Journal of Medicinal Chemistry
Article
1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.04 (dd, J = 5.2, 4.0 Hz, 1H),
3.78 (s, 2H). LC-MS (ESI−) 378.00 (M − H)−. HRMS (ESI−) m/z
calculated for C16H12NO4S3 (M − H)− 377.9934, found 377.9937.
2-(1-Hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)-
benzoic Acid (24). This compound was prepared using the procedure
described for 15a except using thiosalicylic acid (15 mg, 0.1 mmol).
The title compound 24 (19 mg, 99%) was obtained as a white solid;
mp 215 °C (dec.). HPLC 91% (Rt = 18.9 min, 40% CH3CN in 0.1%
127.57, 127.48, 126.48, 126.25, 125.23, 124.13, 123.16, 44.22, 34.18,
26.83, 26.12. LC-MS (ESI+) 481.15 (M + H)+. HRMS (ESI+) m/z
calculated for C24H25N4O3S2 (M + H)+ 481.1363, found 481.1371.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-4-
phenoxybenzenesulfonamide (29). This compound was prepared
using the procedure described for 15d except using 13d (78 mg, 0.2
mmol) and 1H-1,2,4-triazole-3-thiol (20 mg, 0.2 mmol). The title
compound 29 (36 mg, 56.5%, via 2 steps) was obtained as an off-white
solid; mp 176.1 °C (dec.). HPLC 99% (Rt = 23.2 min, 40% CH3CN in
1
TFA water, 40 min). H NMR (400 MHz, DMSO-d6) δ 13.15 (br s,
1
1H), 10.09 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H),
7.92 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.58−7.50 (m, 2H),
7.34−7.31 (m, 2H), 7.17 (t, 7.2 Hz, 1H), 6.91 (s, 2H), 6.47 (d, J = 8.8
Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 168.15, 156.08, 141.87,
140.39, 133.88, 133.34, 133.21, 133.17, 132.65, 131.78, 128.38, 128.17,
126.70, 126.58, 126.18, 125.15, 125.06, 124.21, 123.69, 109.66, 104.98.
LC-MS (ESI+) 475.05 (M + NH4)+. HRMS (ESI+) m/z calculated for
C21H15NO5S3Na (M + Na)+ 480.0005, found 479.9992.
0.1% TFA water, 40 min). H NMR (400 MHz, DMSO-d6) δ 10.12
(br s, 1H, disappeared on D2O shake), 9.78 (s, 1H, disappeared on
D2O shake), 8.53 (br s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.1
Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.46−7.35 (m, 4H), 7.18−7.14 (m,
1H), 6.95 (appd, J = 7.7 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.82 (br s,
1H). 13C NMR (100 MHz, DMSO-d6) δ 160.92, 155.92, 152.67,
134.42, 132.11, 130.99, 130.01, 129.74, 127.56, 126.53, 126.29, 125.28,
125.13, 124.15, 123.18, 120.23, 118.60, 104.99. LC-MS (ESI+) 491.09
(M + H)+. HRMS (ESI+) m/z calculated for C24H19N4O4S2 (M + H)+
491.0842, found 491.0847.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-3,4-
dichlorobenzenesulfonamide (25). This compound was prepared
using the procedure described for 15d except using 13b (82 mg, 0.2
mmol) and 1H-1,2,4-triazole-3-thiol (24 mg, 0.24 mmol). The title
compound 25 (23 mg, 91.3%, via 2 steps) was obtained as a white
solid. HPLC 98% (Rt = 21.0 min, 40% CH3CN in 0.1% TFA water, 40
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-4′-
(trifluoromethyl)biphenyl-4-sulfonamide (30). This compound was
prepared using the procedure described for 15d except using 13l (95
mg, 0.2 mmol) and 1H-1,2,4-triazole-3-thiol (20 mg, 0.2 mmol). The
title compound 30 (31 mg, 79.2%, via 2 steps) was obtained as an off-
white solid; mp 193.8 °C (dec.). HPLC 95% (Rt = 13.7 min, 50%
1
min); mp 154.8 °C (dec.). H NMR (400 MHz, DMSO-d6) δ 10.17
(br s, 1H), 9.95 (s, 1H), 8.55 (br s, 1H), 8.145 (d, J = 7.6 Hz, 1H),
7.91 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.68−7.58 (m, 4H),
7.50−7.39 (m, 5H), 6.94 (br s, 1H). 13C NMR (100 MHz, DMSO-d6)
δ 152.68, 144.69, 139.25, 139.08, 132.05, 129.79, 129.39, 129.18,
128.11, 127.77, 127.70, 127.59, 126.58, 126.30, 125.15, 124.15, 123.19.
LC-MS (ESI+) 475.09 (M + H)+. HRMS (ESI+) m/z calculated for
C24H19N4O3S2 (M + H)+ 475.0893, found 475.0898.
1
CH3CN in 0.1% TFA water, 40 min). H NMR (400 MHz, DMSO-
d6) δ 10.18 (br s, 1H), 9.97 (s, 1H), 8.48 (br s, 1H), 8.12 (d, J = 7.9
Hz, 1H), 7.90−7.79 (m, 5H), 7.76 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8
Hz, 2H), 7.44−7.41 (m 2H), 6.86 (s, 1H). 19F NMR (376 MHz,
DMSO-d6) δ −61.44 (s). LC-MS (ESI+) 543.08 (M + H)+. HRMS
(ESI + ve) m/z calculated for C25H18F3N4O3S2 (M + H)+ 543.0767,
found 543.0781.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-5-
phenylthiophene-2-sulfonamide (26). This compound was prepared
using the procedure described for 15d except using 13c (83 mg, 0.2
mmol) and 1H-1,2,4-triazole-3-thiol (20 mg, 0.2 mmol). The title
compound 26 (12 mg, 43.0%, via 2 steps) was obtained as a gray solid;
mp 172.9 °C (dec.). HPLC 95% (Rt = 20.1 min, 40% CH3CN in 0.1%
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-5-
(phenylsulfonyl)thiophene-2-sulfonamide (31). This compound was
prepared using the procedure described for 15d except using N-(3-
chloro-4-oxonaphthalen-1(4H)-ylidene)-5-(phenylsulfonyl)thiophene-
2-sulfonamide (13m) (96 mg, 0.2 mmol) and 1H-1,2,4-triazole-3-thiol
(20 mg, 0.2 mmol). The title compound 31 (36 mg, 68.9%, via 2
steps) was obtained as an off-white solid; mp 153.3 °C (dec.). HPLC
1
TFA water, 40 min). H NMR (400 MHz, DMSO-d6) δ 10.17 (br s,
2H), 8.52 (br s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz,
1H), 7.62 (appd, J = 7.2 Hz, 2H), 7.50−7.39 (m, 6H), 7.29 (d, J = 4.0
Hz, 1H), 7.04 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 152.94,
150.22, 139.29, 134.02, 132.78, 132.25, 130.04, 129.82, 129.73, 127.73,
126.66, 126.58, 126.31, 124.83, 124.48, 124.03, 123.23, 111.15. LC-MS
(ESI+) 481.05 (M + H)+. HRMS (ESI+) m/z calculated for
C22H17N4O3S3 (M + H)+ 481.0457, found 481.0456.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-4′-
fluorobiphenyl-4-sulfonamide (27). This compound was prepared
using the procedure described for 15d except using 13f (85 mg, 0.2
mmol) and 1H-1,2,4-triazole-3-thiol (20 mg, 0.2 mmol). The title
compound 27 (29 mg, 38.1%, via 2 steps) was obtained as an off-white
solid; mp 194.1 °C (dec.). HPLC 97% (Rt = 24.2 min, 40% CH3CN in
0.1% TFA water, 40 min). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s,
1H), 8.51 (br s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.0 Hz,
1H), 7.70−7.67 (m, 4H), 7.61 (d, J = 8.6 Hz, 2H), 7.45−7.42 (m,
2H), 7.30 (t, J = 8.8 Hz, 2H), 6.88 (br s, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 163.12 (d, J = 244.3 Hz), 145.75, 143.61, 139.26, 135.56,
129.84 (d, J = 8.3 Hz), 128.12, 127.72, 127.54, 126.56, 126.29, 125.04,
124.14, 123.18, 116.64 (d, J = 21.4 Hz). 19F NMR (376 MHz, CDCl3)
δ −114.28 (m). LC-MS (ESI+) 493.09 (M + H)+.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-4-cy-
clohexylbenzenesulfonamide (28). This compound was prepared
using the procedure described for 15d except using 13h (83 mg, 0.2
mmol) and 1H-1,2,4-triazole-3-thiol (20 mg, 0.2 mmol). The title
compound 28 (40 mg, 68.0%, via 2 steps) was obtained as an off-white
solid; mp 154.7 °C (dec.). HPLC 95% (Rt = 14.6 min, 50% CH3CN in
0.1% TFA water 40 min). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (br
s, 1H), 9.77 (s, 1H), 8.59 (br s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.84 (d,
J = 8.4 Hz, 1H), 7.48−7.39 (m, 4H), 7.24 (d, J = 8.4, 2H), 6.84 (br s,
1H), 1.76−1.67 (m, 5H), 1.35−1.30 (m, 5H), 1.25−1.20 (m, 1H). 13C
NMR (100 MHz, DMSO-d6) δ 153.21, 137.76, 132.17, 129.70, 127.86,
1
98% (Rt = 11.5 min, 40% CH3CN in 0.1% TFA water 40 min). H
NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 10.33 (br s, 1H), 8.46
(br s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.74 (d, J
= 7.6 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 3H), 7.40
(t, J = 7.2 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H),
6.99 (s, 1H), approximately 5% baseline impurity was observed. 13C
NMR (100 MHz, DMSO-d6) δ 153.26, 148.25, 147.60, 145.27, 140.93,
140.66, 135.23, 134.43, 133.19, 131.81, 130.76, 130.38, 127.87, 127.70,
126.71, 126.21, 123.81, 123.32, 123.24. LC-MS (ESI+) 545.00 (M +
H)+. HRMS (ESI+) m/z calculated for C22H17N4O5S4 (M + H)+
545.0076, found 545.0096.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-1-
(phenylsulfonyl)-1H-pyrrole-3-sulfonamide (32). This compound
was prepared using the procedure described for 15d except using N-
(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-1-(phenylsulfonyl)-1H-
pyrrole-3-sulfonamide (13n) (92 mg, 0.2 mmol) and 1H-1,2,4-
triazole-3-thiol (20 mg, 0.2 mmol). The title compound 32 (34 mg,
75.2%, via 2 steps) was obtained as an off-white solid; mp 157.1 °C
(dec.). HPLC 99.8% (Rt = 9.8 min, 50% CH3CN in 0.1% TFA water
40 min). 1H NMR (400 MHz, DMSO-d6) δ 10.19 (br s, 1H), 9.81 (s,
1H), 8.47 (br s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 7.5 Hz,
2H), 7.81 (d, J = 8.5 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.9
Hz, 2H), 7.53−7.52 (m, 1H), 7.44−7.36 (m, 3H), 7.30 (t, J = 7.3 Hz,
1H), 6.79 (s, 1H), 6.36 (dd, J = 3.3, 1.6 Hz, 1H), approximately 5%
baseline impurity was observed. 13C NMR (100 MHz, DMSO-d6) δ
171.01, 152.65, 137.54, 136.00, 131.87, 130.77, 129.37, 128.83, 127.84,
127.80, 127.44, 126.53, 126.21, 124.98, 123.99, 123.43, 123.21, 123.17,
112.26. LC-MS (ESI+) 528.05 (M + H)+. HRMS (ESI+) m/z
calculated for C22H18N5O5S3 (M + H)+ 528.0465, found 528.0476.
N-(3-(1H-1,2,4-Triazol-3-ylthio)-4-hydroxynaphthalen-1-yl)-3,4-
dichlorobenzenesulfonamide (33). This compound was prepared
1996
dx.doi.org/10.1021/jm201118h | J. Med. Chem. 2012, 55, 1978−1998