Journal of Medicinal Chemistry
Article
d6): δ 9.46 (s, 1H), 9.02 (s, 1H), 7.91−7.88 (m, 1H), 7.83 (dd, J = 7.6,
1.6 Hz, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.44 (d, J
= 2.0 Hz, 2H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.21−7.15 (m, 2H), 7.05−
7.01 (m, 2H), 6.90 (t, J = 7.6 Hz, 1H), 6.85 (m, 1H), 6.70 (dd, J = 8.0,
1.6 Hz, 1H), 6.42−6.39 (m, 1H), 5.28 (s, 2H), 3.21−3.16 (m, 2H),
2.96−2.92 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 157.5, 154.7,
153.9, 144.0, 142.9, 139.9, 137.9, 133.9, 130.8, 129.9, 129.5, 127.9,
124.8, 121.2, 121.0, 120.1, 118.0, 115.6, 114.9, 114.3, 113.5, 69.8, 42.8;
ESI-MS: m/z 591.8 [M + H]+; DART-HRMS C26H24Cl2N3O5S2 [M +
H]+ calcd, 592.0529; obs., 592.0517.
2.17 (m, 2H), 2.02−1.98 (m, 2H), 1.69−1.63 (m, 2H), 1.52−1.46 (m,
2H); 13C NMR (100 MHz, acetone-d6): δ 155.9, 154.6, 146.1, 143.5,
141.1, 132.8, 132.5, 132.1, 131.8, 131.7, 130.7, 128.8, 125.8, 125.1,
123.1, 122.9, 121.7, 118.4, 114.8, 77.0, 68.9, 44.4, 40.4, 33.0, 29.6; ESI-
MS: m/z 650.1 [M − H]−; ESI-HRMS C27H28N3O5F6S2 [M + H]+
calcd, 652.1369; obs., 652.1373.
N-(2-(3-(3,5-Dichlorophenyl)ureido)ethyl)-5-(2-(((1r,4r)-4-
hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C28).
Overall yield: 25.8%, purity: 95.2%. 1H NMR (400 MHz, acetone-d6): δ
8.39 (s, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J = 4.0 Hz, 1H),
7.56 (d, J = 4.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 2H), 7.34 (t, J = 7.2 Hz,
1H), 7.20 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 2.0
Hz, 1H), 6.82 (m, 1H), 6.12 (m, 1H), 4.60 (m, 1H), 3.75−3.72 (m,
2H), 3.41−3.37 (m, 2H), 3.22−3.17 (m, 2H), 2.21−2.15 (m, 2H),
2.02−1.98 (m, 2H), 1.68−1.65 (m, 2H), 1.50−1.46 (m, 2H); 13C
NMR (100 MHz, acetone-d6): δ 155.9, 154.6, 146.1, 143.8, 141.0,
135.4, 131.6, 130.7, 128.8, 125.0, 122.9, 121.7, 121.5, 116.9, 114.8, 77.0,
68.9, 44.6, 40.3, 33.0, 29.6; ESI-MS: m/z 582.0 [M − H]−; ESI-HRMS
C25H28Cl2N3O5S2 [M + H]+ calcd, 584.0842; obs., 584.0843.
N-(2-(3-(4-Nitrophenyl)thioureido)ethyl)-5-(2-(((1r,4r)-4-
hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C29).
Overall yield: 21.9%, purity: 98.1%. 1H NMR (400 MHz, acetone-d6): δ
9.56 (s, 1H), 8.15−8.13 (m, 2H), 7.90−7.87 (m, 2H), 7.81−7.79 (m,
2H), 7.61 (d, J = 4.0 Hz, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.34 (td, J = 7.6,
1.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.92−
6.89 (m, 1H), 4.64−4.58 (m, 1H), 3.87−3.83 (m, 2H), 3.75−3.71 (m,
2H), 3.39−3.35 (m, 2H), 2.22−2.18 (m, 2H), 2.02−1.98 (m, 2H),
1.70−1.66 (m, 2H), 1.49−1.46 (m, 2H); 13C NMR (100 MHz,
acetone-d6): δ 182.1, 154.6, 146.7, 146.2, 143.9, 140.9, 131.8, 130.7,
128.8, 125.2, 125.1, 122.9, 122.1, 121.7, 114.8, 77.0, 68.9, 44.6, 43.2,
33.1, 29.7; ESI-MS: m/z 575.1 [M − H]−; ESI-HRMS C25H29N4O6S3
[M + H]+ calcd, 577.1244; obs., 577.1244.
N-(2-(3-(4-Methoxyphenyl)ureido)ethyl)-5-(2-((3-
hydroxybenzyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C23).
1
Overall yield: 23.8%, purity: 96.3%. H NMR (400 MHz, acetone-
d6): δ 8.66 (s, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (d, J
= 4.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.35−7.27 (m, 3H), 7.23−7.19
(m, 2H), 7.05−7.01 (m, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.89−6.86 (m,
1H), 6.80 (dd, J = 8.0, 1.6 Hz, 1H), 6.78−6.74 (m, 2H), 5.99−5.96 (m,
1H), 5.26 (s, 2H), 3.71 (s, 3H), 3.39−3.34 (m, 2H), 3.18−3.13 (m,
2H); 13C NMR (100 MHz, acetone-d6): δ 158.6, 157.3, 156.1, 155.4,
145.8, 141.3, 139.0, 133.9, 131.6, 130.7, 130.4, 128.9, 125.4, 122.6,
122.1, 121.6, 119.5, 116.0, 115.5, 114.7, 114.2, 71.1, 55.6, 45.2, 40.3;
ESI-MS: m/z 575.9 [M + Na]+; ESI-HRMS C27H28N3O6S2 [M + H]+
calcd, 554.1414; obs., 554.1401.
N-(2-(3-(3,5-Dimethylphenyl)ureido)ethyl)-5-(2-((3-
hydroxybenzyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C24).
1
Overall yield: 25.7%, purity: 95.3%. H NMR (400 MHz, acetone-
d6): δ 8.60 (s, 1H), 7.89 (s, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.57 (d, J
= 4.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.32 (td, J = 7.6, 1.6 Hz, 1H),
7.22−7.17 (m, 2H), 7.04−7.00 (m, 4H), 6.96 (d, J = 7.6 Hz, 1H),
6.85−6.80 (m, 2H), 6.56 (s, 1H), 6.03−6.02 (m, 1H), 5.24 (s, 2H),
3.39−3.34 (m, 2H), 3.18−3.14 (m, 2H), 2.16 (s, 6H); 13C NMR (100
MHz, acetone-d6): δ 158.6, 156.9, 155.4, 145.8, 141.3, 140.9, 139.0,
138.8, 131.6, 130.7, 130.4, 128.9, 125.4, 124.3, 122.6, 122.1, 119.5,
117.2, 115.9, 115.5, 114.2, 71.1, 45.1, 40.2, 21.5; ESI-MS: m/z 551.6 [M
+ H]+; ESI-HRMS C28H28N3O5S2 [M − H]− calcd, 550.1465; obs.,
550.1465.
N-(2-(3-(4-Nitrophenyl)ureido)ethyl)-5-(2-(((1r,4r)-4-
hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C30).
Overall yield: 15.0%, purity: 99.5%. 1H NMR (400 MHz, acetone-d6): δ
8.73 (s, 1H), 8.11−8.08 (m, 2H), 7.79 (dd, J = 7.6, 1.6 Hz, 1H), 7.68−
7.66 (m, 2H), 7.59 (d, J = 4.0 Hz, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.33
(td, J = 7.6, 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.00 (td, J = 7.6, 0.8
Hz, 1H), 6.83−6.80 (m, 1H), 6.25−6.22 (m, 1H), 4.62−4.56 (m, 1H),
3.75−3.69 (m, 2H), 3.44−3.39 (m, 2H), 3.24−3.20 (m, 2H), 2.21−
2.17 (m, 2H), 2.02−1.97 (m, 2H), 1.71−1.51 (m, 2H), 1.51−1.42 (m,
2H); 13C NMR (100 MHz, acetone-d6): δ 155.6, 154.6, 147.8, 146.1,
142.3, 141.1, 131.6, 130.7, 128.8, 125.7, 125.0, 122.9, 121.7, 117.9,
114.8, 77.0, 68.9, 44.5, 40.3, 33.0, 29.7; ESI-MS: m/z 559.1 [M − H]−;
ESI-HRMS C25H29N4O7S2 [M + H]+ calcd, 561.1472; obs., 561.1473.
N-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)ethyl)-5-(2-
(((1s,4s)-4-hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfona-
N-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)ethyl)-5-(2-
((3-hydroxybenzyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C25).
1
Overall yield: 37.4%, purity: 96.3%. H NMR (400 MHz, acetone-
d6): δ 9.64 (s, 1H), 8.52 (s, 1H), 8.33 (s, 2H), 7.84−7.79 (m, 2H), 7.71
(s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.32 (td, J =
7.6, 1.6 Hz, 1H), 7.25−7.19 (m, 2H), 7.05−6.99 (m, 3H), 6.93−6.90
(m, 1H), 6.82 (dd, J = 8.0, 1.6 Hz, 1H), 5.30 (s, 2H), 3.87−3.82 (m,
2H), 3.36−3.31 (m, 2H); 13C NMR (100 MHz, acetone-d6): δ 182.6,
158.5, 155.4, 146.1, 142.7, 141.0, 139.1, 132.1, 131.9, 131.8, 130.8,
130.5, 128.9, 125.7, 125.5, 123.5, 123.0, 122.5, 122.1, 119.5, 117.6,
115.8, 115.3, 114.3, 71.1, 44.7, 43.1; ESI-MS: m/z 673.9 [M − H]−;
DART-HRMS C28H24N3O4F6S3 [M + H]+ calcd, 676.0828; obs.,
676.0812.
1
mide (TJ-C31). Overall yield: 21.4%, purity: 96.1%. H NMR (400
MHz, acetone-d6): δ 9.54 (s, 1H), 8.32 (s, 2H), 7.82−7.79 (m, 2H),
7.71 (s, 1H), 7.62 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 4.0 Hz, 1H), 7.35 (td,
J = 7.6, 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.01 (td, J = 7.6, 0.8 Hz,
1H), 6.95−6.92 (m, 1H), 4.71−4.70 (m, 1H), 3.94−3.93 (m, 1H),
3.86−3.81 (m, 3H), 3.39−3.34 (m, 2H), 2.14−2.07 (m, 2H), 1.85−
1.73 (m, 6H); 13C NMR (100 MHz, acetone-d6): δ 182.7, 154.6, 146.3,
142.8, 141.0, 132.4, 132.1, 131.8, 131.8, 131.5, 130.8, 129.2, 125.7,
125.3, 123.5, 123.0, 121.7, 117.6, 114.8, 75.4, 67.6, 44.6, 43.2, 31.4,
28.0; ESI-MS: m/z 668.0 [M + H]+; ESI-HRMS C27H28N3O4F6S3 [M +
H]+ calcd, 668.1141; obs., 668.1141.
N-(2-(3-(3-Chlorophenyl)thioureido)ethyl)-5-(2-((3-
hydroxybenzyl)oxy)phenyl)thiophene-2-sulfonamide (TJ-C26).
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Overall yield: 38.8%, purity: 95.1%. H NMR (400 MHz, acetone-
d6): δ 9.14 (s, 1H), 8.50 (s, 1H), 7.81 (dd, J = 7.6, 1.2 Hz, 1H), 7.66 (d, J
= 2.0 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.54−
7.51 (m, 1H), 7.36−7.19 (m, 5H), 7.14 (d, J = 8.0 Hz, 1H), 7.06−6.99
(m, 3H), 6.94−6.91 (m, 1H), 6.82 (dd, J = 7.6, 2.0 Hz, 1H), 5.30 (s,
2H), 3.85−3.80 (m, 2H), 3.33−3.29 (m, 2H); 13C NMR (100 MHz,
acetone-d6): δ 182.5, 158.4, 155.4, 145.9, 141.1, 139.0, 134.5, 131.8,
131.0, 130.7, 130.5, 128.9, 125.5, 125.4, 124.2, 122.7, 122.5, 122.1,
119.5, 115.8, 115.3, 114.3, 71.0, 44.7, 43.5; ESI-MS: m/z 572.0 [M −
H]−; ESI-HRMS C26H25Cl1N3O4S3 [M − H]− calcd, 574.0690; obs.,
574.0686.
N-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)ethyl)-5-(2-
(((1s,4s)-4-hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfona-
1
mide (TJ-C32). Overall yield: 18.0%, purity: 95.7%. H NMR (400
MHz, acetone-d6): δ 8.73 (s, 1H), 8.12 (s, 2H), 7.78 (dd, J = 8.0, 1.6 Hz,
1H), 7.59 (d, J = 4.0 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.51 (s, 1H),
7.34 (td, J = 7.6, 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.00 (td, J = 7.6,
0.8 Hz, 1H), 6.85−6.82 (m, 1H), 6.29 (m, 1H), 4.71−4.68 (m, 1H),
3.96−3.95 (m, 1H), 3.86−3.85 (m, 1H), 3.44−3.39 (m, 2H), 3.26−
3.21 (m, 2H), 2.13−2.06 (m, 2H), 1.84−1.70 (m, 6H); 13C NMR (100
MHz, acetone-d6): δ 155.9, 154.6, 146.2, 143.5, 141.2, 132.8, 132.5,
132.2, 131.9, 131.8, 130.8, 129.2, 125.9, 125.3, 123.1, 123.0, 121.6,
118.4, 114.8, 75.4, 67.6, 44.5, 40.3, 31.4, 28.0; ESI-MS: m/z 650.1 [M −
N-(2-(3-(3,5-Bis(trifluoromethyl)phenyl)ureido)ethyl)-5-(2-
(((1r,4r)-4-hydroxycyclohexyl)oxy)phenyl)thiophene-2-sulfonamide
1
(TJ-C27). Overall yield: 27.0%, purity: 98.8%. H NMR (400 MHz,
acetone-d6): δ 8.79 (s, 1H), 8.13 (s, 2H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H),
7.60 (d, J = 4.0 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.51 (s, 1H), 7.33 (td,
J = 7.6, 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.00 (td, J = 7.6, 0.8 Hz,
1H), 6.86−6.83 (m, 1H), 6.30−6.28 (m, 1H), 4.61−4.59 (m, 1H),
3.76−3.66 (m, 2H), 3.45−3.40 (m, 2H), 3.24−3.20 (m, 2H), 2.21−
10275
J. Med. Chem. 2021, 64, 10260−10285