S. Cascioferro et al. / European Journal of Medicinal Chemistry 167 (2019) 200e210
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solid, yield 45%, mp 285e286 ꢀC, 1HNMR (200 MHz, DMSO‑d6)
3.80 (3H, s, CH3), 3.86 (3H, s, OCH3), 6.87 (1H, d, J ¼ 7.86 Hz, Ar-H),
7.33e7.59 (5H, m, Ar-H), 8.24 (1H, d, J ¼ 1.78 Hz, Ar-H), 8.41 (1H, s,
Ar-H), 8.82 (1H, s, Ar-H), 9.50 (1H, bs, NH). 13C NMR (50 MHz,
d:
m.p. 291e292 ꢀC, IR cmꢂ1
(200 MHz, DMSO‑d6)
:
3478 (NH), 2884 (NH); 1HNMR
d
: 3.81 (3H, s, OCH3), 6.88 (1H, d, J ¼ 6.84 Hz,
Ar-H), 7.28e7.59 (5H, m, Ar-H), 8.14 (1H, d, J ¼ 1.82 Hz, Ar-H), 8.46
(1H, d, J ¼ 2.90 Hz, Ar-H), 8.87 (1H, s, Ar-H), 10.19 (1H, bs, NH), 12.39
DMSO‑d6)
d: 33.3 (q), 55.0 (q), 104.7 (s), 109.7 (d), 113.1 (d), 114.5 (s),
(1H, s, NH). 13C NMR (50 MHz, DMSO‑d6)
d: 55.0 (q), 106.0 (s), 109.8
116.8 (d), 122.6 (d), 125.5 (s), 125.7 (d), 129.6 (d), 129.8 (d), 134.3 (d),
135.9 (s), 142.5 (s), 143.5 (s), 156.7 (s), 159.2 (s), 159.5 (s). Anal. Calcd
for C10H16Br2N4OS (MW: 520.24): C, 46.17%; H, 3.10%; N, 10.77%.
Found: C, 46.28%; H, 3.02%; N, 10.91%.
(d), 111.1 (s), 111.3 (s), 113.2 (d), 114.3 (2xd), 115.4 (s), 116.9 (d), 119.6
(s), 123.4 (d), 124.7 (s), 126.2 (s), 129.8 (d), 131.2 (s), 134.2 (s). Anal.
Calcd for C19H14BrClN4OS (MW: 461.76): C, 49.42%; H, 3.06%; N,
12.13%. Found: C, 49.58%; H, 3.21%; N, 12.25%.
5.1.4.21. 5-Bromo-3-[6-(2,5-dimethoxyphenyl)imidazo[2,1-b][1,3,4]
thiadiazol-2-yl]-1-methyl-1H-indole hydrobromide (9u). Light yel-
low solid, yield 53%, mp 290e291 ꢀC, IR cmꢂ1: 2473e2610 (NH);
5.1.4.27. 5-Chloro-3-[6-(2,5-dimethoxyphenyl)imidazo[2,1-b][1,3,4]
thiadiazol-2-yl]-1H-indole hydrobromide (9aa). White solid, yield:
46%, mp 265e266 ꢀC, IR cmꢂ1: 3473 (NH), 2902 (NH); 1HNMR
1HNMR (200 MHz, DMSO‑d6)
d: 3.77 (3H, s, CH3), 3.88 (3H, s, OCH3),
(200 MHz, DMSO‑d6) d: 3.77 (3H, s, OCH3), 3.93 (3H, s, OCH3),
3.92 (3H, s, OCH3), 6.39 (1H, bs, NH), 6.83e7.07 (2H, m, Ar-H),
7.44e7.63 (3H, m, Ar-H), 8.28 (1H, d, J ¼ 1.68, Ar-H), 8.43 (1H, s,
6.86e6.92 (1H, m, Ar-H), 7.07 (1H, d, J ¼ 9.05 Hz, Ar-H), 7.28e7.33
(1H, m, Ar-H), 7.57 (2H, m, Ar-H), 7.98 (1H, bs, NH), 8.15 (1H, s, Ar-
H), 8.51 (1H, s, Ar-H), 8.76 (1H, s, Ar-H), 12.41 (1H, s, NH). 13C NMR
Ar-H), 8.66 (1H, s, Ar-H). 13C NMR (50 MHz, DMSO‑d6)
d: 33.3 (q),
55.3 (q) 55.8 (q), 99.3 (s),100.7 (d),104.8 (s),106.5 (d), 111.1 (s),111.6
(d), 112.5 (d), 114.6 (s), 122.8 (d), 125.7 (d), 130.6 (d), 134.0 (d), 134.4
(s), 138.0 (s), 139.4 (s), 149.9 (s), 153.1 (s), 157.0 (s). Anal. Calcd for
(50 MHz, DMSO‑d6) d: 55.3 (q), 55.7 (q), 106.1 (s), 112.7 (d), 114.2 (s),
114.8 (d), 116.3 (s), 119.5 (d), 123.3 (d), 124.8 (s), 126.9 (s), 131.4 (d),
135.2 (s), 150.6 (s), 152.7 (s), 152.9 (d), 153.1 (s), 157.3 (s). Anal. Calcd
for C20H16BrClN4O2S (MW: 491.79): C, 48.84%; H, 3.28%; N, 11.39%.
Found: C, 48.96%; H, 3.42%; N, 11.51%.
C
21H18Br2N4O2S (MW: 550.26): C, 45.84%; H, 3.30%; N, 10.18%.
Found: C, 45.93%; H, 3.60%; N, 10.32%.
5.1.4.22. 5-Bromo-3-[6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thia-
diazol-2-yl]-1-methyl-1H-indole hydrobromide (9v). White solid,
yield 48%, mp 293e294 ꢀC, IR cmꢂ1: 2588e2609 (NH); 1HNMR
5.1.4.28. 5-Chloro-3-[6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadia-
zol-2-yl]-1H-indole hydrobromide (9 ab). Light yellow solid, yield:
45%, m.p. 288e289 ꢀC, IR cmꢂ1: 3484 (NH), 2890 (NH); 1HNMR
(200 MHz, DMSO‑d6)
d: 3.88 (3H, s, CH3), 7.21e7.30 (2H, t, Ar-H),
(200 MHz, DMSO‑d6) d: 7.20 (1H, s, NH), 7.23e7.33 (3H, m, Ar-H),
7.55 (2H, m, Ar-H), 7.87 (2H, dd, J ¼ 1.9, 8.69 Hz, Ar-H), 8.28 (1H,
7.57 (1H, d, J ¼ 8.68 Hz, Ar-H), 7.59 (1H, s, Ar-H), 7.86e7.90 (2H,
d, J ¼ 1.62, Ar-H), 8.39 (1H, s, Ar-H), 8.75 (1H, s, Ar-H). Anal. Calcd for
m, Ar-H), 8.15 (1H, d, J ¼ 1.96 Hz, Ar-H), 8.43 (1H, d, J ¼ 2.94, Ar-H),
C
19H13Br2FN4S (MW: 508.20): C, 44.90%; H, 2.58%; N,11.02%. Found:
8.78 (1H, s, Ar-H), 12.34 (1H, s, NH). 13C NMR (50 MHz, DMSO‑d6)
d:
C, 45.06%; H, 2.64%; N, 11.13%.
106.1 (s), 110.6 (d), 114.2 (d), 115.4 (d), 115.8 (d), 119.6 (d), 123.3 (d),
124.7 (s), 126.1 (s), 126.3 (d), 126.5 (d), 130.0 (s), 131.1 (d), 135.2
(s),142.9 (s),143.2 (s),157.0 (s). Anal. Calcd for C18H11BrClFN4S (MW:
449.73): C, 48.07%, H, 2.47%, N,12.46%. Found: C, 48.15%, H, 2.55%, N,
12.52%.
5.1.4.23. 5-Bromo-3-[6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadia-
zol-2-yl]-1-methyl-1H-indole hydrobromide (9w). Orange solid,
yield 46%, mp 320e321 ꢀC, IR cmꢂ1: 2925 (NH); 1HNMR (200 MHz,
DMSO‑d6)
d
: 3.92 (3H, s, CH3), 7.53 (1H, d, J ¼ 2.08, Ar-H), 7.63e7.68
(1H, m, Ar-H), 8.12 (2H, d, J ¼ 8.86, Ar-H), 8.28e8.33(3H, m, Ar-H),
5.1.4.29. 5-Chloro-3-[6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadia-
8.47 (1H, s, Ar-H), 9.08 (1H, s, Ar-H). Anal. Calcd for
zol-2-yl]-1H-indole hydrobromide (9ac). Yellow solid, yield: 42%,
C
19H13Br2N5O2S (MW: 535.21): C, 42.64%; H, 2.45%; N, 13.08%.
m.p. 342e343 ꢀC, IR cmꢂ1 3381 (NH), 2890 (NH); 1HNMR
:
Found: C, 42.78%; H, 2.58%; N, 13.23%.
(200 MHz, DMSO‑d6)
d
: 7.35 (1H, s, Ar-H), 7.58 (1H, d, J ¼ 8.84 Hz,
Ar-H), 8.15e8.47 (7H, m, Ar-H), 9.07 (1H, s, NH), 12.37 (1H, s, NH).
Anal. Calcd for C18H11BrClN5O2S (MW: 476.73): C, 45.35%, H, 2.33%,
N, 14.69%. Found: C, 45.45%, H, 2.38%, N, 14.75%.
5.1.4.24. 5-Bromo-3-[6-(4-trifluoromethylphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-2-yl]-1-methyl-1H-indole (10x). Yellow solid, yield
42%, m.p. 254e255 ꢀC, 1HNMR (200 MHz, DMSO‑d6)
d: 3.84 (3H, s,
CH3), 7.41e7.57 (2H, m, 2xAr-H), 7.71 (2H, d, J ¼ 8.38 Hz, Ar-H), 8.00
5.1.4.30. 5-Chloro-3-[6-(4-trifluoromethylphenyl)imidazo[2,1-b]
[1,3,4]thiadiazol-2-yl]-1H-indole (10ad). White solid, yield: 46%,
m.p. 312e313 ꢀC, IR cmꢂ1: 2884 (NH); 1HNMR (200 MHz, DMSO‑d6)
(2H, d, J ¼ 8.09 Hz, Ar-H), 8.23 (1H, d, J ¼ 1.72 Hz, Ar-H), 8.32 (1H, s,
Ar-H), 8.85 (1H, s, Ar-H). 13C NMR (50 MHz, DMSO‑d6)
d: 33.3 (q),
104.9 (s), 112.1 (d), 113.1 (d), 114.5 (s), 122.7 (2xd), 124.7 (d), 125.5
(d), 125.5 (d), 125.7 (d), 127.3 (s), 134.2 (d), 135.9 (s), 137.9 (s), 143.1
(s), 143.3 (s), 156.6 (s). Anal. Calcd for C20H12BrF3N4S (MW: 477.30):
C, 50.33%; H, 2.53%; N, 11.74%. Found: C, 50.54%; H, 2.72%; N, 11.88%.
d
: 7.28 (1H, d, J ¼ 6.96 Hz, Ar-H), 7.55 (1H, d, J ¼ 6.96 Hz, Ar-H), 7.74
(2H, d, J ¼ 8.12 Hz, Ar-H), 8.02e8.14 (3H, m, Ar-H), 8.40 (1H, s, Ar-H),
8.92 (1H, s, Ar-H), 12.34 (1H, s, NH). 13C NMR (50 MHz, DMSO‑d6)
d:
106.1 (s), 112.2 (d), 114.2 (d), 119.6 (d), 123.2 (d), 124.7 (s), 124.7 (s),
124.8 (2xd), 125.6 (d), 125.6 (d), 126.1 (s), 131.2 (d), 135.2 (s), 137.6
(s), 142.8 (s), 143.5 (s), 157.4 (s). Anal. Calcd for C19H10ClF3N4S (MW:
418.82): C, 54.49%, H, 2.41%, N,13.38%. Found: C, 54.56%, H, 2.52%, N,
13.43%.
5.1.4.25. 5-Chloro-3-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
1H-indole hydrobromide (9y). Light yellow solid, yield: 45%, m.p.
297e298 ꢀC, IR cmꢂ1: 2890 (NH), 3445 (NH); 1HNMR (200 MHz,
DMSO‑d6)
8.17 (1H, d, J ¼ 1.82 Hz, Ar-H), 8.40 (1H, d, J ¼ 2.86 Hz, Ar-H), 8.76
(1H, s, Ar-H),12.31 (1H, s, NH). 13C NMR (50 MHz, DMSO‑d6)
: 106.3
(s), 110.6 (d), 114.8 (d), 119.6 (d), 123.2 (d), 124.4 (2xd), 124.8 (s),
126.1 (s), 127.0 (d), 128.6 (2xd), 130.9 (d), 134.0 (s), 135.2 (s), 142.9
(s), 144.8 (s), 156.6 (s). Anal. Calcd for C18H12BrClN4S (MW 558.21):
C, 50.08%; H, 2.80%; N,12.98%. Found: C, 50.25%; H, 2.91%; N,12.90%.
d
: 7.27e7.58 (5H, m, Ar-H), 7.87 (2H, d, J ¼ 7.14 Hz, Ar-H),
5.1.4.31. 5-Chloro-1-methyl-3-(6-phenylimidazo[2,1-b][1,3,4]thiadia-
d
zol-2-yl)-1H-indole (10ae). White solid, yield: 42%, m.p.
290e291 ꢀC, 1HNMR (200 MHz, DMSO‑d6)
d: 3.88 (3H, s, CH3),
7.27e7.39 (4H, m, Ar-H), 7.43 (1H, d, J ¼ 7.18 Hz, Ar-H), 7.64 (2H, d,
J ¼ 8.76 Hz, Ar-H), 8.13 (1H, s, Ar-H), 8.38 (1H, s, Ar-H), 8.72 (1H, s,
Ar-H). 13C NMR (50 MHz, DMSO‑d6)
d: 55.9 (q), 99.5 (s), 105.1 (s),
110.6 (d), 112.8 (d), 119.7 (d), 123.2 (d), 124.4 (d), 124.9 (d), 126.5 (s),
127.1 (2xd), 128.6 (d), 133.9 (s), 134.3 (d), 135.7 (s), 142.7 (s), 144.8
(s),156.1(s). Anal. Calcd for C19H13ClN4S (MW: 364.85): C, 62.55%, H,
5.1.4.26. 5-Chloro-3-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3,4]thia-
diazol-2-yl]-1H-indole hydrobromide (9z). White solid, yield: 46%,