M. Zhu, H. Zhou, L. Ma et al.
European Journal of Medicinal Chemistry 220 (2021) 113450
7d (71.1 mg, 0.16 mmol) by following the same procedure outlined
for 3m to give a yellowish oil: yield 82.4 mg (83.3%); 1H NMR
4.1.28. tert-Butyl 4-(((2S, 3R)-4-((4-amino-N-isobutylphenyl)
sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)
piperidine-1-carboxylate (11k)
(500 MHz, CD3OD)
d 8.08e8.02 (m, 2H), 7.98e7.90 (m, 2H),
7.27e7.21 (m, 4H), 7.21e7.16 (m, 1H), 4.04e3.94 (m, 2H), 3.83e3.73
(m, 1H), 3.64e3.38 (m, 1H), 3.23e3.18 (m, 2H), 3.14e3.02 (m, 2H),
3.00e2.95 (m, 1H), 2.72 (s, 1H), 2.64e2.58 (m, 1H), 2.24e2.14 (m,
1H), 2.10e2.04 (m,1H),1.63e1.57 (m,1H),1.44 (s, 9H),1.36e1.27 (m,
4H), 0.95 (d, J ¼ 6.0 Hz, 3H), 0.88 (d, J ¼ 6.0 Hz, 3H); LC-MS (ESI)
[MþNa]þ m/z 678.7.
Compound 11k was prepared from 10d (34.4 mg, 0.15 mmol)
and 7c (61.6 mg, 0.16 mmol) by following the same procedure
outlined for 3m to give a white powder: yield 86.2 mg (95.4%); 1H
NMR (500 MHz, CD3OD)
d
7.49 (d, J ¼ 8.5 Hz, 2H), 7.27e7.22 (m, 4H),
7.20e7.16 (m, 1H), 6.71 (d, J ¼ 8.5 Hz, 2H), 4.06e4.01 (m, 2H),
3.95e3.90 (m, 1H), 3.84e3.80 (m, 1H), 3.39e3.34 (m, 1H),
3.26e3.22 (m, 1H), 3.06e3.01 (m, 1H), 2.89e2.79 (m, 2H), 2.72 (s,
2H), 2.64e2.58 (m, 1H), 2.25e2.20 (m, 1H), 2.06e1.99 (m, 1H),
1.60e1.56 (m, 1H), 1.46 (s, 9H), 1.35e1.31 (m, 2H), 1.26e1.17 (m, 1H),
0.95 (d, J ¼ 6.5 Hz, 3H), 0.89 (d, J ¼ 6.5 Hz, 3H).
4.1.24. tert-Butyl (S)-2-(((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-
methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamoyl)
piperidine-1-carboxylate (11g)
Compound 11g was prepared from 10c (34.4 mg, 0.15 mmol) and
7a (63.9 mg, 0.16 mmol) by following the same procedure outlined
for 3m to give a yellow oil: yield 49.9 mg (53.9%); 1H NMR
4.1.29. tert-Butyl 4-(((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-
(trifluoromethyl)phenyl)sulfonamido)-1-phenylbutan-2-yl)
carbamoyl)piperidine-1-carboxylate (11l)
Compound 11l was prepared from 10d (34.4 mg, 0.15 mmol) and
7d (70.0 mg, 0.16 mmol) by following the same procedure outlined
for 3m to give a white powder: yield 89.3 mg (90.7%); 1H NMR
(500 MHz, CD3OD)
d
7.79 (d, J ¼ 7.0 Hz, 2H), 7.25 (s, 4H), 7.18 (s, 1H),
7.09 (d, J ¼ 7.0 Hz, 2H), 4.47 (s, 1H), 4.23e4.03 (m, 1H), 3.89 (s, 3H),
3.83 (s, 2H), 3.45e3.38 (m, 1H), 3.29e3.20 (m, 1H), 3.10e2.91 (m,
4H), 2.64 (s, 1H), 2.07e2.00 (m, 1H), 1.79e1.64 (m, 1H), 1.47 (s, 2H),
1.40 (s, 9H), 1.35e1.23 (m, 3H), 0.93 (d, J ¼ 5.5 Hz, 3H), 0.89 (d,
J ¼ 6.0 Hz, 3H); LC-MS (APCI) [MþH]þ m/z 618.7.
(500 MHz, CD3OD)
d
8.04 (d, J ¼ 8.0 Hz, 2H), 7.91 (d, J ¼ 8.0 Hz, 2H),
7.28e7.21 (m, 4H), 7.20e7.17 (m, 1H), 4.05e4.00 (m, 2H), 3.93 (d,
J ¼ 13.5 Hz, 1H), 3.79e3.74 (m, 1H), 3.47 (d, J ¼ 13.5 Hz, 1H),
3.22e3.18 (m, 2H), 3.11e3.06 (m, 1H), 3.01e2.97 (m, 1H), 2.72 (s,
2H), 2.64e2.58 (m, 1H), 2.26e2.20 (m, 1H), 2.10e2.01 (m, 1H),
1.60e1.54 (m, 1H), 1.46 (s, 9H), 1.37e1.30 (m, 2H), 1.28e1.19 (m, 1H),
0.94 (d, J ¼ 6.5 Hz, 3H), 0.89 (d, J ¼ 6.5 Hz, 3H).
4.1.25. tert-Butyl (S)-2-(((2S, 3R)-4-((4-amino-N-isobutylphenyl)
sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)
piperidine-1-carboxylate (11h)
Compound 11h was prepared from 10c (27.5 mg, 0.12 mmol) and
7c (49.2 mg, 0.13 mmol) by following the same procedure outlined
for 3m to give a yellow oil: yield 47.5 mg (65.8%); 1H NMR
4.1.30. (R)-N-((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-
methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)piperidine-3-
carboxamide (3a)
(500 MHz, CDCl3)
d
7.56 (d, J ¼ 8.5 Hz, 2H), 7.32e7.26 (m, 3H),
7.26e7.18 (m, 2H), 6.69 (d, J ¼ 8.5 Hz, 2H), 6.30 (s, 1H), 4.61 (s, 1H),
4.16 (s, 1H), 4.05e3.80 (m, 2H), 3.13e3.02 (m, 3H), 2.97 (s, 2H), 2.90
(s, 2H), 2.86e2.82 (m, 1H), 2.66e2.36 (m, 1H), 2.12e2.01 (m, 1H),
1.91e1.81 (m, 1H), 1.59e1.53 (m, 1H), 1.52e1.46 (m, 2H), 1.44 (s, 9H),
1.35e1.27 (m, 3H), 0.92e0.87 (m, 6H); LC-MS (APCI) [MþH]þ m/z
603.7.
To a stirred solution of 11a (58.4 mg, 0.09 mmol) in CH2Cl2
(1 mL) was bubbled hydrochloric acid gas at 25 ꢁC for 0.5 h. The
reaction mixture was concentrated under reduced pressure, and
the residue was neutralized with saturated aqueous NaHCO3 to pH
7.0, extracted with CH2Cl2 (3 ꢂ 5 mL), and then dried over anhy-
drous Na2SO4. The solvent was evaporated under reduced pressure
to give 3a as a white powder: yield 41.1 mg (88.3%); mp
183.7e185.8 ꢁC; 1H NMR (500 MHz, DMSO‑d6)
d
7.75 (d, J ¼ 8.0 Hz,
4.1.26. tert-Butyl (S)-2-(((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-
(trifluoromethyl)phenyl)sulfonamido)-1-phenylbutan-2-yl)
carbamoyl)piperidine-1-carboxylate (11i)
Compound 11i was prepared from 10c (34.4 mg, 0.15 mmol) and
7d (70.0 mg, 0.16 mmol) by following the same procedure outlined
for 3m to give a yellowish oil: yield 89.1 mg (90.6%); 1H NMR
1H), 7.70 (d, J ¼ 7.5 Hz, 2H), 7.25e7.12 (m, 5H), 7.09 (d, J ¼ 7.5 Hz,
2H), 5.05 (s,1H), 3.83 (s, 3H), 3.81e3.75 (m,1H), 3.57 (s,1H), 3.28 (d,
J ¼ 14.0 Hz, 1H), 3.09e2.97 (m, 2H), 2.82e2.68 (m, 3H), 2.57e2.52
(m, 1H), 2.33 (t, J ¼ 9.5 Hz, 1H), 2.25 (t, J ¼ 10.0 Hz, 1H), 2.11e2.03
(m, 1H), 2.01e1.93 (m, 1H), 1.61e1.53 (m, 1H), 1.44e1.31 (m, 2H),
1.23 (s, 2H), 0.84 (d, J ¼ 5.0 Hz, 3H), 0.79 (d, J ¼ 5.0 Hz, 3H); 13C NMR
(500 MHz, CD3OD)
d
8.07 (d, J ¼ 8.0 Hz, 2H), 7.91 (d, J ¼ 8.0 Hz, 2H),
7.28e7.22 (m, 4H), 7.21e7.16 (m, 1H), 4.52e4.46 (m, 1H), 4.18e3.99
(m, 1H), 3.90e3.74 (m, 2H), 3.53e3.45 (m, 1H), 3.29e3.11 (m, 3H),
3.01 (s, 2H), 2.68e2.57 (m, 1H), 2.09e2.03 (m, 1H), 1.79e1.65 (m,
1H), 1.52e1.45 (m, 2H), 1.40 (s, 9H), 1.34e1.22 (m, 3H), 0.93 (d,
J ¼ 6.0 Hz, 3H), 0.89 (d, J ¼ 5.5 Hz, 3H); LC-MS (APCI) [MþH]þ m/z
656.7.
(101 MHz, DMSO‑d6) d 174.21, 162.78, 139.63, 131.01, 129.70, 129.60,
128.40, 126.37, 114.82, 72.65, 57.14, 56.11, 53.43, 52.73, 48.57, 45.78,
43.46, 35.64, 27.79, 26.71, 24.98, 20.39; HRMS (ESI) m/z calcd. for
C
27H39N3O5S ([M ꢀ H]-): 516.2532, found 516.2525.
4.1.31. (R)-N-((2S, 3R)-4-((4-amino-N-isobutylphenyl)
sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)piperidine-3-
carboxamide (3b)
Compound 3b was prepared from 11b (75.0 mg, 0.12 mmol) by
following the same procedure outlined for 3a to give a white
powder: yield 53.4 mg (88.6%); mp 220.1e222.4 ꢁC; 1H NMR
4.1.27. tert-Butyl 4-(((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-
methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)carbamoyl)
piperidine-1-carboxylate (11j)
Compound 11j was prepared from 10d (34.4 mg, 0.15 mmol) and
7a (63.9 mg, 0.16 mmol) by following the same procedure outlined
for 3m to give a yellow powder: yield 88.3 mg (95.4%); 1H NMR
(500 MHz, CD3OD)
d
7.50 (d, J ¼ 8.5 Hz, 2H), 7.28e7.21 (m, 4H),
7.20e7.15 (m, 1H), 6.71 (d, J ¼ 8.5 Hz, 2H), 4.07e4.01 (m, 1H),
3.84e3.79 (m, 1H), 3.38e3.35 (m, 1H), 3.26e3.20 (m, 1H),
3.07e2.99 (m, 1H), 2.93e2.80 (m, 3H), 2.66e2.51 (m, 3H),
2.46e2.40 (m, 1H), 2.29e2.20 (m, 1H), 2.09e1.89 (m, 1H), 1.81e1.74
(m, 1H), 1.70e1.60 (m, 1H), 1.59e1.41 (m, 2H), 0.94 (d, J ¼ 6.5 Hz,
(500 MHz, CD3OD)
d
7.76 (d, J ¼ 8.0 Hz, 2H), 7.27e7.21 (m, 4H),
7.20e7.15 (m, 1H), 7.09 (d, J ¼ 8.0 Hz, 2H), 4.07e4.00 (m, 2H),
3.96e3.91 (m, 1H), 3.89 (s, 3H), 3.83e3.78 (m, 1H), 3.43e3.38 (m,
1H), 3.25e3.20 (m, 1H), 3.12e3.06 (m, 1H), 2.96e2.86 (m, 2H), 2.72
(s, 2H), 2.64e2.58 (m, 1H), 2.26e2.20 (m, 1H), 2.08e2.00 (m, 1H),
1.61e1.55 (m, 1H), 1.48e1.43 (m, 10H), 1.35e1.32 (m, 1H), 1.28e1.19
(m, 1H), 0.94 (d, J ¼ 6.5 Hz, 3H), 0.88 (d, J ¼ 6.5 Hz, 3H).
3H), 0.89 (d, J ¼ 6.5 Hz, 3H); 13C NMR (101 MHz, CD3OD)
d 176.19,
154.33, 140.15, 130.45, 130.41, 129.18, 127.20, 125.87, 114.38, 74.58,
59.28, 54.93, 54.38, 46.44, 44.35, 36.89, 28.39, 28.16, 25.42, 20.58,
13