S. Wang, H. Yang, M. Su et al.
European Journal of Medicinal Chemistry 222 (2021) 113592
J ¼ 8.4 Hz, 1H), 8.18 (d, J ¼ 7.3 Hz, 1H), 7.80e7.62 (m, 3H), 7.16e7.07
(m, 5H), 4.04 (d, J ¼ 6.1 Hz, 2H), 3.10 (s, 6H). 13C NMR (125 MHz,
J ¼ 7.4, 1.0 Hz, 1H), 7.66e7.59 (m, 2H), 7.35 (d, J ¼ 7.6 Hz, 1H),
7.09e7.00 (m, 5H), 4.06 (s, 2H), 3.96 (tt, J ¼ 11.3, 3.9 Hz, 1H),
3.67e3.62 (m, 2H), 3.18 (t, J ¼ 12.4 Hz, 2H), 2.90 (s, 3H), 2.38 (d,
J ¼ 14.2 Hz, 2H), 2.20e2.08 (m, 2H). 13C NMR (125 MHz, CD3OD)
DMSO‑d6)
d 137.48, 136.74, 128.81, 128.24, 127.93, 127.56, 127.42,
127.21, 126.98, 124.97, 123.33, 117.88, 45.97, 45.87. ESI-LRMS m/z:
341.2 [M þ H]þ. ESI-HRMS calcd for C19H21N2O2S [M þ H]þ
341.1318, found 341.1319.N-Benzyl-5-((cyclopropylmethyl)amino)
naphthalene-1-sulfonamide hydrochloride (11u).
d
138.40,137.97,137.78,130.91,130.82,129.11,129.03,128.74,128.24,
127.70, 127.11, 125.62, 121.54, 115.66, 54.42, 52.74, 47.70, 43.79,
29.29. ESI-LRMS m/z: 408.1 [M
C
ꢂ
H]-. ESI-HRMS calcd for
To a stirred solution of compound 9c (150 mg, 0.430 mmol) in
23H26N3O2S [M ꢂ H]- 408.1751, found 408.1759.
anhydrous MeOH (8 mL) was added trimethylamine (60
0.430 mmol) at room temperature. After 10 min, cyclo-
propanecarboxaldehyde 19a (32 L, 0.430 mmol) and acetic acid
(25 L, 0.430 mmol) were added to the reaction mixture. Then,
mL,
4.1.34. N-benzyl-5-((1-ethylpiperidin-4-yl)amino)naphthalene-1-
sulfonamide dihydrochloride (11y)
m
m
Compound 11y was prepared in a similar manner as described
sodium cyanoborohydride (30 mg, 0.473 mmol) was added after
0.5 h. After 5 h, TLC showed completion of the reaction. The reac-
tion mixture was concentrated and diluted with water (10 mL),
then extracted with DCM (5 mL x 3). The combined layer was
concentrated under vacuum and purified by silica gel column
chromatography (DCM/MeOH ¼ 50/1e20/1) to afford white solid,
which was subsequently dissolved in 4 N HCl in dioxane (5 mL) and
stirred for 2 h at room temperature. Finally, the reaction mixture
was concentrated to afford compound 11u as a white solid (117 mg,
for compound 11u. Yield: 65%. Mp 192e194 ꢀC. 1H NMR (500 MHz,
CD3OD)
d
8.58 (d, J ¼ 8.7 Hz, 1H), 8.37 (d, J ¼ 8.6 Hz, 1H), 8.27 (dd,
J ¼ 7.3, 1.0 Hz, 1H), 7.71e7.65 (m, 2H), 7.51 (d, J ¼ 7.6 Hz, 1H),
7.09e7.01 (m, 5H), 4.08 (s, 2H), 4.03e3.97 (m, 1H), 3.71 (d,
J ¼ 12.9 Hz, 2H), 3.21 (q, J ¼ 7.3 Hz, 2H), 3.10 (td, J ¼ 13.1, 2.7 Hz, 2H),
2.39 (d, J ¼ 13.9 Hz, 2H), 2.22 (qd, J ¼ 13.1, 3.9 Hz, 2H), 1.38 (t,
J ¼ 7.3 Hz, 3H). 13C NMR (125 MHz, CD3OD)
d 138.36, 135.69, 131.00,
130.93, 130.64, 129.12, 128.75, 128.25, 127.52, 127.42, 126.32, 124.96,
123.67, 118.31, 54.42, 53.30, 51.83, 47.71, 28.71, 9.74. ESI-LRMS m/z:
421.9 [M ꢂ H]-. ESI-HRMS calcd for C24H28N3O2S [M ꢂ H]- 422.1908,
found 422.1917.
yield: 68%). Mp 160e161 ꢀC. 1H NMR (500 MHz, DMSO‑d6)
d 8.52
(dt, J ¼ 8.5,1.1 Hz,1H), 8.47 (t, J ¼ 6.2 Hz,1H), 8.21e8.15 (m,1H), 8.12
(dd, J ¼ 7.4,1.1 Hz,1H), 7.60e7.54 (m, 3H), 7.21e7.10 (m, 5H), 4.00 (d,
J ¼ 6.1 Hz, 2H), 3.19 (d, J ¼ 6.9 Hz, 2H), 1.21e1.14 (m, 1H), 0.54e0.49
4.1.35. 5-((1-Acetylpiperidin-4-yl)amino)-N-benzylnaphthalene-1-
sulfonamide hydrochloride (11z)
(m, 2H), 0.33e0.29 (m, 2H). 13C NMR (125 MHz, DMSO‑d6)
d 137.72,
135.96, 128.79, 128.50, 128.28, 127.99, 127.39, 127.31, 126.97, 124.72,
123.24, 59.73, 45.92, 9.18, 3.91. ESI-LRMS m/z: 365.0 [M ꢂ H]-. ESI-
HRMS calcd for C21H21N2O2S [M ꢂ H]- 365.1329, found 365.1332.
Compound 11z was prepared in a similar manner as described
for compound 11u. Yield: 60%. Mp 162e163 ꢀC. 1H NMR (400 MHz,
CD3OD)
d
8.89 (d, J ¼ 8.0 Hz, 1H), 8.37e8.29 (m, 2H), 7.84e7.74 (m,
3H), 7.05e6.96 (m, 5H), 4.67 (d, J ¼ 13.1 Hz,1H), 4.11 (s, 2H), 3.98 (tt,
J ¼ 11.6, 4.0 Hz, 1H), 3.67e3.64 (m, 1H), 3.23e3.11 (m, 1H), 2.67 (t,
J ¼ 12.2 Hz, 1H), 2.16 (s, 3H), 2.14e2.06 (m, 2H), 1.97e1.71 (m, 2H).
4.1.31. N-benzyl-5-(cyclohexylamino)naphthalene-1-sulfonamide
hydrochloride (11v)
Compound 11v was prepared in a similar manner as described
13C NMR (125 MHz, CD3OD)
d 171.84, 139.16, 138.21, 131.44, 130.87,
for compound 11u. Yield: 68%. Mp 185e187 ꢀC. 1H NMR (500 MHz,
130.84, 129.07, 128.76, 128.50, 128.21, 128.19, 128.13, 127.83, 127.12,
124.58, 60.61, 47.67, 45.68, 41.00, 30.47, 29.79, 21.09. ESI-LRMS m/z:
438.4 [M þ H]þ. ESI-HRMS calcd for C24H26N3O3S [M þ H]þ
438.1846, found 438.1844.
DMSO‑d6)
d
8.61e8.55 (m, 1H), 8.51 (d, J ¼ 8.6 Hz, 1H), 8.45e8.28
(m,1H), 8.15 (d, J ¼ 7.3 Hz,1H), 7.67e7.58 (m, 2H), 7.51e7.31 (m,1H),
7.19e7.04 (m, 5H), 4.03 (d, J ¼ 6.1 Hz, 2H), 3.45 (tt, J ¼ 11.2, 3.8 Hz,
1H), 2.01 (dd, J ¼ 12.8, 3.8 Hz, 2H), 1.77 (dt, J ¼ 13.3, 3.5 Hz, 2H), 1.62
(dt, J ¼ 12.9, 3.5 Hz, 1H), 1.52 (q, J ¼ 10.2 Hz, 2H), 1.29 (q, J ¼ 12.6 Hz,
2H), 1.16 (qt, J ¼ 12.6, 3.4 Hz, 1H). 13C NMR (125 MHz, DMSO‑d6)
4.1.36. 5-((1-Benzoylpiperidin-4-yl)amino)-N-benzylnaphthalene-
1-sulfonamide hydrochloride (11aa)
d
137.61,136.30,128.90,128.77,127.95,127.78,127.49,127.41,126.93,
Compound 11aa was prepared in a similar manner as described
125.65, 124.06, 56.53, 45.93, 30.43, 25.10, 24.37. ESI-LRMS m/z:
395.3 [M þ H]þ. ESI-HRMS calcd for C23H27N2O2S [M þ H]þ
395.1788, found 395.1791.
for compound 11u. Yield: 59%. Mp 258e260 ꢀC. 1H NMR (500 MHz,
DMSO‑d6)
d
8.50 (d, J ¼ 8.6 Hz, 1H), 8.36 (t, J ¼ 6.3 Hz, 1H), 8.07 (d,
J ¼ 7.2 Hz, 1H), 7.89 (d, J ¼ 8.5 Hz, 1H), 7.50e7.38 (m, 6H), 7.23e7.14
(m, 5H), 6.79 (d, J ¼ 7.9 Hz, 1H), 6.10 (d, J ¼ 7.5 Hz, 1H), 4.48 (s, 1H),
3.98 (d, J ¼ 6.2 Hz, 2H), 3.86e3.76 (m, 1H), 3.72e3.58 (m, 1H),
3.30e3.19 (m, 1H), 3.12e2.97 (m, 1H), 2.19e1.94 (m, 2H), 1.63e1.48
4.1.32. N-benzyl-5-(piperidin-4-ylamino)naphthalene-1-
sulfonamide dihydrochloride (11w)
Compound 11w was prepared in a similar manner as described
(m, 2H). 13C NMR (125 MHz, DMSO‑d6)
d 169.00, 143.63, 137.89,
for compound 11u. Yield: 60%. Mp > 250 ꢀC. 1H NMR (500 MHz,
136.34, 135.49, 129.41, 129.09, 128.74, 128.46, 128.21, 128.03, 127.48,
127.40, 126.98, 126.60, 123.92, 121.96, 112.12, 104.85, 49.20, 46.20,
45.91, 40.70, 31.74, 31.00. ESI-LRMS m/z: 498.0 [M ꢂ H]-. ESI-HRMS
calcd for C29H28N3O3S [M ꢂ H]- 498.1857, found 498.1862.
DMSO‑d6)
d
9.24 (d, J ¼ 11.1 Hz, 1H), 9.17e9.07 (m, 1H), 8.58 (d,
J ¼ 8.5 Hz,1H), 8.41 (t, J ¼ 6.2 Hz,1H), 8.07 (d, J ¼ 7.2 Hz,1H), 7.92 (d,
J ¼ 8.5 Hz, 1H), 7.47 (dt, J ¼ 12.1, 8.3 Hz, 2H), 7.25e7.14 (m, 5H), 6.82
(d, J ¼ 7.8 Hz, 1H), 3.98 (d, J ¼ 6.2 Hz, 2H), 3.78 (tt, J ¼ 10.2, 3.6 Hz,
1H), 3.34 (dt, J ¼ 12.8, 3.3 Hz, 2H), 3.04 (q, J ¼ 11.6 Hz, 2H), 2.15 (dd,
J ¼ 14.2, 3.8 Hz, 2H), 1.91e1.79 (m, 2H). 13C NMR (125 MHz,
4.1.37. Benzyl 4-((5-(N-benzylsulfamoyl)naphthalen-1-yl)amino)
piperidine-1-carboxylate hydrochloride (11 ab)
DMSO‑d6)
d
143.12, 137.89, 135.55, 129.07, 128.62, 128.22, 128.02,
Compound 11 ab was prepared in a similar manner as described
127.77, 127.41, 126.98, 124.06, 122.08, 112.79, 105.43, 47.22, 45.91,
for compound 11u. Yield: 62%. Mp 145e147 ꢀC. 1H NMR (400 MHz,
42.15, 27.90. ESI-LRMS m/z: 396.3 [M þ H]þ. ESI-HRMS calcd for
DMSO‑d6)
d
8.52 (d, J ¼ 8.6 Hz,1H), 8.48 (d, J ¼ 6.1 Hz,1H), 8.16e8.14
C
22H26N3O2S [M þ H]þ 396.1740, found 396.1744.
(m, 1H), 8.11 (d, J ¼ 7.2 Hz, 1H), 7.55 (td, J ¼ 8.3, 3.5 Hz, 2H),
7.41e7.35 (m, 4H), 7.35e7.28 (m, 1H), 7.21e7.11 (m, 6H), 5.10 (s, 2H),
4.07 (d, J ¼ 13.4 Hz, 2H), 4.00 (d, J ¼ 6.0 Hz, 2H), 3.73 (tt, J ¼ 10.2,
3.4 Hz, 1H), 2.98 (s, 2H), 2.02 (d, J ¼ 10.6 Hz, 2H), 1.60 (q, J ¼ 11.4 Hz,
4.1.33. N-benzyl-5-((1-methylpiperidin-4-yl)amino)naphthalene-
1-sulfonamide dihydrochloride (11x)
Compound 11x was prepared in a similar manner as described
2H). 13C NMR (125 MHz, DMSO‑d6)
d 154.41, 137.77, 137.01, 135.93,
for compound 11u. Yield: 66%. Mp 159e160 ꢀC. 1H NMR (500 MHz,
129.01, 128.51, 128.45, 128.25, 128.01, 127.84, 127.52, 127.42, 126.99,
CD3OD)
d
8.44 (d, J ¼ 8.7 Hz, 1H), 8.37 (d, J ¼ 8.5 Hz, 1H), 8.23 (dd,
124.81, 123.08, 66.20, 51.77, 45.92, 42.52, 30.28. ESI-LRMS m/z:
16