10.1002/cmdc.201700270
ChemMedChem
FULL PAPER
40.4, 32.9, 28.8; HRMS (ESI-TOF) m/z calculated for C20H21N2O5S [M-H]-
401.1177, found 401.1174; LC-MS m/z: 403.1 [M+H]+, purity >95% (ELSD).
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-
nitrobenzenesulfonamide (14b) (40.0 mg, 0.100 mmol) was dissolved in
EtOAc:DMF (4:1, 2.5 mL) and stirred at room temperature for 1 h under
hydrogen atmosphere with 10% palladium on carbon (5 mol%) catalyst.
Filtration through celite and purification by MPLC afforded the titled
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-(7-methoxy
-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-
yl)ethyl)benzenesulfonamide (5b)
1
compound as a white solid (16 mg, 43%): H NMR (600 MHz, DMSO-d6)
10.08 (br s, 1H), 7.95 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 6.59
(d, J = 8.8 Hz, 2H), 6.05 (s, 2H), 2.77 (t, J = 7.5 Hz, 4H), 2.55 (t, J = 7.5
Hz, 4H), 1.92 (p, J = 7.5 Hz, 4H); 13C NMR (151 MHz, DMSO-d6) 153.0,
149.4, 142.9, 136.8, 129.2, 128.9, 124.9, 117.6, 112.1, 32.3, 30.0, 24.9;
HRMS (ESI-TOF) m/z calculated for C19H20N3O3S [M-H]- 370.1231, found
370.1225; LC-MS m/z 372.1 [M+H]+, purity >95% (ELSD).
4-(2-(7-Methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-
yl)ethyl)benzene sulfonamide (5a) (111 mg, 0.276 mmol) was treated as
per general method A to afford the titled compound as a white solid (85
mg, 52%): 1H NMR (600 MHz, DMSO-d6) 10.72 (br s, 1H), 7.91 (s, 1H),
7.80 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H),
7.39 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.7, 2.9 Hz, 1H), 6.88 (s, 1H), 4.13
(t, J = 7.5 Hz, 2H), 3.83 (s, 3H), 2.93 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.4 Hz,
4H), 2.55 (t, J = 7.4 Hz, 4H), 1.90 (p, J = 7.4 Hz, 4H), 1.42 (s, 6H); 13C
NMR (151 MHz, DMSO) 176.3, 163.1, 158.0, 150.1, 143.5, 142.8, 137.1,
136.9, 129.1, 129.0, 127.4, 127.1, 125.6, 124.1, 121.4, 117.4, 110.4, 55.3,
42.3, 40.3, 33.0, 32.3, 30.0, 28.8, 24.9; HRMS (ESI-TOF) m/z calculated
for C33H34N3O6S [M-H]- 600.2174, found 600.2183; LC-MS m/z 602.4
[M+H]+, purity >95% (ELSD).
5-Methyl-N-(4-sulfamoylphenethyl)pyrazine-2-carboxamide (10a)
N-(4-(N-(Cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5-methylpyrazine-2-
carboxamide (11) (250 mg, 0.56 mmol) dissolved in pyridine (8 mL) was
treated with phthalic anhydride (83 mg, 0.56 mmol) and DMAP (10 mg,
0.082 mmol), then heated at reflux for 5 h under N2 atmosphere. The
reaction mixture was purified by MPLC affording the titled compound as
an amorphous white solid (113 mg, 63%): 1H NMR (600 MHz, DMSO-d6)
9.03 (d, J = 1.4 Hz, 1H), 8.96 (t, J = 6.0 Hz, 1H), 8.61 (m, 1H), 7.73 (d, J
= 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.30 (s, 2H), 3.57 (dt, J = 7.3, 6.0
Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H), 2.58 (s, 3H); 13C NMR (151 MHz, DMSO-
d6) 162.8, 156.7, 143.4, 142.7, 142.3, 141.9, 141.9, 129.0, 125.6, 39.9,
34.6, 21.2; HRMS (ESI-TOF) m/z calculated for C14H17N4O3S [M+H]+
321.1016, found 321.1029; LC-MS m/z 321.0 [M+H]+, purity >95% (ELSD).
5-Methyl-N-(4-sulfamoylphenethyl)isoxazole-3-carboxamide (6a)
5-Methylisoxazole-3-carboxylic acid (150 mg, 1.18 mmol) dissolved in
toluene (2 mL) was treated with DMF (1 drop) and thionyl chloride (1.42
mmol, 103 L) then heated to reflux for 5 h. The solvent was removed in
vacuo to afford crude 5-methylisoxazole-3-carbonyl chloride (155 mg, 1.06
mmol) as a brown oil. The crude acid chloride was dissolved in THF (4 mL),
treated with Et3N (155 L, 1.06 mmol) and stirred for 5 min, before adding
4-(2-aminoethyl)benzenesulfonamide (220 mg, 1.10 mmol). The reaction
was stirred at room temperature for 15 h under N2 atmosphere. The
reaction was concentrated in vacuo and purified by MPLC, affording the
titled compound as an amorphous white solid (205 mg, 62%): 1H NMR
(600 MHz, DMSO-d6) 8.79 (t, J = 5.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H),
7.41 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 6.50 (q, J = 0.8 Hz, 1H), 3.49 (m,
2H), 2.91 (t, J = 7.2 Hz, 2H), 2.45 (d, J = 0.8 Hz, 3H); 13C NMR (151 MHz,
DMSO-d6) 171.0, 158.8, 158.5, 143.3, 142.0, 129.0, 125. 6, 101.1, 39.8,
34.3, 11.7; HRMS (ESI-TOF) m/z calculated for C13H14N3O4S [M-H]-
308.0711, found 308.0708; LC-MS m/z 308.0 [M+H]+, purity >99% (ELSD).
N-(4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)
phenethyl)-5-methylpyrazine-2-carboxamide (10b)
5-Methyl-N-(4-sulfamoylphenethyl)pyrazine-2-carboxamide (10a) (100 mg,
0.312 mmol) was treated as per general method A to afford a crude white
solid (72 mg). Further HPLC purification using a 0.1% formic acid(aq)
/
CH3CN mobile phase and 10% DMSO / CH3CN loading solvent, whereby
fractions were neutralised with 10 mM NH4HCO3(aq), yielded a white solid
(14 mg, 9%): 1H NMR (600 MHz, DMSO-d6) 9.03 (d, J = 1.0 Hz, 1H),
8.93 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H),
7.36 (d, J = 8.1 Hz, 2H), 6.84 (s, 1H), 6.53 (br s, 1H), 3.58 – 3.51 (m, 2H),
2.93 (t, J = 7.3 Hz, 2H), 2.74 (t, J = 7.3 Hz, 4H), 2.58 (s, 3H), 2.55 (t, J =
7.3 Hz, 4H), 1.88 (p, J = 7.4 Hz, 4H); 13C NMR (151 MHz, DMSO-d6)
162.8, 156.7, 147.7, 143.0, 142.7, 142.5, 142.3, 141.9, 141.6, 136.7, 128.4,
126.8, 125.6, 116.7, 39.9, 34.6, 32.4, 30.1, 24.9, 21.2; HRMS (ESI-TOF)
m/z calculated for C27H30N5O4S [M+H]+ 520.2020, found 520.2030; LC-MS
m/z 520.1 [M+H]+, purity >95% (ELSD).
N-(4-(N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)
phenethyl)-5-methylisoxazole-3-carboxamide (6b)
5-Methyl-N-(4-sulfamoylphenethyl) isoxazole-3-carboxamide (6a) (14 mg,
0.044 mmol) was treated as per general method A. Further MPLC
purification used 0.05% formic acid(aq) / 0.05% formic acid in CH3CN
gradient elution. Lyophilisation of the appropriate fractions afforded the
titled compound as a white solid (14 mg, 62%): 1H NMR (600 MHz, DMSO-
d6) 10.73 (br s, 1H), 8.81 (t, J = 5.8 Hz, 1H) 8.09 (s, 1H), 7.86 (d, J = 8.2
Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 6.49 (s, 1H), 3.49 (m, 2H),
2.93 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 7.2 Hz, 4H), 2.52 (m, 4H), 2.44 (s, 3H),
1.90 (p, J = 7.2 Hz, 4H); 13C NMR (151 MHz, DMSO-d6) 171.0, 158.7,
158.5, 148.9, 145.0, 142.9, 137.8, 137.1, 129.1, 128.5, 127.2, 117.9, 101.1,
39. 9, 34.4, 32.3, 29.9, 24.9, 11.70; HRMS (ESI-TOF) m/z calculated for
C26H27N4O5S [M-H]- 507.1708, found 507.1709; LC-MS m/z 509.4 [M+H]+,
purity >95% (ELSD).
N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-4-
nitrobenzenesulfonamide (14b)
4-Nitrobenzenesulfonyl chloride (300 mg, 1.35 mmol) dissolved in acetone
(1 mL) was added drop-wise to NH4HCO3(aq) (450 mg, 5.42 mmol, 4 mL)
and stirred at room temperature for 2 h. The reaction mixture was then
acidified with 1 M HCl (to pH ~2) and extracted with EtOAc (3 x 10 mL).
The organic layers were combined, washed with brine (20 mL), water (20
mL) and dried (MgSO4). Solvent was removed in vacuo to afford 4-
nitrobenzenesulfonamide as a pale orange solid (157 mg, 57%): 1H NMR
(600 MHz, DMSO-d6) 8.42 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 9.0 Hz, 2H,
7.74 (s, 2H); HRMS (ESI-TOF) m/z calculated for C6H5N2O4S [M-H]-
200.9976, found 200.9984; LC-MS m/z 200.9 [M-H]-, purity >99% (ELSD).
4-Nitrobenzenesulfonamide (124 mg, 0.613 mmol) was treated as per
general method A to afford the titled compound as a pale yellow solid (148
4-Acetyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)
benzenesulfonamide (7b)
4-Acetylbenzenesulfonamide (7a) (100 mg, 0.50 mmol) was treated as per
general method A to afford the titled compound as a white solid (31 mg,
1
1
mg, 60%): H NMR (600 MHz, DMSO-d6) 10.00 (br s, 1H), 8.21 (d, J =
16%): H NMR (600 MHz, DMSO-d6) 11.03 (br s, 1H), 8.08 (d, J = 8.5
9.0 Hz, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 6.75 (s, 1H), 2.73 (t, J
= 7.4 Hz, 4H), 2.61 (t, J = 7.4 Hz, 4H), 1.87 (p, J = 7.4 Hz, 4H); 13C NMR
(151 MHz, DMSO-d6) 158.0, 153.8, 147.4, 141.9, 136.4, 132.5, 127.8,
122.8, 115.4, 32.5, 30.4, 25.0; HRMS (ESI-TOF) m/z calculated for
C19H18N3O5S [M-H]- 400.0973, found 400.0979; LC-MS m/z 402.1 [M+H]+,
purity >95% (ELSD).
Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 7.07 (br s, 1H), 6.87 (s, 1H), 2.75 (t, J =
7.4 Hz, 4H), 2.62 (s, 3H), 2.56 (t, J = 7.4 Hz, 4H), 1.90 (p, J = 7.4 Hz, 4H);
13C NMR (151 MHz, DMSO-d6) 197.3, 151.8, 142.6, 138.9, 136.9, 129.7,
128.2, 127.2, 117.1, 32.4, 30.1, 26.9, 24.9; HRMS (ESI-TOF) m/z
calculated for C21H21N2O4S [M-H]- 397.1228, found 397.1225; LC-MS m/z
399.1 [M+H]+, purity >95% (ELSD).
4-Amino-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)
benzenesulfonamide (8b)
8
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