W. Nguyen, M.G. Dans, A. Ngo et al.
European Journal of Medicinal Chemistry 214 (2021) 113253
tetrahydroquinoline (20 mg, 0. 15 mmol) to afford 31 as a solid
1.42e1.32 (m, 9H), 1.24e1.14 (m, 3H). 13C NMR (75 MHz, CDCl3,
rotamers) d 170.6, 156.6, 156.5, 134.7, 133.8, 133.2, 132.8, 132.5,
(29.3 mg, 81%). 1H NMR (300 MHz, CDCl3, rotamers):
d
7.69e7.58
(m, 2H), 7.57e7.46 (m, 2H), 7.21e6.90 (m, 4H), 4.05e3.75 (m, 2H),
3.68e3.44 (m, 1H), 2.91 (app s, 4H), 2.76e2.38 (m, 6H), 2.09e1.76
(m, 2H), 1.39e1.31 (m, 9H), 1.20 (d, J 6.7 Hz, 3H). 13C NMR (75 MHz,
128.9,128.2,127.7,127.6,126.8,126.7,126.6,126.5,126.0,125.8, 60.3,
60.0, 48.2, 47.6, 46.1, 45.8, 44.5, 43.2, 40.7, 35.1, 31.1, 29.6, 28.1, 11.1.
MS, m/z 470 (100) [MþH]þ. HRMS acquired: (M þ H) 470.2476;
CDCl3, rotamers)
d
171.2,156.1,138.8,133.6,131.8, 127.9, 127.3, 125.7,
C
26H35N3O3S requires (M þ H), 470.2471.
125.5, 125.1, 123.6, 58.0, 47.6, 45.8, 42.0, 34.7, 30.6, 26.2, 23.6, 12.3.
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-(1-methyl-
MS, m/z 370 (100) [MþH]þ. HRMS acquired: (M þ H) 470.2477;
3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one
(37).
General
C
26H35N3O3S requires (M þ H), 470.2471.
Method B was replicated employing 3 (20 mg, 0.051 mmol) and 1-
methyl-1,2,3,4-tetrahydroisoquinoline (15 mg, 0. 10 mmol) to
afford 37 as a solid mixture of diastereomers (24.2 mg, 98%). 1H
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-indolin-1-yl-
propan-1-one (32). General Method B was replicated employing 3
(30 mg, 0.077 mmol) and indoline (17 L, 0.15 mmol) to afford 32 as
a solid (35 mg, 100%). 1H NMR (300 MHz, CDCl3, rotamers):
8.24
m
NMR (400 MHz, CDCl3, rotamers): d 7.73e7.61 (m, 2H), 7.61e7.45
d
(m, 2H), 7.22e6.94 (m, 3.5H), 6.90e6.81 (m, 0.5H), 5.68e5.53 (m,
1H), 5.38e5.24 (m, 0.5H), 5.14e5.05 (m, 0.5), 4.71e4.55 (m, 1H),
4.04 (d, J 14.1 Hz, 0.5H), 3.96 (d, J 10.6 Hz, 0.5H), 3.70e3.41 (m, 1H),
3.34 (dt, J 3.5, 12.3 Hz, 1H), 3.18e3.05 (m, 2H), 3.05e2.92 (m, 2H),
2.90e2.78 (m, 2H), 2.76e2.50 (m, 5H), 1.43e1.34 (m, 9H), 1.24e1.15
(d, J 7.9 Hz, 1H), 7.73e7.62 (m, J 8.4 Hz, 2H), 7.58e7.48 (m, J 8.4 Hz,
2H), 7.26e7.11 (m, 2H), 7.09e6.97 (m, 1H), 4.39e4.23 (m, 1H),
4.09e3.92 (m, 1H), 3.59e3.42 (m, 1H), 3.24e2.93 (m, 6H),
2.88e2.55 (m, 4H), 1.36 (s, 9H), 1.28 (d, J 6.6 Hz, 3H). 13C NMR
(75 MHz, CDCl3, rotamers)
d
170.1, 156.6, 143.0, 132.4, 131.2, 127.6,
(m, 3H). 13C NMR (75 MHz, CDCl3, rotamers)
d 170.0, 156.6, 156.3,
127.4, 126.0, 124.4, 123.9, 117.2, 61.9, 48.3, 47.6, 46.2, 35.1, 31.0, 28.1,
10.5. MS, m/z 456 (100) [MþH]þ. HRMS acquired: (M þ H)
456.2320; C25H33N3O3S requires (M þ H), 456.2315.
138.5, 138.3, 133.8, 133.1, 132.9, 132.9, 132.7, 132.5, 132.3, 129.3,
129.1, 128.5, 127.7, 127.6, 127.5, 127.2, 127.1, 126.8, 126.5, 126.4, 126.4,
126.3, 126.3, 126.1, 126.0, 125.9, 125.8, 60.3, 59.9, 59.6, 51.8, 48.7,
48.6, 48.5, 48.1, 47.9, 46.1, 45.8, 39.4, 39.1, 35.4, 35.1, 31.0, 29.6, 28.2,
23.3, 23.0, 21.6, 21.3, 11.9, 10.7. MS, m/z 484 (100) [MþH]þ. HRMS
acquired: (M þ H) 484.2622; C27H37N3O3S requires (M þ H),
484.2628.
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-(1,1-dimethyl-
3,4-dihydroisoquinolin-2-yl)propan-1-one (38). General Method B
was replicated employing 3 (20 mg, 0.051 mmol) and 1,1-dimethyl-
1,2,3,4-tetrahydroisoquinoline (16.5 mg, 0. 10 mmol) to afford 38 as
a solid (18.3 mg, 72%). 1H NMR (300 MHz, CDCl3, rotamers):
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-isoindolin-2-
yl-propan-1-one (33). General Method B was replicated employing
3 (25 mg, 0.064 mmol) and isoindoline (15
33 as a solid (34.9 mg, 100%). 1H NMR (300 MHz, CDCl3, rotamers):
7.72e7.63 (m, 2H), 7.56e7.47 (m, 2H), 7.33e7.16 (m, 4H),
mL, 0. 15 mmol) to afford
d
5.09e4.94 (m, 1H), 4.83e4.70 (m, 3H), 3.55e3.36 (m, 1H), 3.07 (app
s, 4H), 2.91e2.51 (m, 4H), 1.39e1.18 (m, 12H). MS, m/z 456 (100)
[MþH]þ. HRMS acquired: (M þ H) 456.2320; C25H33N3O3S requires
(M þ H), 456.2315.
N-Benzyl-2-[4-(4-tert-butylphenyl)sulfonylpiperazin-1-yl]-N-
d 7.75e7.63 (m, J 8.4 Hz, 2H), 7.61e7.49 (m, J 8.3 Hz, 2H), 7.35e7.20
methyl-propanamide (34). General Method
employing 3 (30 mg, 0.077 mmol) and N-methylbenzylamine
(20
L, 0. 15 mmol) to afford 34 as a solid (31 mg, 88%). 1H NMR
(300 MHz, CDCl3, rotamers): 7.68 (t, J 8.5 Hz, 2H), 7.55 (d, J 8.3 Hz,
B
was replicated
(m, 2H), 7.14 (t, J 7.2 Hz, 1H), 7.01 (d, J 7.3 Hz, 1H), 3.77e3.55 (m, 2H),
3.51e3.36 (m, 1H), 3.06 (app s, 4H), 2.82e2.67 (m, 4H), 2.67e2.54
(m, 2H), 1.80 (s, 6H), 1.38 (s, 9H), 1.20 (d, J 6.4 Hz, 3H). MS, m/z 498
(100) [MþH]þ. HRMS acquired: (M þ H) 498.2790; C28H39N3O3S
requires (M þ H), 498.2785.
m
d
2H), 7.34e7.04 (m, 5H), 4.72e4.43 (m, 2H), 3.63e3.48 (m, 1H),
3.15e2.89 (m, 7H), 2.82e2.48 (m, 4H), 1.38 (d, J 6.0 Hz, 9H), 1.21 (dd,
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-(1,1-diethyl-
3,4-dihydroisoquinolin-2-yl)propan-1-one (39). General Method B
was replicated employing 3 (20 mg, 0.051 mmol) and 82 (19.4 mg,
0. 10 mmol) to afford 39 as a solid (2.5 mg, 9%). 1H NMR (400 MHz,
J 6.7, 10.9 Hz, 3H). 13C NMR (75 MHz, CDCl3, rotamers)
d 172.4, 172.1,
156.5, 156.5, 137.3, 136.9, 132.5, 128.6, 128.5, 127.8, 127.7, 127.4,
127.3, 126.2, 125.9, 59.5, 53.0, 51.1, 48.4, 48.2, 46.2, 46.0, 35.1, 34.7,
34.3, 31.1, 31.0, 11.4, 10.9. MS, m/z 458 (100) [MþH]þ. HRMS ac-
quired: (M þ H) 458.2477; C25H35N3O3S requires (M þ H), 458.2471.
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-N-methyl-N-(2-
phenylethyl)propenamide (35). General Method B was replicated
CDCl3, rotamers):
d 7.72e7.61 (m, J 7.4 Hz, 2H), 7.58e7.47 (m, J
7.8 Hz, 2H), 7.26e7.19 (m, 2H), 7.16e7.10 (m, 1H), 7.02 (d, J 7.4 Hz,
1H), 3.76e3.53 (m, 3H), 3.14e3.02 (m, 4H), 2.79e2.57 (m, 6H),
1.78e1.63 (m, 4H), 1.35 (s, 9H), 1.21 (d, J 6.7 Hz, 3H), 0.59e0.41 (m,
6H). MS, m/z 526 (100) [MþH]þ. HRMS acquired: (M þ H) 526.3088;
employing
phenylethanamine (15
(22.7 mg, 94%). 1H NMR (300 MHz, CDCl3, rotamers):
3
(20 mg, 0.051 mmol) and N-methyl-2-
L, 0. 10 mmol) to afford 35 as a solid
7.67 (t, J
m
C
30H43N3O3S requires (M þ H), 526.3098.
d
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-spiro[3,4-
6.9 Hz, 2H), 7.48e7.58 (m, 2H), 7.11e7.32 (m, 4H), 7.07 (d, J 6.9 Hz,
1H), 3.88e3.56 (m, 1H), 3.53e3.15 (m, 2H), 3.08e2.91 (m, 5H),
2.90e2.72 (m, 4H), 2.68e2.37 (m, 4H), 1.33 (s, 4.5H), 1.37 (s, 4.5H),
1.12 (d, J 6.3 Hz, 1.5H), 1.00 (d, J 6.5 Hz, 1.5H). 13C NMR (75 MHz,
dihydroisoquinoline-1,10-cyclopentane]-2-yl-propan-1-one
(40).
General Method B was replicated employing 3 (12 mg, 0.031 mmol)
and 84 (6.5 mg, 0. 035 mmol) to afford 40 as a solid (10.6 mg, 66%).
1H NMR (300 MHz, CDCl3, rotamers):
d 7.73e7.61 (m, J 8.4 Hz, 2H),
CDCl3, rotamers)
d
171.4, 156.6, 138.8, 138.0, 132.5, 132.4, 128.8,
7.59e7.49 (m, J 8.4 Hz, 2H), 7.24e7.07 (m, 3H), 6.99 (d, J 7.2 Hz, 1H),
3.86e3.69 (m, 1H), 3.65e3.46 (m, 2H), 3.03 (app s, 4H), 2.82e2.46
(m, 8H), 2.30e2.03 (m, 2H), 1.96e1.71 (m, 4H), 1.42e1.30 (m, 9H),
128.8, 128.6, 128.3, 127.6, 126.8, 126.3, 126.0, 59.4, 58.9, 51.2, 49.5,
48.2, 46.0, 35.7, 35.1, 35.1, 34.9, 33.6, 33.5, 31.0, 31.0, 11.6, 11.3. MS,
m/z 472 (100) [MþH]þ. HRMS acquired: (M þ H) 472.2632;
1.18 (d, J 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3, rotamers)
d 171.1,
C
26H37N3O3S requires (M þ H), 472.2628.
156.7, 145.6, 134.2, 132.7, 127.6, 126.6, 126.1, 125.8, 125.5, 70.5, 61.7,
48.1, 46.1, 44.2, 40.6, 40.4, 35.2, 31.1, 30.9, 26.3, 26.1, 11.1. MS, m/z
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-(3,4-dihydro-
1H-isoquinolin-2-yl)propan-1-one (36). General Method B was
replicated employing (30 mg, 0.077 mmol) and 1,2,3,4-
tetrahydroisoquinoline (20 L, 0. 153 mmol) to afford 36 as a
solid (24.2 mg, 67%). 1H NMR (300 MHz, CDCl3, rotamers):
7.72e7.57 (m, 2H), 7.57e7.46 (m, 2H), 7.24e7.02 (m, 3H),
524 (100) [MþH]þ. HRMS acquired: (M
þ
H) 524.2950;
3
C
30H41N3O3S requires (M þ H), 524.2959.
m
2-[4-(4-tert-Butylphenyl)sulfonylpiperazin-1-yl]-1-spiro[3,4-
dihydroisoquinoline-1,10-cyclohexane]-2-yl-propan-1-one (41). Gen-
eral Method B was replicated employing 3 (25 mg, 0.064 mmol)
and 86 (26 mg, 0.13 mmol) to afford 41 as a solid (1.9 mg, 6%). 1H
d
6.97e6.83 (m, 1H), 4.78 (dd, J 10.2, 16.5 Hz, 1H), 4.58 (dd, J 7.2,
16.6 Hz, 1H), 4.01e3.88 (m, 0.5H), 3.86e3.75 (m, 0.5H), 3.70e3.49
(m, 2H), 3.04 (t, J 4.1 Hz, 2H), 2.96e2.87 (m, 1H), 2.86e2.52 (m, 7H),
NMR (400 MHz, CDCl3, rotamers):
d 7.73e7.63 (m, 2H), 7.60e7.49
(m, 2H), 7.33 (d, J 7.8 Hz,1H), 7.19e7.04 (m, 2H), 6.83 (d, J 7.0 Hz,1H),
17