Journal of Medicinal Chemistry
Article
7.86 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz,
1H), 7.47 (t, J = 7.5 Hz, 2H), 7.39 (dd, J = 8.4, 6.2 Hz, 1H), 7.34−
7.27 (m, 3H), 7.24−7.20 (m, 1H), 7.18 (s, 1H), 5.43 (s, 2H), 5.39 (s,
2H), 5.32 (s, 1H), 3.89 (s, 2H), 3.83 (s, 1H), 3.00 (d, J = 4.9 Hz,
1H), 2.23 (s, 3H), 1.14 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz,
DMSO): δ 170.07, 161.99, 155.02, 142.62, 141.62, 137.92, 134.83,
134.39, 133.09, 132.44, 132.18, 131.64, 130.33, 129.58 (2C), 128.73
(3C), 128.61, 128.21, 127.47, 126.05, 119.15, 114.35, 111.99, 100.17,
70.76, 70.12, 66.54, 66.04, 44.73, 20.99, 16.30. LCMS: tR 6.415 min;
purity, 99.2%.
112.04, 100.27, 70.78, 70.10, 56.97, 49.43, 44.20, 16.35. LCMS: tR
6.425 min; purity, 97.7%.
N-(2-((3-Cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)-
methoxy)-5-nitrobenzyl)-N-methylglycine (B8). White solid in 53%
1
yield. mp 163−165 °C. MS (ESI): m/z 552.2 [M + H]+; H NMR
(300 MHz, DMSO): δ 8.06 (s, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.80 (d,
J = 6.8 Hz, 2H), 7.63 (d, J = 6.3 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H),
7.46 (d, J = 7.5 Hz, 2H), 7.40 (d, J = 6.7 Hz, 1H), 7.33 (d, J = 7.3 Hz,
3H), 7.28−7.21 (m, 2H), 5.52 (s, 2H), 5.44 (s, 2H), 3.69 (s, 2H),
3.21 (s, 2H), 2.29 (s, 3H), 2.25 (s, 3H). LCMS: tR 6.841 min; purity,
98.9%.
(2-((3-Cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)-
(4-((2-Methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-nitro-2-(pyridin-3-
ylmethoxy)benzyl)-L-serine (B9). White solid in 54% yield. mp 130−
132 °C. MS (ESI): m/z 544.2 [M + H]+; 1H NMR (300 MHz,
DMSO): δ 8.09 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84
(d, J = 7.1 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H),
7.50−7.43 (m, 2H), 7.40 (d, J = 6.7 Hz, 1H), 7.34−7.26 (m, 3H),
7.24−7.16 (m, 2H), 5.44 (s, 2H), 5.38 (s, 2H), 5.31 (s, 1H), 3.86 (s,
2H), 3.58−3.54 (m, 2H), 3.05−2.98 (m, 1H), 2.22 (s, 3H). LCMS: tR
5.884 min; purity, 98.4%.
(4-((2-Methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-nitro-2-(pyridin-3-
ylmethoxy)benzyl)-L-threonine (B10). White solid in 57% yield. mp
135−137 °C. MS (ESI): m/z 558.2 [M + H]+; 1H NMR (300 MHz,
DMSO): δ 8.14 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J = 14.4, 7.1 Hz, 2H),
7.68−7.61 (m, 1H), 7.56−7.49 (m, 2H), 7.46 (d, J = 7.4 Hz, 2H),
7.40 (d, J = 7.2 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.25−7.17 (m,
2H), 5.47 (s, 1H), 5.44 (s, 2H), 5.39 (s, 2H), 3.91 (s, 2H), 3.86 (s,
2H), 3.02 (d, J = 4.8 Hz, 1H), 2.23 (s, 3H), 1.15 (d, J = 6.2 Hz, 3H).
LCMS: tR 6.785 min; purity, 97.8%.
(S)-1-(4-((2-Methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-nitro-2-(pyri-
din-3-ylmethoxy)benzyl)piperidine-2-carboxylic Acid (B11). White
solid in 55% yield. mp 142−144 °C. MS (ESI): m/z 568.2 [M + H]+;
1H NMR (300 MHz, DMSO): δ 7.99 (s, 1H), 7.87−7.83 (m, 2H),
7.67−7.63 (m, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 7.4 Hz,
2H), 7.40 (d, J = 6.2 Hz, 1H), 7.32 (d, J = 7.3 Hz, 3H), 7.22 (d, J =
7.6 Hz, 1H), 7.16 (s, 1H), 5.43 (s, 2H), 5.37 (s, 2H), 3.78 (d, J = 14.4
Hz, 1H), 3.61 (d, J = 14.5 Hz, 1H), 3.20−3.15 (m, 1H), 2.30−2.26
(m, 1H), 2.23 (s, 3H), 2.18 (d, J = 11.8 Hz, 1H), 1.78 (s, 2H), 1.49
(s, 4H). LCMS: tR 6.895 min; purity, 98.5%.
methoxy)-5-nitrobenzyl)-L-proline (B3). White solid in 62% yield.
1
mp 156−158 °C. MS (ESI): m/z 578.2 [M + H]+; H NMR (300
MHz, DMSO): δ 8.24 (s, 1H), 8.08 (s, 1H), 7.94 (d, J = 7.1 Hz, 1H),
7.87 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 7.5 Hz,
1H), 7.51−7.44 (m, 2H), 7.40 (d, J = 6.8 Hz, 1H), 7.34−7.27 (m,
4H), 7.23 (d, J = 7.2 Hz, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.45−4.27
(m, 2H), 4.17−3.99 (m, 2H), 3.06 (s, 2H), 2.24 (s, 3H), 1.99 (s, 2H),
1.88−1.81 (m, 1H). LCMS: tR 6.512 min; purity, 97.7%.
(S)-1-(2-((3-Cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)-
methoxy)-5-nitrobenzyl)piperidine-2-carboxylic Acid (B4). White
solid in 62% yield. mp 126−128 °C. MS (ESI): m/z 592.2 [M + H]+;
1H NMR (300 MHz, DMSO): δ 8.08 (s, 1H), 7.96 (d, J = 7.1 Hz,
1H), 7.79 (q, J = 7.6 Hz, 2H), 7.64−7.59 (m, 1H), 7.57 (d, J = 7.3
Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.34−7.28
(m, 3H), 7.26 (s, 1H), 7.22 (d, J = 6.8 Hz, 1H), 5.50 (d, J = 6.4 Hz,
2H), 5.43 (s, 2H), 3.57 (d, J = 10.6 Hz, 2H), 3.15 (d, J = 4.6 Hz, 1H),
2.85 (s, 1H), 2.24 (s, 3H), 2.23−2.19 (m, 1H), 1.74 (d, J = 7.3 Hz,
2H), 1.49−1.34 (m, 4H). 13C NMR (101 MHz, DMSO): δ 161.52,
153.73, 143.57, 142.66, 142.66, 141.70, 138.36, 135.04, 134.34,
132.90, 132.47, 132.46, 131.55, 130.36, 130.33, 130.27, 129.63 (2C),
128.74 (2C), 128.19, 128.09, 127.48, 126.08, 119.09, 112.08, 100.16,
70.60, 69.60, 52.74, 49.71, 29.23, 25.18, 22.25, 16.32. LCMS: tR 6.892
min; purity, 98.2%.
N-(2-((2-((3-Cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)-
methoxy)-5-nitrobenzyl)amino)ethyl)acetamide (B5). White solid
1
in 58% yield. mp 146−148 °C. MS (ESI): m/z 565.2 [M + H]+; H
NMR (300 MHz, DMSO): δ 8.02 (s, 1H), 7.99 (s, 1H), 7.85 (dd, J =
11.6, 4.6 Hz, 3H), 7.66 (t, J = 7.9 Hz, 1H), 7.55−7.49 (m, 1H), 7.47
(d, J = 1.5 Hz, 1H), 7.45 (s, 1H), 7.42−7.37 (m, 1H), 7.31 (dd, J =
8.2, 1.4 Hz, 3H), 7.24 (dd, J = 10.2, 8.8 Hz, 2H), 7.16 (s, 1H), 5.42
(s, 2H), 5.37 (s, 2H), 3.70 (s, 2H), 3.13 (dd, J = 12.1, 6.2 Hz, 2H),
2.56 (t, J = 6.5 Hz, 2H), 2.23 (s, 3H), 1.78 (s, 3H). LCMS: tR 6.782
min; purity, 97.9%.
(2-((2-Cyanopyridin-4-yl)methoxy)-4-((2-methyl-[1,1′-biphenyl]-
3-yl)methoxy)-5-nitrobenzyl)-L-serine (B12). White solid in 47%
1
yield. mp 136−138 °C. MS (ESI): m/z 569.2 [M + H]+; H NMR
(300 MHz, DMSO): δ 8.68 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 8.17 (d,
J = 2.4 Hz, 1H), 7.70 (d, J = 5.2 Hz, 2H), 7.47 (s, 1H), 7.44 (s, 1H),
7.40 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 6.7 Hz, 2H), 7.30−7.24 (m,
1H), 7.22 (d, J = 6.1 Hz, 2H), 5.61 (s, 2H), 5.37 (s, 2H), 3.96−3.81
(m, 2H), 3.65−3.60 (m, 2H), 3.54 (s, 1H), 3.21−3.16 (m, 1H), 2.23
(s, 3H). LCMS: tR 7.255 min; purity, 97.5%.
3-((2-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-((2-methyl-
[1,1′-biphenyl]-3-yl)methoxy)-4-nitrophenoxy)methyl)benzonitrile
(B6). White solid in 55% yield. mp 132−134 °C. MS (ESI): m/z
554.2 [M + H]+; 1H NMR (300 MHz, DMSO): δ 8.19 (s, 1H), 7.89
(d, J = 7.0 Hz, 2H), 7.78 (d, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H),
7.55 (t, J = 7.0 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.44−7.36 (m, 2H),
7.33 (d, J = 7.2 Hz, 1H), 7.27−7.22 (m, 3H), 7.18 (dd, J = 10.9, 6.1
Hz, 2H), 5.50 (s, 2H), 5.41 (s, 2H), 5.07 (s, 2H), 4.13 (s, 2H), 3.50
(m, 4H), 2.95 (s, 1H), 2.17 (s, 3H). 13C NMR (101 MHz, DMSO): δ
161.97, 155.11, 142.68, 141.66, 138.05, 134.85, 134.45, 133.21,
132.52, 132.22, 131.82, 130.40, 130.32, 130.20, 129.62 (2C), 128.76
(2C), 128.28, 127.50, 126.09, 119.15, 113.64, 112.04, 100.26, 70.79,
70.10, 56.96 (2C), 49.41, 44.22, 16.35. LCMS: tR 6.612 min; purity,
98.3%.
(2-((2-Cyanopyridin-4-yl)methoxy)-4-((2-methyl-[1,1′-biphenyl]-
3-yl)methoxy)-5-nitrobenzyl)-L-threonine (B13). White solid in 47%
1
yield. mp 122−124 °C. MS (ESI): m/z 583.2 [M + H]+; H NMR
(300 MHz, DMSO): δ 8.04 (s, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.86
(d, J = 1.7 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.47 (s, 1H), 7.44 (s,
1H), 7.42−7.37 (m, 1H), 7.33−7.26 (m, 3H), 7.21 (dd, J = 7.6, 1.2
Hz, 1H), 7.15 (s, 1H), 5.41 (s, 2H), 5.37 (s, 2H), 4.72 (d, J = 5.4 Hz,
1H), 3.83 (d, J = 5.3 Hz, 1H), 3.70 (s, 1H), 3.63 (d, J = 14.5 Hz, 1H),
3.10 (d, J = 4.7 Hz, 1H), 2.22 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H).
LCMS: tR 7.156 min; purity, 98.9%.
(S)-1-(2-((2-Cyanopyridin-4-yl)methoxy)-4-((2-methyl-[1,1′-bi-
phenyl]-3-yl)methoxy)-5-nitrobenzyl)piperidine-2-carboxylic Acid
(B14). White solid in 44% yield. mp 126−128 °C. MS (ESI): m/z
593.2 [M + H]+; 1H NMR (300 MHz, DMSO): δ 8.06 (s, 1H), 7.94
(d, J = 7.3 Hz, 1H), 7.77 (t, J = 7.1 Hz, 2H), 7.62−7.57 (m, 1H), 7.55
(d, J = 6.1 Hz, 1H), 7.44 (t, J = 7.1 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H),
7.31 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.20 (d, J = 6.5 Hz, 1H), 5.48
(s, 2H), 5.41 (s, 2H), 3.21 (d, J = 5.1 Hz, 2H), 3.13 (d, J = 4.9 Hz,
1H), 2.83 (s, 1H), 2.22 (s, 3H), 2.21−2.17 (m, 1H), 1.72 (d, J = 11.2
Hz, 2H), 1.47−1.32 (m, 4H). LCMS: tR 7.241 min; purity, 98.0%.
(S)-1-(2-((3-Cyanobenzyl)oxy)-4-((2-methyl-[1,1′-biphenyl]-3-yl)-
methoxy)-5-nitrobenzyl)-N-(2-hydroxy-2-methylpropyl)piperidine-
2-carboxamide (B15). White solid in 47% yield. mp 146−148 °C.
3-((2-(((2-Hydroxyethyl)amino)methyl)-5-((2-methyl-[1,1′-bi-
phenyl]-3-yl)methoxy)-4-nitrophenoxy)methyl)benzonitrile (B7).
White solid in 42% yield. mp 168−170 °C. MS (ESI): m/z 524.2
[M + H]+; 1H NMR (300 MHz, DMSO): δ 8.21 (s, 1H), 7.97 (d, J =
7.3 Hz, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.79 (t, J = 7.0 Hz, 1H), 7.62
(t, J = 7.7 Hz, 1H), 7.57 (d, J = 6.7 Hz, 1H), 7.47 (t, J = 7.2 Hz, 2H),
7.40 (d, J = 7.2 Hz, 1H), 7.37−7.28 (m, 5H), 7.23 (d, J = 6.7 Hz,
1H), 5.57 (s, 2H), 5.47 (s, 2H), 4.97 (s, 1H), 3.99 (s, 2H), 3.56 (t, J =
5.7 Hz, 2H), 2.79 (t, J = 5.3 Hz, 2H), 2.25 (s, 3H). 13C NMR (101
MHz, DMSO): δ 161.97, 155.11, 142.68, 141.66, 138.06, 134.85,
134.44, 133.22, 132.52, 132.22, 131.83, 130.40, 130.32, 130.20,
129.63 (2C), 128.75 (2C), 128.27, 127.49, 126.09, 119.15, 113.65,
7662
J. Med. Chem. 2021, 64, 7646−7666