþNa]þ), 327.9 ([MþH]þ). and Anal. Calcd. for
C
19H22N2O3:C, 69.92; H, 6.79; N, 8.58; Found: C, 70.11; H, 6.90; N,
8.35.
4 . 1. 1. 8 . N - ( 2 - c h l o r o p h e n y l ) - 3 - c y c l o p e n t y l o x y - 4 -
difluoromethoxybenzamide (7i). Yield: 45%. 1H NMR (400 MHz,
4.1.1.3. N-methyl-N-(pyridin-2-yl)-3-cyclopropylmethoxy-4-
CDCl3)
d
8.53 (dd, J ¼ 8.3, 1.6 Hz, 1H), 8.40 (s, 1H), 7.60 (d, J ¼ 2.0 Hz,
methoxybenzamide (7d). Yield: 44%. 1H NMR (400 MHz, CDCl3)
1H), 7.12e7.01 (m, 1H), 7.40e7.32 (m, 2H), 7.27e7.24 (m, 2H),
7.11e7.07 (m, 1H), 6.63 (t, J ¼ 75.0 Hz, 1H), 4.95e4.90 (m, 1H),
2.04e1.77 (m, 6H), 1.71e1.62 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
8.47 (d, J ¼ 4.8 Hz, 1H), 7.47 (t, J ¼ 7.8 Hz, 1H), 7.10e7.04 (m, 1H),
6.94 (d, J ¼ 8.4 Hz, 1H), 6.90 (s, 1H), 6.80 (d, J ¼ 8.0 Hz, 1H), 6.69 (d,
J ¼ 8.0 Hz, 1H), 3.84 (s, 3H), 3.66 (d, J ¼ 7.2 Hz, 2H), 3.60 (s, 3H),
1.23e1.15 (m, 1H), 0.62e0.58 (m, 2H), 0.31e0.27 (m, 2H). 13C NMR
d
164.4, 150.1, 143.8, 134.6, 132.9, 129.1, 127.9, 124.9, 123.0, 122.7,
121.4, 118.6, 118.5 (-CHF2), 115.9 (-CHF2), 114.6, 113.3 (-CHF2), 81.0,
32.8, 23.9. Negative ESI-MS (m/z): 380.4 ([M-H]-). and Anal. Calcd.
for C19H18ClF2NO3: C, 59.77; H, 4.75; N, 3.67; Found: C, 59.51; H,
4.90; N, 3.49.
(100 MHz, CDCl3)
d 170.6, 157.1, 151.4, 148.0, 147.8, 138.0, 127.7,
122.6, 121.9, 120.6, 113.8, 110.5, 73.9, 55.9, 36.3, 10.1, 3.4. ESI-MS (m/
z): 335.6. ([MþNa]þ), 313.6 ([MþH]þ). and Anal. Calcd. for
C
18H20N2O3: C, 69.21; H, 6.45; N, 8.97; Found: C, 69.49; H, 6.59; N,
9.25.
4.1.1. 9. N-(2-chlorophenyl)-3-cyclopropylmethoxy-4-
difluoromethoxybenzamide (7j). Yield: 46%. 1H NMR (400 MHz,
4 . 1 . 1 . 4 . N - ( p y r i d i n - 3 - y l ) - 3 - c y c l o p e n t y l o x y - 4 -
CDCl3)
d
8.52 (dd, J ¼ 8.2, 1.4 Hz, 1H), 8.39 (s, 1H), 7.59 (d, J ¼ 2.0 Hz,
difluoromethoxybenzamide (7e). Yield: 51%. 1H NMR (400 MHz,
1H), 7.45e7.31 (m, 3H), 7.30e7.26 (m, 2H), 7.13e7.06 (m, 1H), 6.73
(t, J ¼ 75.0 Hz, 1H), 3.98 (d, J ¼ 6.9 Hz, 2H), 1.38e1.29 (m, 1H),
0.73e0.62 (m, 2H), 0.43e0.33 (m, 2H). 13C NMR (100 MHz, CDCl3)
CDCl3)
d
9.40 (s, 1H), 9.25 (d, J ¼ 2.0 Hz, 1H), 8.84 (d, J ¼ 8.4 Hz, 1H),
8.34 (dd, J ¼ 5.2, 0.8 Hz, 1H), 7.70 (d, J ¼ 2.0 Hz, 1H), 7.61 (dd, J ¼ 8.4
2.0 Hz, 1H), 7.57e7.52 (m, 1H), 7.23 (d, J ¼ 8.4 Hz, 1H), 6.63 (t,
J ¼ 74.8 Hz, 1H, -CHF2), 5.01e4.97 (m, 1H), 1.99e1.76 (m, 6H),
d
164.3, 150.9, 143.3, 134.6, 133.0, 129.1, 127.9, 124.9, 123.1, 122.3,
121.5, 118.9, 118.4 (-CHF2), 115.8 (-CHF2), 113.9, 113.2 (-CHF2), 74.2,
1.70e1.61 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
165.6, 149.9, 144.0,
10.0, 3.3. ESI-MS (m/z): 390.6 ([MþNa]þ). and Anal. Calcd. for
143.1, 140.0 (t, J ¼ 3.1 Hz), 136.1, 132.0, 129.4, 124.4, 122.4, 119.2,
118.5 (-CHF2),115.9 (-CHF2),114.9,113.3 (-CHF2), 81.1, 32.7, 23.9. ESI-
MS (m/z): 371.4 ([MþNa]þ), 349.5 ([MþH]þ). and Anal. Calcd. for
C18H16ClF2NO3: C, 58.78; H, 4.39; N, 3.81; Found: C, 58.59; H, 4.17;
N, 3.62.
C
18H18F2N2O3: C, 62.06; H, 5.21; N, 8.04; Found: C, 62.31; H, 5.31; N,
4.1.1.10. N-phenyl-3-cyclopentyloxy-4-difluoromethoxybenzamide
8.39.
(7k). Yield: 86%. 1H NMR (400 MHz, CDCl3)
d 7.79 (s, 1H), 7.67e7.59
(m, 2H), 7.56 (d, J ¼ 2.0 Hz, 1H), 7.41e7.34 (m, 2H), 7.30 (dd, J ¼ 8.2,
2.0 Hz, 1H), 7.23e7.13 (m, 2H), 6.61 (t, J ¼ 75.1 Hz, 1H), 4.93e4.86
(m, 1H), 2.00e1.77 (m, 6H), 1.70e1.62 (m, 2H). 13C NMR (100 MHz,
4 .1.1. 5 . N - ( p y r i d i n - 3 - y l ) - 3 - c y c l o p r o p y l m e t h o x y - 4 -
difluoromethoxybenzamide (7f). Yield: 60%. 1H NMR (400 MHz,
CDCl3)
d
8.86 (d, J ¼ 2.4 Hz, 1H), 8.53 (s, 1H), 8.44 (d, J ¼ 8.4 Hz, 1H),
CDCl3) d 164.9, 150.0, 143.5, 137.8, 133.3, 129.1, 124.8, 122.4, 120.3,
8.37 (d, J ¼ 4.8 Hz, 1H), 7.60 (d, J ¼ 1.6 Hz, 1H), 7.46 (dd, J ¼ 8.2,
1.8 Hz, 1H), 7.40 (dd, J ¼ 8.4, 4.8 Hz, 1H), 7.24 (d, J ¼ 8.4 Hz, 1H), 6.73
(t, J ¼ 74.8 Hz, 1H), 3.96 (d, J ¼ 6.8 Hz, 2H), 1.34e1.28 (m, 1H),
0.68e0.64 (m, 2H), 0.38e0.34 (m, 2H). 13C NMR (100 MHz, CDCl3)
118.5 (-CHF2), 118.3, 115.9 (-CHF2), 114.7, 113.3 (-CHF2), 81.0, 32.7,
23.9. Negative ESI-MS (m/z): 346.5 ([M-H]-). and Anal. Calcd. for
C19H19F2NO3: C, 65.70; H, 5.51; N, 4.03; Found: C, 65.39; H, 5.27; N,
3.96.
d
165.5, 150.7, 143.9, 140.6, 135.7, 132.1, 128.9, 124.3, 122.0, 119.6,
118.4 (-CHF2), 115.8 (-CHF2), 114.0, 114.0, 113.2 (-CHF2), 74.2, 10.0,
3.26. ESI-MS (m/z): 357.5 ([MþNa]þ), 335.5 ([MþH]þ) and Anal.
Calcd. for C17H16F2N2O3: C, 61.07; H, 4.82; N, 8.38; Found: C, 61.30;
H, 4.97; N, 8.59.
4 . 1 . 1 . 1 1 . N - p h e n y l - 3 - c y c l o p r o p y l m e t h o x y - 4 -
difluoromethoxybenzamide (7l). Yield: 82%. 1H NMR (400 MHz,
CDCl3)
d
7.80 (s, 1H), 7.67e7.59 (m, 2H), 7.54 (d, J ¼ 1.6 Hz, 1H),
7.42e7.30 (m, 3H), 7.25e7.13 (m, 2H), 6.71 (t, J ¼ 75.1 Hz, 1H), 3.94
(d, J ¼ 6.9 Hz, 2H), 1.37e1.29 (m, 1H), 0.70e0.60 (m, 2H), 0.41e0.30
4.1.1.6. N-methyl-N-(pyridin-2-yl)-3-cyclopentyloxy-4-
(m, 2H). 13C NMR (100 MHz, CDCl3)
d 164.8,150.8,143.0,137.7,133.3,
difluoromethoxybenzamide (7g). Yield: 73%. 1H NMR (400 MHz,
129.1, 124.8, 122.2, 120.3, 118.8, 118.4 (-CHF2), 115.8 (-CHF2), 113.9,
113.2 (-CHF2), 74.1, 10.0, 3.3. Negative ESI-MS (m/z): 332.5 ([M-H]-).
and Anal. Calcd. for C18H17F2NO3: C, 64.86; H, 5.14; N, 4.20; Found:
C, 64.58; H, 5.03; N, 4.37.
CDCl3)
d
8.48 (dd, J ¼ 5.0, 1.4 Hz, 1H), 7.57e7.11 (m, 1H), 7.14e7.11
(m, 1H), 7.00 (d, J ¼ 8.4 Hz, 1H), 6.97 (d, J ¼ 1.6 Hz, 1H), 6.92 (dd,
J ¼ 8.0, 2.0 Hz, 1H), 6.87 (d, J ¼ 8.4 Hz, 1H), 6.50 (t, J ¼ 75.2 Hz, 1H,
-CHF2), 4.65e4.58 (m, 1H), 3.61 (s, 3H),1.84e1.66 (m, 6H),1.64e1.55
(m, 2H). 13C NMR (100 MHz, CDCl3)
d
169.9, 156.7, 149.0, 148.7, 142.2
4.2. Pharmacology
(t, J ¼ 3.1 Hz), 137.9, 134.0, 122.1, 121.6, 121.4, 121.2, 118.6 (-CHF2),
116.0 (-CHF2), 115.6, 113.4 (-CHF2), 80.7, 36.2, 32.6, 23.8. ESI-MS (m/
z): 385.5 ([MþNa]þ), 363.5 ([MþH]þ). and Anal. Calcd. for
4.2.1. Materials
Compounds 7a-l were dissolved in DMSO and stored as stock
solutions (100 mM) at ꢀ20 ꢂC. For experimental use, all the com-
pounds were prepared from stock solutions, diluted with growth
medium and used immediately. FAM-Cyclic-30,5’ eAMP and IMAP
binding reagent IMAP binding reagent were purchased from Mo-
lecular Devices Inc. PDE4CAT and Other PDEs were purchased from
C
19H20F2N2O3:C, 62.98; H, 5.56; N, 7.73; Found: C, 62.69; H, 5.31; N,
7.61.
4.1.1.7. N-methyl-N-(pyridin-2-yl)-3-cyclopropylmethoxy-4-
difluoromethoxybenzamide (7h). Yield: 83%. 1H NMR (400 MHz,