T.-j. Zhang et al. / European Journal of Medicinal Chemistry 183 (2019) 111717
7
123.40, 121.96, 118.20, 116.04, 81.43, 32.53, 23.76. ESI-HRMS calcd.
C
21H17N6O2 [M ꢁ H]- 385.1413, found: 385.1416.
for C18H17N6O2 [M ꢁ H]- 349.1413, found: 349.1416.
4.1.6.14. N-(4-((4-methylbenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)
4.1.6.8. N-(4-((2-ethylpropanyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)iso-
isonicotinamide (2n). A yellow powder, yield 80.5%. 1H NMR
nicotinamide (2h). An off-white powder, yield 78.3%. 1H NMR
(600 MHz, DMSO‑d6)
d
10.69 (s, 1H), 9.81 (s, 1H), 8.81 (d, J ¼ 5.6 Hz,
(500 MHz, DMSO‑d6)
d
10.76 (s, 1H), 9.74 (d, J ¼ 9.8 Hz, 1H), 8.80 (d,
2H), 8.21 (d, J ¼ 2.4 Hz, 1H), 7.93 (dd, J ¼ 9.1, 2.5 Hz, 1H), 7.88 (d,
J ¼ 5.9 Hz, 2H), 7.50 (d, J ¼ 9.1 Hz,1H), 7.27 (d, J ¼ 7.9 Hz, 2H), 7.18 (d,
J ¼ 7.8 Hz, 2H), 5.20 (s, 2H), 2.29 (s, 3H). 13C NMR (150 MHz,
J ¼ 4.8 Hz, 2H), 8.21 (s,1H), 7.94 (d, J ¼ 9.1 Hz,1H), 7.90 (d, J ¼ 4.8 Hz,
2H), 7.43 (d, J ¼ 9.1 Hz, 1H), 4.43e4.35 (m, 1H), 1.61e1.50 (m, 4H),
0.78 (t, J ¼ 7.4 Hz, 6H).13C NMR (125 MHz, DMSO‑d6)
d
163.71,
DMSO‑d6) d 164.29, 150.73, 147.43, 145.02, 141.86, 137.86, 133.34,
150.16, 146.92, 144.52, 141.32, 131.79, 123.35, 122.78, 121.37, 117.84,
115.49, 81.04, 24.90, 8.79. ESI-HRMS calcd. for C18H19N6O2 [M ꢁ H]-
351.1569, found: 351.1573.
132.70, 129.45, 128.15, 123.64, 122.81, 121.88, 118.13, 115.31, 70.95,
21.14. ESI-HRMS calcd. for C21H17N6O2 [M ꢁ H]- 385.1413, found:
385.1416.
4.1.6.9. N-(4-(hexyloxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide
4.1.6.15. N-(4-((2-methoxybenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)
(2i). A light yellow powder, yield 80.2%. 1H NMR (600 MHz,
isonicotinamide (2o). A yellow powder, yield 79.3%. 1H NMR
DMSO‑d6)
d
10.68 (s, 1H), 9.80 (s, 1H), 8.81 (d, J ¼ 5.8 Hz, 2H), 8.20
(600 MHz, DMSO‑d6)
d
10.72 (s, 1H), 9.73 (s, 1H), 8.82 (d, J ¼ 4.1 Hz,
(d, J ¼ 2.4 Hz, 1H), 7.94 (dd, J ¼ 9.0, 2.4 Hz, 1H), 7.89 (d, J ¼ 5.9 Hz,
2H), 7.41 (d, J ¼ 9.1 Hz,1H), 4.11 (t, J ¼ 6.4 Hz, 2H),1.70e1.63 (m, 2H),
1.29e1.20 (m, 6H), 0.84 (t, J ¼ 6.8 Hz, 3H). 13C NMR (150 MHz,
2H), 8.24 (d, J ¼ 2.5 Hz, 1H), 7.96 (dd, J ¼ 9.1, 2.5 Hz, 1H), 7.90 (d,
J ¼ 5.8 Hz, 2H), 7.53 (d, J ¼ 9.1 Hz, 1H), 7.37e7.32 (m, 1H), 7.30 (d,
J ¼ 7.4 Hz, 1H), 7.05 (d, J ¼ 8.2 Hz, 1H), 6.94 (t, J ¼ 7.4 Hz, 1H), 5.23 (s,
DMSO‑d6)
d
164.25, 150.72, 147.78, 145.01, 141.87, 132.42, 123.72,
2H), 3.80 (s, 3H). 13C NMR (150 MHz, DMSO‑d6)
d 164.28, 157.36,
122.55, 121.88, 118.02, 114.70, 69.48, 31.16, 28.57, 25.29, 22.34, 14.18.
150.68, 147.34, 144.86, 141.89, 132.85, 130.24, 129.63, 123.91, 123.60,
123.02, 121.93, 120.68, 117.87, 115.66, 111.36, 67.04, 55.76. ESI-HRMS
calcd. for C21H17N6O3 [M ꢁ H]- 401.1362, found: 401.1365.
ESI-HRMS calcd. for
365.1728.
C
19H21N6O2 [M ꢁ H]- 365.1726, found:
4.1.6.10. N-(4-(octyloxy)-3-(1H-tetrazol-1-yl)phenyl)isonicotinamide
4.1.6.16. N-(4-((3-methoxy-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)
(2j). A white powder, yield 77.3%. 1H NMR (600 MHz, DMSO‑d6)
phenyl)isonicotinamide (2p). An off-white powder, yield 67.3%. 1H
d
10.68 (s, 1H), 9.79 (s, 1H), 8.81 (dd, J ¼ 4.5, 1.5 Hz, 2H), 8.21 (d,
NMR (500 MHz, DMSO‑d6) d 10.73 (s, 1H), 9.87 (s, 1H), 8.80 (s, 2H),
J ¼ 2.5 Hz, 1H), 7.94 (dd, J ¼ 9.1, 2.5 Hz, 1H), 7.89 (dd, J ¼ 4.5, 1.5 Hz,
2H), 7.41 (d, J ¼ 9.1 Hz,1H), 4.10 (t, J ¼ 6.4 Hz, 2H),1.70e1.64 (m, 2H),
1.28e1.19 (m, 10H), 0.86 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz,
8.22 (s, 1H), 7.94 (d, J ¼ 8.9 Hz, 1H), 7.88 (s, 2H), 7.48 (d, J ¼ 8.8 Hz,
1H), 7.28 (t, J ¼ 7.3 Hz, 1H), 6.93 (s, 2H), 6.88 (d, J ¼ 8.0 Hz, 1H), 5.22
(s, 2H), 3.74 (s, 3H). 13C NMR (125 MHz, DMSO‑d6)
d 163.77, 159.21,
DMSO‑d6)
d
164.23, 150.72, 147.73, 144.97, 141.86, 132.43, 123.67,
150.16, 146.90, 144.56, 141.41, 137.47, 132.42, 129.44, 123.23, 122.32,
121.34, 119.33, 117.76, 114.74, 113.54, 112.61, 70.29, 54.85. ESI-HRMS
calcd. for C21H17N6O3 [M ꢁ H]- 401.1362, found: 401.1365.
122.55, 121.87, 117.96, 114.68, 69.48, 31.52, 28.94, 28.61, 25.64,
22.44, 14.31. ESI-HRMS calcd. for C21H25N6O2 [M ꢁ H]- 393.2039,
found: 393.2041.
4.1.6.17. N-(4-((4-methoxy-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)
4.1.6.11. N-(4-(benzyloxy)-3-(1H-tetrazol-1-yl)phenyl)iso-
phenyl)isonicotinamide (2q). An off-white powder, yield 65.9%. 1H
NMR (600 MHz, DMSO‑d6) d 10.67 (s, 1H), 9.77 (s, 1H), 8.81 (d,
nicotinamide (2k). A yellow powder, yield 88.6%. 1H NMR
(600 MHz, DMSO‑d6)
d
10.72 (s, 1H), 9.85 (s, 1H), 8.81 (d, J ¼ 4.9 Hz,
J ¼ 4.8 Hz, 2H), 8.21 (d, J ¼ 2.4 Hz, 1H), 7.94 (dd, J ¼ 9.0, 2.4 Hz, 1H),
7.88 (d, J ¼ 5.8 Hz, 2H), 7.51 (d, J ¼ 9.1 Hz,1H), 7.33 (d, J ¼ 8.5 Hz, 2H),
6.93 (d, J ¼ 8.6 Hz, 2H), 5.17 (s, 2H), 3.75 (s, 3H). 13C NMR (150 MHz,
2H), 8.23 (d, J ¼ 2.5 Hz, 1H), 7.95 (dd, J ¼ 9.1, 2.5 Hz, 1H), 7.89 (d,
J ¼ 5.9 Hz, 2H), 7.51 (d, J ¼ 9.1 Hz, 1H), 7.39 (s, 2H), 7.38 (d, J ¼ 1.5 Hz,
2H), 7.36e7.31 (m, 1H), 5.27 (s, 2H). 13C NMR (150 MHz, DMSO‑d6)
DMSO‑d6)
d 164.39, 159.69, 150.82, 147.55, 145.04, 141.97, 132.80,
d
164.41, 150.82, 147.58, 145.13, 141.96, 136.53, 132.88, 128.98,
129.97, 128.32, 123.73, 122.99, 121.96, 118.19, 115.55, 114.39, 71.01,
55.57. ESI-HRMS calcd. for C21H17N6O3 [M ꢁ H]- 401.1362, found:
401.1365.
128.59, 128.02, 123.81, 122.97, 121.96, 118.35, 115.44, 71.14. ESI-
HRMS calcd. for C20H15N6O2 [M ꢁ H]- 372.1256, found: 371.1259.
4.1.6.12. N-(4-((2-methylbenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)
4.1.6.18. N-(4-((2-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)iso-
isonicotinamide(2l). A yellow powder, yield 78.3%. 1H NMR
nicotinamide (2r). An off-white powder, yield 72.3%. 1H NMR
(600 MHz, DMSO‑d6)
d
10.74 (s, 1H), 9.77 (s, 1H), 8.81 (d, J ¼ 5.7 Hz,
(500 MHz, DMSO‑d6)
d
10.77 (s, 1H), 9.75 (s, 1H), 8.80 (d, J ¼ 3.5 Hz,
2H), 8.20 (d, J ¼ 2.5 Hz, 1H), 7.97 (dd, J ¼ 9.1, 2.5 Hz, 1H), 7.90 (d,
J ¼ 5.9 Hz, 2H), 7.58 (d, J ¼ 9.1 Hz, 1H), 7.30 (d, J ¼ 7.4 Hz, 1H), 7.24 (t,
J ¼ 7.0 Hz, 1H), 7.18 (m, 2H), 5.25 (s, 2H), 2.20 (s, 3H). 13C NMR
2H), 8.23 (s, 1H), 7.97 (d, J ¼ 9.0 Hz, 1H), 7.88 (s, 3H), 7.74 (t,
J ¼ 7.3 Hz, 1H), 7.64 (d, J ¼ 7.6 Hz, 1H), 7.59e7.54 (m, 2H), 5.43 (s,
2H). 13C NMR (125 MHz, DMSO‑d6)
d 163.83, 150.18, 146.43, 144.36,
(150 MHz, DMSO‑d6)
d
164.40, 150.81, 147.91, 145.16, 141.95, 136.91,
141.34, 138.90, 133.32, 133.18, 132.82, 129.17, 129.13, 123.17, 122.43,
121.35, 117.77, 116.85, 114.90, 110.81, 68.76. ESI-HRMS calcd. for
134.40, 132.86, 130.67, 128.78, 128.76, 126.27, 123.99, 122.95, 121.97,
118.65, 115.54, 69.83, 18.71. ESI-HRMS calcd. for
C
21H17N6O2
C
21H14N7O2 [M ꢁ H]- 396.1209, found: 396.1212.
[M ꢁ H]- 385.1413, found: 385.1416.
4.1.6.19. N-(4-((3-cyanobenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)iso-
4.1.6.13. N-(4-((3-methylbenzyl)oxy)-3-(1H-tetrazol-1-yl)phenyl)
nicotinamide (2s). An off-white powder, yield 81.2%. 1H NMR
isonicotinamide (2m). A yellow powder, yield 76.9%. 1H NMR
(600 MHz, DMSO‑d6)
d
10.72 (s, 1H), 9.91 (s, 1H), 8.82 (d, J ¼ 5.6 Hz,
(600 MHz, DMSO‑d6)
d
10.72 (s, 1H), 9.85 (s, 1H), 8.81 (dd, J ¼ 4.5,
2H), 8.24 (d, J ¼ 2.3 Hz, 1H), 7.96 (dd, J ¼ 9.0, 2.3 Hz, 1H), 7.89 (d,
J ¼ 5.7 Hz, 3H), 7.82 (d, J ¼ 7.7 Hz, 1H), 7.74 (d, J ¼ 7.8 Hz, 1H), 7.61 (t,
J ¼ 7.7 Hz, 1H), 7.49 (d, J ¼ 9.1 Hz, 1H), 5.33 (s, 2H). 13C NMR
1.4 Hz, 2H), 8.23 (d, J ¼ 2.5 Hz, 1H), 7.95 (dd, J ¼ 9.1, 2.6 Hz, 1H), 7.89
(dd, J ¼ 4.5, 1.5 Hz, 2H), 7.50 (d, J ¼ 9.1 Hz, 1H), 7.26 (t, J ¼ 7.8 Hz,1H),
7.17 (d, J ¼ 7.2 Hz, 2H), 7.14 (d, J ¼ 7.5 Hz, 1H), 5.22 (s, 2H), 2.30 (s,
(150 MHz, DMSO‑d6) d 164.42, 150.82, 147.16, 145.22, 141.92, 138.24,
3H). 13C NMR (150 MHz, DMSO‑d6)
d
164.40, 150.81, 147.60, 145.13,
133.12, 132.78, 132.40, 131.53, 130.26, 123.78, 122.96, 121.97, 119.05,
118.39, 115.33, 112.02, 69.95. ESI-HRMS calcd. for C21H14N7O2
[M ꢁ H]- 396.1209, found: 396.1212.
141.96, 138.16, 136.45, 132.89, 129.19, 128.88, 128.57, 125.07, 123.81,
123.01, 121.97, 118.31, 115.49, 71.24, 21.41. ESI-HRMS calcd. for