M.A. Khanfar et al. / European Journal of Medicinal Chemistry 76 (2014) 414e426
423
DMSO)
d
38.4, 55.3, 105.7, 114.1, 119.0, 120.4, 126.7, 127.9, 129.6,
146.0, 164.8. HRMS LC-TOF (M þ Hþ) calcd for C22H19N3O5S2
130.6, 132.4, 133.2, 133.3, 135.1, 136.5, 143.1, 158.3, 164.6. HRMS LC-
470.0844, found 470.0840.
TOF (M þ Hþ) calcd for C22H19N3O4S 422.1175, found 422.1167.
4.2.14. N-(4-chlorophenyl)-3-(N-methyl-N-(4-(methylsulfonyl)
phenyl)sulfamoyl)benzamide (117)
4.2.9. 3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-N-(4-
chlorophenyl)benzamide (102)
Compound 117 was prepared according to procedure C from 6-
chloroaniline (18.9 mg, 0.149 mmol) and 16 (50 mg, 0.135 mmol) to
Compound 102 was prepared according to procedure C from 4-
chloroaniline (21.6 mg, 0.169 mmol) and 14 (50 mg, 0.150 mmol) to
afford 56.9 mg of 117 (88%). 1H NMR (500 MHz, CDCl3)
d 3.08 (s, 3H),
afford 59.1 mg of 102 (89%). 1H NMR (500 MHz, CDCl3)
d 2.57 (s, 3H),
3.26 (s, 3H), 7.33e7.37 (m, 4H), 7.60e7.65 (m, 4H), 7.89 (d,
3.20 (s, 3H), 7.19 (d, J ¼ 8.7 Hz, 2H), 7.31 (d, J ¼ 8.7 Hz, 2H), 7.56e7.60
J ¼ 8.8 Hz, 2H), 8.06 (s, 1H), 8.15 (dd, J ¼ 1.6, 7.3 Hz, 1H). 13C NMR
(m, 4H), 7.88 (d, J ¼ 8.6 Hz, 2H), 8.01 (s, 1H), 8.13 (dt, J ¼ 1.9, 6.6 Hz,
(126 MHz, CDCl3) d 37.9, 44.4, 121.6, 121.7, 125.9, 126.5, 128.5, 129.2,
1H), 8.27 (s, 1H). 13C NMR (126 MHz, CDCl3)
d 26.7, 37.9, 121.7, 125.6,
129.9, 130.1, 130.5, 132.4, 136.1, 136.8, 138.9, 146.0, 163.9. HRMS LC-
125.9, 129.1, 129.2, 129.7, 130.1, 130.5, 132.4, 135.6, 135.8, 136.0,
TOF (M þ Hþ) calcd for C21H19ClN2O5S2 479.0502, found 479.0503.
136.8, 145.1, 164.0, 197.1. HRMS LC-TOF (M þ Hþ) calcd for
C
22H19ClN2O4S 443.0832, found 443.0826.
4.2.15. 3-(N-(5-chloropyridin-2-yl)-N-methylsulfamoyl)-N-(4-
cyanophenyl)benzamide (124)
4.2.10. 3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-N-(5-
chloropyridin-2-yl)benzamide (103)
Compound 103 was prepared according to procedure C from 2-
amino-5-chloropyridine (21.7 mg, 0.169 mmol) and 14 (50 mg,
0.150 mmol) to afford 45.8 mg of 103 (67%). 1H NMR (500 MHz,
Compound 124 was prepared according to procedure C to afford
46 mg of white powder (70%). 1H NMR (500 MHz, CDCl3)
d 3.25 (s,
3H), 7.57e7.62 (m, 2H), 7.67e7.71 (m, 4H), 7.82 (d, J ¼ 8.8 Hz, 2H),
8.13e8.14 (m, 2H), 8.22 (dd, J ¼ 0.5, 2.6 Hz,1H), 8.36 (s,1H). 13C NMR
(126 MHz, CDCl3)
d 36.0, 107.8, 120.2, 121.7, 125.9, 129.8, 129.9,
CDCl3)
d
2.61 (s, 3H), 3.25 (s, 3H), 7.25 (d, J ¼ 8.7 Hz, 2H), 7.63 (t,
130.9,132.4,133.4,135.2, 137.7,137.8,141.6,146.8,151.5,164.1. HRMS
J ¼ 7.8 Hz, 1H), 7.71 (dt, J ¼ 1.3, 8.0 Hz, 1H), 7.74 (dd, J ¼ 2.6, 8.9 Hz,
1H), 7.94 (d, J ¼ 8.7 Hz, 2H), 8.01 (t, J ¼ 1.6 Hz, 1H), 8.15 (dt, J ¼ 1.4,
7.9 Hz, 1H), 8.25 (d, J ¼ 2.3 Hz, 1H), 8.31 (d, J ¼ 8.9 Hz, 1H), 8.44 (brs,
LCQ (M þ Hþ) 427.0550.
1H). 13C NMR (126 MHz, CDCl3)
d 26.7, 37.9,114.8,125.8,126.0,127.5,
4.2.16. N-(4-cyanophenyl)-3-(N-(4-(1-hydroxyethyl)phenyl)-N-
methylsulfamoyl)benzamide (126)
129.3,129.8,131.0, 131.9, 134.9, 135.7, 137.1, 138.2, 145.2, 146.7, 149.2,
163.6, 196.9. HRMS LC-TOF (M þ Hþ) calcd for C21H18ClN3O4S
444.0785, found 444.0782.
Compound 126 was prepared according to procedure K from
103 (25 mg, 0.058 mmol) to afford 23.1 mg of 126 (93%). 1H NMR
(500 MHz, CDCl3)
d
1.46 (d, J ¼ 6.3 Hz, 3H), 3.20 (s, 3H), 4.89 (q,
4.2.11. 3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-N-(4-
cyanophenyl)benzamide (106)
Compound 106 was prepared according to procedure C from 4-
aminobenzonitrile (20.2 mg, 0.169 mmol) and 14 (50 mg,
0.150 mmol) to afford 47.5 mg of 106 (73%). 1H NMR (500 MHz,
J ¼ 6.3 Hz, 1H), 7.05 (d, J ¼ 8.5 Hz, 2H), 7.32 (d, J ¼ 8.5 Hz, 2H), 7.64e
7.68 (m, 3H), 7.75 (d, J ¼ 7.9 Hz, 1H), 7.81 (d, J ¼ 8.7 Hz, 2H), 7.93 (t,
J ¼ 1.5 Hz, 1H), 8.18 (d, J ¼ 7.8 Hz, 1H), 8.24 (s, 1H). 13C NMR
(126 MHz, CDCl3)
d 25.4, 38.4, 69.7, 107.9, 118.7, 120.2, 125.7, 126.2,
126.8, 129.8, 131.1, 132.4, 133.4, 135.0, 137.2, 140.0, 141.6, 145.6,
164.2. HRMS LC-TOF (M þ Naþ) calcd for C23H21N3O4S 458.1150,
found 458.1141.
CDCl3)
d
2.60 (s, 3H), 3.25 (s, 3H), 7.22 (d, J ¼ 8.7 Hz, 2H), 7.61e7.69
(m, 4H), 7.80 (d, J ¼ 8.8 Hz, 2H), 7.91 (d, J ¼ 8.7 Hz, 2H), 8.02 (s, 1H),
8.16 (dt, J ¼ 1.6, 7.4 Hz, 1H), 8.24 (s, 1H). 13C NMR (126 MHz, CDCl3)
d
26.7, 38.0,108.0,118.7, 120.2,125.6,126.0,129.3,130.0,131.0,132.5,
4.2.17. 3-(N-(4-bromophenyl)-N-methylsulfamoyl)-N-(4-chloro-2-
fluorophenyl)-N-methylbenzamide (165)
133.4, 135.3, 135.7, 137.1, 141.5, 145.1, 164.1, 197.1. HRMS LC-TOF
(M þ Hþ) calcd for C23H19N3O4S 434.1175, found 434.1169.
Compound 165 was prepared according to procedure C from 4-
chloro-2-fluoro-N-methylaniline (34.3 mg, 0.29 mmol) and 11
(80.8 mg, 0.26 mmol) to afford 89.6 mg of 165 as white solid (84%).
4.2.12. N-(4-acetylphenyl)-3-(N-(4-acetylphenyl)-N-
methylsulfamoyl)benzamide (109)
Compound 109 was prepared according to procedure C from 6-
amino-3-pyridinecarbonitrile (20.1 mg, 0.169 mmol) and 10
(50 mg, 0.154 mmol) to afford 60.8 mg of 109 (90%). 1H NMR
1H NMR (500 MHz, CDCl3)
d
3.00 (s, 3H), 3.41 (s, 3H), 6.88 (d, J ¼ 5.0
Hz 2H), 7.06 (m, 3H), 7.31 (m, 2H), 7.41 (d, J ¼ 5.0 Hz, 1H), 7.43 (d,
J ¼ 5.0 Hz, 1H), 7.57 (s, 1H), 7.62 (s, 1H). 13C NMR (126 MHz, CDCl3)
d
37.6, 37.9, 117.6 (d, J ¼ 23.4 Hz), 121.2, 125.5 (d, J ¼ 3.7 Hz), 127.1,
(500 MHz, CDCl3)
d 2.48 (s, 3H), 2.49 (s, 3H), 3.15 (s, 3H), 7.14 (d,
128.0, 128.8, 129.2, 130.0, 132.2, 132.3, 134.5 (d, J ¼ 9.5 Hz), 136.1,
136.2, 140.1, 156.4 (d, J ¼ 253.5 Hz), 169.5. HRMS (ESI) (M þ Hþ)
calcd for C21H18BrClFN2O3S 510.9894, found 510.9867.
J ¼ 7.1 Hz, 2H), 7.48e7.49 (m, 2H), 7.72 (d, J ¼ 7.3 Hz, 2H), 7.80 (d,
J ¼ 7.1 Hz, 2H), 7.87 (d, J ¼ 7.3 Hz, 2H), 8.08e8.10 (m, 2H). 13C NMR
(126 MHz, CDCl3)
d 30.3, 30.5, 41.8, 123.8, 129.8, 130.5, 133.2, 133.4,
133.6, 134.4, 136.4, 136.8, 139.3, 139.8, 140.7, 146.8, 149.3, 169.1,
201.9, 202.1. HRMS LC-TOF (M þ Hþ) calcd for C24H22N2O5S
451.1328, found 451.1327.
4.2.18. N-(4-bromo-2-fluorophenyl)-3-(N-(4-bromophenyl)-N-
methylsulfamoyl)-N-methylbenzamide (166)
Compound 166 was prepared according to procedure C from 4-
bromo-2-fluoro-N-methylaniline (34.3 mg, 0.29 mmol) and 11
(80.8 mg, 0.26 mmol) to afford 89.6 mg of 166 as white solid (84%).
4.2.13. N-(4-cyanophenyl)-3-(N-methyl-N-(4-(methylsulfonyl)
phenyl)sulfamoyl)benzamide (115)
Compound 115 was prepared according to procedure C from 4-
aminobenzonitrile (16.0 mg, 0.149 mmol) and 16 (50 mg,
0.135 mmol) to afford 41.8 mg of 117 (66%). 1H NMR (500 MHz,
1H NMR (500 MHz, CDCl3)
d
3.0 (s, 3H), 3.40 (s, 3H), 6.88 (d, J ¼ 8.2
Hz, 2H), 7.06e6.99 (t, J ¼ 7.7 Hz, 1H), 7.22 (d, J ¼ 8.3 Hz, 2H), 7.35e
7.29 (m, 1H), 7.44e7.40 (m, 2H), 7.60e7.55 (m, 1H), 7.62 (s, 1H). 13
NMR (126 MHz, CDCl3)
C
CDCl3)
d
3.09 (s, 3H), 3.28 (s, 3H), 7.38 (d, J ¼ 8.5 Hz, 2H), 7.64e7.68
d
37.5, 37.9, 120.5 (d, J ¼ 23.1 Hz), 121.8 (d,
(m, 4H), 7.88e7.92 (m, 4H), 8.17 (s, 1H), 8.21 (d, J ¼ 6.9 Hz, 1H). 13
C
J ¼ 8.8 Hz), 127.0, 128.4 (d, J ¼ 3.9 Hz), 128.8, 129.2, 130.3, 132.1,
132.3, 136.0, 136.2, 140.1, 156.9 (d, J ¼ 254.7 Hz), 169.0. HRMS (ESI)
[MꢁMe]ꢁ calcd for C20H14Br2FN2O3S: 540.9055, found 540.9086.
NMR (126 MHz, CDCl3)
d 37.8, 44.3, 107.2, 118.9, 120.4, 120.5, 126.4,
126.5, 128.4, 129.7, 130.5, 132.8, 133.2, 135.7, 136.6, 138.6, 142.4,