T. Zhao et al. / European Journal of Medicinal Chemistry 182 (2019) 111619
11
4.1.7. (R)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-
4.1.11. (R)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-
(pyridin-3-ylmethyl)pyrrolidin-3-yl)-1H- indole-2-carboxamide
(23)
(methylsulfonyl)pyrrolidin-3-yl)-1H-indole-2-carboxamide (27)
20
White solid. Yield: 68.6%, M. p.: >200. [
a
]
þ17.30 (c 1.0 in
D
White solid. Yield: 52.7%, M. p.: 186e188 ꢀC. ESI-MS: m/z 523.5
(Mþ1), 445.5 (Mþ23). C27H27ClN4O3S [522.15]. 1H NMR (400 MHz,
CH3OH). ESI-MS: m/z 510.5 (Mþ1), 527.4 (Mþ18). C22H24ClN3O5S2
[509.08]. 1H NMR (400 MHz, DMSO‑d6)
d
13.07 (s, 1H, NH), 9.31 (s,
DMSO‑d6)
d
13.06 (s, 1H, NH), 9.24 (s, 1H, NH), 8.58 (s, 1H, Pyridine-
1H, NH), 7.90 (d, J ¼ 2.0 Hz, 1H, Indole-H), 7.67 (s, 2H, Ph-H), 7.55 (d,
J ¼ 8.7 Hz, 1H, Indole-H), 7.34 (dd, J ¼ 8.7, 2.1 Hz, 1H, Indole-H), 7.26
(s, 1H, Ph-H), 4.57 (dtd, J ¼ 11.0, 6.5, 4.4 Hz, 1H, Pyrrolidine-H), 3.63
(dd, J ¼ 10.5, 6.4 Hz, 1H, Pyrrolidine-H), 3.44e3.42 (m, 2H,
Pyrrolidine-H), 3.28 (dd, J ¼ 10.5, 4.0 Hz, 1H, Pyrrolidine-H), 2.96 (s,
3H, CH3), 2.32 (s, 6H, 2 ꢄ CH3), 2.29e2.22 (m, 1H, Pyrrolidine-H),
2.04e1.97 (m, 1H, Pyrrolidine-H). 13C NMR (100 MHz, DMSO‑d6)
H), 8.48e8.47 (m, 1H, Pyridine-H), 7.96 (d, J ¼ 2.0 Hz, 1H, Indole-H),
7.79 (s, 1H, Pyridine-H), 7.63 (s, 2H, Ph-H), 7.55 (d, J ¼ 8.8 Hz, 1H,
Indole-H), 7.35 (dd, J ¼ 8.7, 2.2 Hz, 2H, Indole-H þ Pyridine-H), 7.26
(s, 1H, Ph-H), 4.47 (s, 1H, Pyrrolidine-H), 3.72 (s, 2H, CH2), 3.07 (q,
J ¼ 7.3 Hz, 4H, Pyrrolidine-H), 2.90e2.66 (m, 2H, Pyrrolidine-H),
2.28 (s, 6H, 2 ꢄ CH3). 13C NMR (100 MHz, DMSO‑d6)
d 162.97,
159.24, 150.30, 148.86, 148.58, 139.43 (2 ꢄ C), 137.52, 135.18, 134.83,
133.27, 127.71, 125.70, 125.14, 124.13 (2 ꢄ C), 123.90, 119.37, 115.34,
111.89, 61.10, 52.68, 49.46, 45.94, 21.21 (2 ꢄ C), 8.99.
d
160.15, 142.99, 139.39 (2 ꢄ C), 138.01, 135.09, 133.36, 127.64,
125.34, 125.06, 124.30 (2 ꢄ C), 119.19, 115.29, 112.02, 56.50, 53.07,
50.18, 46.53, 31.10, 19.03 (2 ꢄ C).
4.1.8. (R)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-((4-
methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)pyrrolidin-
3-yl)-1H-indole-2-carboxamide (24)
4.1.12. (R)-N-(1-(2-amino-2-oxoethyl)pyrrolidin-3-yl)-5-chloro-3-
((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (28)
20
Gray solid. Yield: 56.6%, M. p.: 192e195 ꢀC. [
a
]
ꢃ40.30 (c 1.0
D
White solid. Yield: 66.5%, M. p.: >200 ꢀC. ESI-MS: m/z 543.6
(Mþ1), 465.5 (Mþ23). C25H27ClN6O4S [542.15]. 1H NMR (400 MHz,
in CH3OH). ESI-MS: m/z 489.4 (Mþ1), 511.4 (Mþ23). C23H25ClN4O4S
[488.13]. 1H NMR (400 MHz, DMSO‑d6)
d
9.22 (s, 1H, NH), 7.93 (d,
DMSO‑d6)
d
13.10 (s, 1H, NH), 11.54 (s, 1H, NH), 9.28 (s, 1H, NH), 7.91
J ¼ 2.0 Hz, 1H, Indole-H), 7.65 (s, 2H, Ph-H), 7.54 (d, J ¼ 8.8 Hz, 1H,
Indole-H), 7.34 (dd, J ¼ 8.6, 2.2 Hz, 2H, Indole-H þ NH), 7.27 (s, 1H,
Ph-H), 7.22 (s, 1H, NH), 4.53e4.46 (m, J ¼ 3.5 Hz, 1H, Pyrrolidine-H),
3.13 (s,1H, Pyrrolidine-H), 3.07 (s,1H, Pyrrolidine-H), 2.93e2.90 (m,
1H, Pyrrolidine-H), 2.80e2.75 (m, 2H, CH2), 2.68 (s, 1H), 2.48e2.46
(m, 1H, Pyrrolidine-H), 2.32 (s, 6H, 2 ꢄ CH3), 2.29e2.20 (m, 1H,
Pyrrolidine-H), 1.85e1.77 (m, 1H, Pyrrolidine-H). 13C NMR
(d, J ¼ 2.1 Hz, 1H, Indole-H), 7.66 (s, 2H, Ph-H), 7.55 (dd, J ¼ 8.8,
4.5 Hz, 1H, Indole-H), 7.35 (dt, J ¼ 8.8, 2.0 Hz, 1H, Indole-H), 7.27 (s,
1H, Ph-H), 4.46 (s, 1H, Pyrrolidine-H), 3.57 (s, 2H, CH2), 3.17 (s, 3H,
CH3), 3.10 (s, 2H, Pyrrolidine-H), 3.05 (s, 2H, Pyrrolidine-H),
2.90e2.61 (m, 2H, Pyrrolidine-H), 2.3 (s, 6H, 2 ꢄ CH3). 13C NMR
(100 MHz, DMSO‑d6)
d 160.34, 158.43, 155.75, 142.99, 139.44
(2 ꢄ C), 137.61, 135.17, 133.29, 127.68, 125.12, 124.45, 124.14 (2 ꢄ C),
119.32, 115.35, 111.83, 52.77, 49.47, 45.92, 29.98, 27.22, 21.22 (2 ꢄ C),
8.94.
(100 MHz, DMSO)
135.13, 133.31, 127.64, 125.54, 125.05, 124.22 (2 ꢄ C), 119.26, 115.29,
111.81, 59.87, 58.62, 52.93, 49.67, 31.92, 21.26 (2 ꢄ C).
d
172.19, 159.31, 143.03, 139.41 (2 ꢄ C), 138.10,
4.1.9. (R)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-(2-
fluorobenzyl)pyrrolidin-3-yl)-1H-indole-2-carboxamide (25)
White solid. Yield: 49.8%, M. p.: 178e181 ꢀC. ESI-MS: m/z 540.5
(Mþ1). C28H27ClFN3O3S [539.14]. 1H NMR (400 MHz, DMSO‑d6)
4.1.13. (S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-
(pyridin-3-ylmethyl)pyrrolidin-3-yl)-1H-indole-2-carboxamide
(29)
White solid. Yield: 58.4%, M. p.: 181e185 ꢀC. ESI-MS: m/z 523.5
(Mþ1), 545.5 (Mþ23). C27H27ClN4O3S [522.15]. 1H NMR (400 MHz,
d
13.02 (s, 1H, NH), 9.21 (s, 1H, NH), 7.96 (d, J ¼ 2.1 Hz, 1H, Indole-H),
7.63 (s, 2H, Ph-H), 7.53 (d, J ¼ 8.8 Hz, 1H, Indole-H), 7.49 (td, J ¼ 7.6,
1.7 Hz, 1H, Ph’-H), 7.34 (dd, J ¼ 8.8, 2.1 Hz, 1H, Indole-H), 7.30 (ddd,
J ¼ 7.3, 5.6, 1.7 Hz, 1H, Ph’-H), 7.25 (s, 1H, Ph-H), 7.20e7.13 (m, 2H,
Ph’-H), 4.44 (s, 1H, Pyrrolidine-H), 3.71 (s, 2H, CH2), 2.84e2.73 (m,
2H, Pyrrolidine-H), 2.63 (dd, J ¼ 9.7, 4.1 Hz, 1H, Pyrrolidine-H),
2.48e2.44 (m, 1H, Pyrrolidine-H), 2.28 (s, 6H, 2 ꢄ CH3), 1.80e1.72
(m, 1H, Pyrrolidine-H), 1.2 m (m, 1H, Pyrrolidine-H). 13C NMR
DMSO‑d6) d 13.02 (s, 1H, NH), 9.23 (s, 1H, NH), 8.56 (s, 1H, Pyridine-
H), 8.46 (dd, J ¼ 4.8, 1.6 Hz, 1H, Pyridine-H), 7.97 (d, J ¼ 2.0 Hz, 1H,
Indole-H), 7.76 (dt, J ¼ 7.8,1.9 Hz,1H, Pyridine-H), 7.62 (s, 2H, Ph-H),
7.54 (d, J ¼ 8.8 Hz, 1H, Indole-H), 7.36e7.32 (m, 2H, Pyridine-
H þ Indole-H), 7.26 (s, 1H, Ph-H), 4.49e4.41 (m, 1H, Pyrrolidine-H),
3.68 (s, 2H, CH2), 2.80e2.74 (m, 2H, Pyrrolidine-H), 2.63 (dd, J ¼ 9.6,
4.0 Hz, 1H, Pyrrolidine-H), 2.45 (q, J ¼ 7.9 Hz, 1H, Pyrrolidine-H),
(100 MHz, DMSO‑d6)
d
162.16, 159.73, 159.21, 143.00, 139.43 (2 ꢄ C),
2.28 (s, 7H, 2 ꢄ CH3
þ
Pyrrolidine-H), 1.82e1.73 (m, 1H,
159.15, 150.16,
137.53, 135.17, 133.26, 131.78, 127.70, 125.72, 125.13, 124.66, 124.12
(2 ꢄ C), 119.37, 115.67, 115.45, 115.32, 111.86, 59.71, 56.50, 52.66,
49.48, 31.68, 21.20 (2 ꢄ C).
Pyrrolidine-H). 13C NMR (100 MHz, DMSO‑d6)
d
148.71, 143.01, 139.46 (2 ꢄ C), 137.47, 136.65, 135.20, 134.77, 133.27,
127.73, 125.76, 125.16, 124.10 (2 ꢄ C), 123.87, 119.40, 115.34, 111.86,
59.78, 56.85, 52.72, 49.52, 31.74, 21.21 (2 ꢄ C).
4.1.10. (R)-5-Chloro-N-(1-(2-cyanobenzyl)pyrrolidin-3-yl)-3-((3,5-
dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (26)
4.1.14. (S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-((4-
methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)pyrrolidin-
3-yl)-1H-indole-2-carboxamide (30)
White solid. Yield: 60.1%, M. p.: 190e193 ꢀC. ESI-MS: m/z 547.7
(Mþ1). C29H27ClN4O3S [546.15]. 1H NMR (400 MHz, DMSO‑d6)
d
13.02 (s, 1H, NH), 9.21 (s, 1H, NH), 7.96 (s, 1H, Indole-H), 7.82 (d,
White solid. Yield: 70.2%, M. p.: >200 ꢀC. ESI-MS: m/z 543.6
(Mþ1), 565.5 (Mþ23). C25H27ClN6O4S [542.15]. 1H NMR (400 MHz,
J ¼ 7.6 Hz, 1H, Ph’-H), 7.67e7.65 (m, 2H, Ph’-H), 7.62 (s, 2H, Ph-H),
7.54 (d, J ¼ 8.7 Hz, 1H, Indole-H), 7.48 (d, J ¼ 7.4 Hz, 1H, Ph’-H),
7.36e7.33 (m, 1H, Indole-H), 7.26 (s, 1H, Ph-H), 4.47e4.22 (m, 1H,
Pyrrolidine-H), 3.86 (q, J ¼ 13.9 Hz, 2H, CH2), 2.91e2.87 (m, 1H,
Pyrrolidine-H), Pyrrolidine-H, 2.78 (p, J ¼ 9.4, 8.7 Hz, 1H,
Pyrrolidine-H), 2.65e2.55 (m, 2H, Pyrrolidine-H), 2.29 (s, 7H,
2 ꢄ CH3 þ Pyrrolidine-H), 1.79 (dq, J ¼ 12.9, 6.5 Hz, 1H, Pyrrolidine-
DMSO‑d6) d 13.03 (s, 1H, NH), 11.51 (s, 1H, NH), 9.20 (s, 1H, NH), 7.95
(d, J ¼ 2.0 Hz, 1H, Indole-H), 7.62 (s, 2H, Ph-H), 7.54 (d, J ¼ 8.7 Hz, 1H,
Indole-H), 7.35 (dd, J ¼ 8.8, 2.1 Hz, 1H, Indole-H), 7.26 (s, 1H, Ph-H),
4.49e4.41 (m, 1H, Pyrrolidine-H), 3.56 (s, 2H, CH2), 3.17 (s, 3H,
CH3), 2.84e2.75 (m, 2H, Pyrrolidine-H), 2.64 (dd, J ¼ 9.7, 3.9 Hz, 1H,
Pyrrolidine-H), 2.49e2.45 (m, 1H, Pyrrolidine-H), 2.30 (s, 7H,
2 ꢄ CH3 þ Pyrrolidine-H), 1.81e1.73 (m, 1H, Pyrrolidine-H). 13C NMR
H). 13C NMR (100 MHz, DMSO‑d6)
d 159.26, 143.01, 142.93, 139.43
(2 ꢄ C), 137.58, 135.17, 133.60, 133.30, 133.28, 130.31, 128.39, 127.71,
125.72, 125.13, 124.13 (2 ꢄ C), 119.38, 118.12, 115.33, 111.99, 111.88,
59.70, 57.38, 52.79, 49.52, 31.70, 21.23 (2 ꢄ C).
(100 MHz, DMSO‑d6)
d
159.22, 155.79, 145.83, 142.97, 139.46 (2 ꢄ C),
137.55, 135.21, 133.27, 127.71, 125.70, 125.15, 124.10 (2 ꢄ C), 119.36,
115.34, 111.81, 59.65, 52.73, 50.49, 49.52, 31.81, 27.20, 21.21 (2 ꢄ C).