14
L.K. Forsberg et al. / Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
4.3.48. 30,6-Dimethoxy-N-((1r,4r)-4-(4-(piperidin-3-yloxy)
12.3, 8.4, 3.4 Hz, 2H), 2.47 (tt, J = 12.1, 3.4 Hz, 1H), 2.30 (t, J =
10.0 Hz, 1H), 2.25–2.18 (m, 2H), 2.10–2.02 (m, 2H), 1.98–1.88 (m,
2H), 1.75 (dtd, J = 12.0, 8.0, 3.7 Hz, 2H), 1.62 (qd, J = 13.2, 3.3 Hz,
2H), 1.36 (qd, J = 12.6, 3.5 Hz, 2H); 13C NMR (126 MHz, CDCl3) d
166.32, 159.42, 159.01, 155.57, 139.26, 139.20, 130.52, 129.39,
129.24, 128.31, 127.84 (2C), 127.36, 122.14, 116.13 (2C), 115.49,
112.91, 110.98, 72.45, 55.94, 55.48, 48.83, 43.35 (2C), 42.86,
33.79 (2C), 33.34 (2C), 31.57 (2C); HRMS (ESI+) m/z [M+H] calcu-
lated for C32H39N2O4: 515.2910, found 515.2893.
phenyl)cyclohexyl)-[1,10-biphenyl]-3-carboxamide (26a)
1H NMR (500 MHz, CDCl3) d 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.67 (d,
J = 2.4 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.13–7.09 (m, 3H), 7.07 (dd, J
= 2.6, 1.6 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 1.0
Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 5.93 (d, J = 8.2 Hz, 1H), 4.35 (tt, J =
7.0, 3.4 Hz, 1H), 4.04 (tdt, J = 11.5, 7.7, 3.8 Hz, 1H), 3.86 (s, 3H), 3.85
(s, 3H), 3.23 (dd, J = 12.6, 2.2 Hz, 1H), 3.04 (d, J = 12.9 Hz, 1H), 3.00–
2.83 (m, 2H), 2.46 (tt, J = 12.1, 3.4 Hz, 1H), 2.24–2.18 (m, 2H), 2.13–
2.04 (m, 1H), 2.04–1.72 (m, 4H), 1.72–1.51 (m, 4H), 1.43–1.31 (m,
2H); 13C NMR (126 MHz, CDCl3) d 166.33, 159.42, 159.00, 155.49,
139.42, 139.19, 130.51, 129.40, 129.23, 128.30, 127.87 (2C),
127.35, 122.13, 116.06 (2C), 115.48, 112.91, 110.97, 71.42, 55.93,
55.47, 49.76, 48.83, 45.74, 42.86, 33.77 (2C), 33.32 (2C), 29.31,
4.3.52. N-((1r,4r)-4-(4-((1-(2-Hydroxyethyl)piperidin-4-yl)oxy)
phenyl)cyclohexyl)-30,6-dimethoxy-[1,10-biphenyl]-3-carboxamide
(26e)
1H NMR (600 MHz, CDCl3) d 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.68 (d,
J = 2.4 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.14–7.09 (m, 3H), 7.07 (t, J =
2.1 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 0.9 Hz,
1H), 6.84 (d, J = 8.6 Hz, 2H), 5.91 (d, J = 8.1 Hz, 1H), 4.32 (bs, 1H),
4.04 (tdt, J = 11.8, 8.0, 4.0 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.63
(t, J = 5.4 Hz, 2H), 2.81 (bs, 2H), 2.59 (t, J = 5.4 Hz, 2H), 2.51–2.37
(m, 3H), 2.25–2.16 (m, 3H), 2.05–1.98 (m, 2H), 1.95 (d, J = 12.7
Hz, 2H), 1.89–1.78 (m, 2H), 1.62 (qd, J = 13.2, 3.3 Hz, 2H), 1.36
(qd, J = 12.6, 3.4 Hz, 2H); 13C NMR (151 MHz, CDCl3) d 166.34,
159.45, 159.04, 155.76, 139.21, 139.19, 130.56, 129.40, 129.23,
128.30, 127.81 (2C), 127.39, 122.15, 116.15 (2C), 115.52, 112.93,
111.01, 72.22, 59.39, 57.95, 55.94, 55.48, 50.43 (2C), 48.86, 42.87,
33.80 (2C), 33.35 (2C), 30.90 (2C); HRMS (ESI+) m/z [M+H] calcu-
lated for C34H43N2O5: 559.3172, found 559.3090.
22.85; HRMS (ESI+) m/z [M+H] calculated for
C32H39N2O4:
515.2910, found 515.2887.
4.3.49. N-((1r,4r)-4-(4-((1-(2-Hydroxyethyl)piperidin-3-yl)oxy)
phenyl)cyclohexyl)-30,6-dimethoxy-[1,10-biphenyl]-3-carboxamide
(26b)
1H NMR (600 MHz, CDCl3) d 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.68 (d,
J = 2.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.13–7.09 (m, 3H), 7.07 (t, J =
2.1 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.91 (dt, J = 8.3, 1.6 Hz, 1H),
6.85 (d, J = 8.6 Hz, 2H), 5.91 (d, J = 8.1 Hz, 1H), 4.31 (tt, J = 8.6,
4.0 Hz, 1H), 4.04 (tdt, J = 11.8, 8.0, 4.0 Hz, 1H), 3.86 (s, 3H), 3.85
(s, 3H), 3.61 (t, J = 5.4 Hz, 2H), 3.06 (d, J = 11.0 Hz, 1H), 2.76 (d, J
= 11.1 Hz, 1H), 2.58 (t, J = 5.4 Hz, 2H), 2.47 (tt, J = 12.2, 3.5 Hz,
1H), 2.26 (t, J = 9.8 Hz, 1H), 2.24–2.16 (m, 4H), 2.10–2.04 (m, 1H),
1.98–1.91 (m, 2H), 1.83 (dp, J = 12.6, 4.2 Hz, 1H), 1.67–1.56 (m,
3H), 1.54–1.45 (m, 1H), 1.36 (qd, J = 12.6, 3.4 Hz, 2H); 13C NMR
4.3.53. 30,6-Dimethoxy-N-((1r,4r)-4-(4-((1-(2-methoxyethyl)
piperidin-4-yl)oxy)phenyl)cyclohexyl)-[1,10-biphenyl]-3-carboxamide
(26f)
(151 MHz, CDCl3)
d 166.33, 159.45, 159.03, 155.90, 139.29,
139.22, 130.56, 129.41, 129.23, 128.30, 127.85 (2C), 127.41,
122.15, 116.02 (2C), 115.51, 112.94, 111.01, 73.07, 59.40, 57.99,
57.83, 55.94, 55.48, 53.28, 48.86, 42.88, 33.81 (2C), 33.33 (2C),
30.21, 23.32; HRMS (ESI+) m/z [M+H] calculated for C34H43N2O5:
559.3172, found 559.3150.
1H NMR (500 MHz, CDCl3) d 7.81 (dd, J = 8.6, 2.4 Hz, 1H), 7.67 (d,
J = 2.4 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.10
(dt, J = 7.6, 1.2 Hz, 1H), 7.07 (dd, J = 2.7, 1.6 Hz, 1H), 7.01 (d, J =
8.6 Hz, 1H), 6.91 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.83 (d, J = 8.7 Hz,
2H), 5.91 (d, J = 8.0 Hz, 1H), 4.55 (s, 1H), 4.04 (tdt, J = 11.2, 7.4,
3.7 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.37 (s, 3H), 3.28–2.93 (m,
8H), 2.57–2.41 (m, 3H), 2.25–2.17 (m, 2H), 2.10 (d, J = 14.3 Hz,
2H), 1.97–1.88 (m, 2H), 1.62 (qd, J = 13.2, 3.3 Hz, 2H), 1.42–1.32
(m, 2H); 13C NMR (126 MHz, CDCl3) d 166.36, 159.46, 159.06,
154.88, 140.00, 139.21, 130.57, 129.40, 129.24, 128.32, 128.08
(2C), 127.35, 122.15, 116.03 (2C), 115.54, 112.92, 111.03, 77.36,
67.96, 59.11, 57.50, 55.94, 55.48, 49.53 (2C), 48.82, 42.87, 33.74
(2C), 33.32, (2C) 27.79 (2C); HRMS (ESI+) m/z [M+H] calculated
for C35H45N2O5: 573.3328, found 573.3301.
4.3.50. 30,6-Dimethoxy-N-((1r,4r)-4-(4-((1-(2-methoxyethyl)
piperidin-3-yl)oxy)phenyl)cyclohexyl)-[1,10-biphenyl]-3-carboxamide
(26c)
1H NMR (500 MHz, CDCl3) d 7.81 (dd, J = 8.6, 2.3 Hz, 1H), 7.67 (d,
J = 2.4 Hz, 1H), 7.39–7.29 (m, 1H), 7.13–7.09 (m, 3H), 7.07 (dd, J =
2.6, 1.5 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.91 (ddd, J = 8.2, 2.6, 0.9
Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 5.88 (d, J = 8.1 Hz, 1H), 4.36 (bs,
1H), 4.04 (dtd, J = 11.7, 7.8, 4.0 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H),
3.52 (bs, 2H), 3.34 (s, 3H), 3.14 (bs, 1H), 2.82 (bs, 1H), 2.63 (bs,
2H), 2.46 (tt, J = 12.1, 3.5 Hz, 1H), 2.26–2.17 (m, 3H), 2.19–2.01
(m, 2H), 1.95 (d, J = 13.3 Hz, 2H), 1.85–1.75 (m, 1H), 1.70–1.52
(m, 4H), 1.36 (qd, J = 12.7, 3.5 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d 166.34, 159.46, 159.04, 155.34, 139.23, 139.10, 130.58, 129.41,
129.24, 128.30, 127.80 (2C), 127.43, 122.16, 115.92 (2C), 115.52,
112.96, 111.02, 73.04, 59.06, 58.50, 58.09, 55.95, 55.49, 54.04,
53.91, 48.87, 42.89, 33.83 (2C), 33.35 (2C), 30.25, 23.32; HRMS
(ESI+) m/z [M+H] calculated for C35H45N2O5: 573.3328, found
573.3325.
4.3.54. N-((1R,4r)-4-(4-(((1s,4S)-4-Aminocyclohexyl)oxy)
phenyl)cyclohexyl)-30,6-dimethoxy-[1,10-biphenyl]-3-carboxamide
(26g)
Compound 5.18b was obtained following the procedure for the
synthesis of 16a as a white amorphous solid (70%): 1H NMR (500
MHz, Methylene Chloride-d2) d 7.78 (ddd, J = 8.7, 6.2, 2.5 Hz, 1H),
7.69 (t, J = 2.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.15–7.10 (m, 2H),
7.05 (td, J = 9.0, 6.2 Hz, 2H), 6.89 (dd, J = 8.3, 2.6 Hz, 1H), 6.84–
6.78 (m, 2H), 4.26 (t, J = 3.8 Hz, 1H), 4.17 (dd, J = 9.7, 4.6 Hz, 1H),
3.94 (ddt, J = 11.4, 7.5, 4.3 Hz, 1H), 3.85 (d, J = 2.6 Hz, 3H), 3.82
(d, J = 2.3 Hz, 3H), 3.13–3.07 (m, 1H), 2.52–2.42 (m, 1H), 2.23–
2.05 (m, 5H), 2.01–1.96 (m, 1H), 1.94–1.88 (m, 1H), 1.83–1.73
(m, 1H), 1.71–1.35 (m, 8H). 13C NMR (126 MHz, CD2Cl2) d 159.53,
159.50, 155.78, 139.81, 139.36, 130.51, 129.56, 129.16, 127.85,
122.11, 116.21, 115.51, 112.88, 111.05, 74.40, 55.85, 55.40, 42.87,
33.41, 29.65, 29.60, 29.12, 28.49. HRMS (ESI+), m/z [M+H+] calcu-
lated for C33H40N2O4 529.3076; found 529.3056.
4.3.51. 30,6-Dimethoxy-N-((1r,4r)-4-(4-(piperidin-4-yloxy)
phenyl)cyclohexyl)-[1,10-biphenyl]-3-carboxamide (26d)
1H NMR (500 MHz, CDCl3) d 7.82 (dd, J = 8.6, 2.4 Hz, 1H), 7.68 (d,
J = 2.4 Hz, 1H), 7.38–7.31 (m, 1H), 7.14–7.09 (m, 3H), 7.07 (dd, J =
2.6, 1.6 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.92 (ddd, J = 8.2, 2.6, 0.9
Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 5.90 (d, J = 8.1 Hz, 1H), 4.38 (tt, J
= 7.6, 3.6 Hz, 1H), 4.04 (tdt, J = 10.7, 6.9, 3.5 Hz, 1H), 3.86 (s, 3H),
3.85 (s, 3H), 3.19 (ddd, J = 12.7, 6.9, 3.7 Hz, 2H), 2.83 (ddd, J =