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L. Kollar, M. Gobec, B. Szilagyi et al.
European Journal of Medicinal Chemistry 219 (2021) 113455
thione (40, 100 mg, 0.55 mmol), HATU (343 mg, 0.82 mmol), and 2-
(pyridin-3-yl)acetic acid hydrochloride (155 mg, 0.82 mmol) to give
compound 51 (119 mg, 72% yield) as a white solid. Mp.: 127e130 ꢀC;
[MþH]þ, calcd. for C15H14N3O2S: 284.0857, found: 284.0859; Purity
by HPLC: 100%.
N-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-
yl)-2-(pyridin-3-yl)acetamide (52). The reaction was carried out
according to the General acylation procedure 1, starting from 6-
amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-thione (42,
91 mg, 0.51 mmol), HATU (291 mg, 0.77 mmol), and 2-(pyridin-3-
yl)acetic acid hydrochloride (134 mg, 0.77 mmol) to give com-
pound 52 (85 mg, 56% yield) as a white solid. Mp.: 291 ꢀC; 1H NMR
1H NMR (500 MHz, DMSO‑d6)
d 13.66 (s, 1H), 10.41 (s, 1H), 8.64 (s,
1H), 8.58 (d, J ¼ 5.1 Hz, 1H), 8.01 (d, J ¼ 2.0 Hz, 1H), 7.99 (d,
J ¼ 7.7 Hz, 1H), 7.58 (dd, J ¼ 7.9, 5.1 Hz, 1H), 7.49 (dd, J ¼ 8.7, 2.1 Hz,
1H), 7.25 (d, J ¼ 8.7 Hz, 1H), 3.80 (s, 2H); 13C NMR (126 MHz,
DMSO‑d6)
d 189.03, 168.01, 147.02, 144.82, 140.93, 137.18, 135.67,
129.87, 124.65, 118.99, 112.50, 111.98, 39.64; HRMS (ESIþ) m/z
[MþH]þ, calcd. for C14H12N3OS2: 302.0422, found: 302.0416 Purity
by HPLC: 99.0%.
(500 MHz, DMSO‑d6)
d 12.69 (s, 1H), 10.87 (s, 1H), 8.94 (s, 1H), 8.84
(d, J ¼ 5.4 Hz, 1H), 8.57 (d, J ¼ 7.1 Hz, 1H), 8.03 (dd, J ¼ 8.0, 5.7 Hz,
1H), 7.80 (d, J ¼ 3.3 Hz, 1H), 7.33 (dd, J ¼ 8.5, 1.8 Hz, 1H), 7.13 (d,
J ¼ 8.5 Hz, 1H), 4.06 (s, 2H), 3.57 (s, 3H); 13C NMR (126 MHz,
6-[3-(Pyridin-3-yl)propanamido]benzo[d]thiazole-2(3H)-
thione (54). The reaction was carried out according to the General
acylation procedure 1, starting from 6-aminobenzo[d]thiazole-
2(3H)-thione (40, 100 mg, 0.55 mmol), HATU (343 mg, 0.82 mmol),
and 3-(pyridin-3-yl)propanoic acid (155 mg, 0.82 mmol) to give
compound 54 (80 mg, 46% yield) as a white solid. Mp.: 119e121 ꢀC;
DMSO‑d6)
d 168.52, 167.12, 146.60, 142.28, 140.18, 135.76, 134.35,
133.05, 126.81, 126.50, 114.76, 109.59, 100.48, 39.14, 29.85; HRMS
(APCIþ) m/z [MþH]þ, calcd. for C15H15N4OS: 299.0966, found:
299.0973; Purity by HPLC: 100%.
N-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-
yl)-3-(pyridin-3-yl)propanamide (55). The reaction was carried
out according to the General acylation procedure 2, starting from 6-
amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-thione (42,
54 mg, 0.30 mmol), HATU (136 mg, 0.36 mmol), 3-(pyridin-3-yl)
1H NMR (500 MHz, DMSO‑d6)
d
13.64 (s, 1H), 10.10 (s, 1H), 8.69 (s,
1H), 8.61 (s, 1H), 8.13 (dt, J ¼ 8.1, 1.6 Hz, 1H), 8.00 (d, J ¼ 2.0 Hz, 1H),
7.69 (dd, J ¼ 7.9, 5.2 Hz, 1H), 7.42 (dd, J ¼ 8.7, 2.1 Hz, 1H), 7.23 (d,
J ¼ 8.7 Hz, 1H), 3.04 (t, J ¼ 7.3 Hz, 2H), 2.74 (t, J ¼ 7.4 Hz, 2H); 13C
NMR (126 MHz, DMSO‑d6)
d 188.99, 169.89, 144.79, 142.81, 141.99,
139.38, 137.03, 135.78, 129.88, 125.44, 118.89, 112.51, 111.84, 36.55,
27.55; HRMS (ESIþ) m/z [MþH]þ, calcd. for C12H14N3OS2: 316.0578,
found: 316.0573; Purity by HPLC: 99%.
propanoic acid (54 mg, 0.36 mmol), and Et3N (50
give compound 55 (25 mg, 27% yield) as a white solid. Mp.: 128 ꢀC;
1H NMR (500 MHz, DMSO‑d6)
12.66 (s, 1H), 10.05 (s, 1H),
mL, 0.36 mmol) to
d
6-[(R)-pyrrolidine-2-carboxamido]benzo[d]thiazole-2(3H)-
thione (57). The reaction was carried out according to the General
acylation procedure 1, starting from 6-aminobenzo[d]thiazole-
2(3H)-thione (40, 100 mg, 0.55 mmol), HATU (343 mg, 0.82 mmol),
and (R)-pyrrolidine-2-carboxylic acid (103 mg, 0.82 mmol) to give
8.68e8.72 (m, 2H), 8.14 (d, J ¼ 7.8 Hz, 1H), 7.72 (d, J ¼ 12.2 Hz, 2H),
7.20 (dd, J ¼ 8.5, 1.5 Hz, 1H), 7.10 (d, J ¼ 8.5 Hz, 1H), 3.60 (s, 3H), 3.05
(t, J ¼ 7.3 Hz, 2H), 2.74 (t, J ¼ 7.3 Hz, 2H); 13C NMR (126 MHz,
DMSO‑d6)
d 169.67, 168.54, 145.38, 143.35, 141.15, 134.42, 133.09,
126.59, 114.64, 109.57, 100.39, 36.65, 29.89, 27.62; HRMS (APCIþ) m/
z [MþH]þ, calcd. for C16H17N4OS: 313.1123, found: 313.1130. Purity
by HPLC: 100%.
compound 57 (103 mg, 67% yield) as
a
white solid. Mp.:
138e140 ꢀC; 1H NMR (500 MHz, DMSO‑d6)
d
10.61 (s, 1H), 7.99 (s,
1H), 7.50 (dd, J ¼ 8.7, 1.9 Hz, 1H), 7.31 (d, J ¼ 8.7 Hz, 1H), 4.31 (t,
J ¼ 7.4 Hz, 1H), 3.35e3.19 (m, 2H), 2.68 (s, 1H), 2.43e2.33 (m, 1H),
2.03e1.89 (m, 3H), resonance for NH missing; 13C NMR (126 MHz,
(R)-N-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imid-
azole-5-yl)pyrrolidine-2-carboxamide (58). The reaction was
carried out according to the General acylation procedure 1, starting
DMSO‑d6)
d
189.33, 166.81, 137.86, 134.62, 130.07, 119.35, 112.69,
from
6-amino-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-
112.51, 59.83, 45.92, 29.51, 23.49; HRMS (ESIþ) m/z [MþH]þ, calcd.
thione (42, 95 mg, 0.53 mmol), HATU (242 mg, 0.64 mmol), and
(R)-pyrrolidine-2-carboxylic acid (73 mg, 0.64 mmol) to give
compound 58 (14 mg,10% yield) as a white gum. 1H NMR (500 MHz,
for C12H14N3OS2: 280.0578, found: 280.0574; Purity by HPLC: 100%.
4.8. Preparation of 6-(acylamino)-1-methylbenzo[d]imidazole-
2(3H)-thione derivatives 46, 49, 52, 55, and 58
DMSO‑d6)
d
10.14 (s, 1H), 7.77 (d, J ¼ 1.6 Hz, 1H), 7.38 (dd, J ¼ 8.5,
1.8 Hz, 1H), 7.12 (d, J ¼ 8.5 Hz, 1H), 3.83 (dd, J ¼ 8.6, 6.0 Hz, 1H), 3.61
(s, 3H), 2.98 (t, J ¼ 6.8 Hz, 2H), 2.89 (s, 1H), 2.10 (dt, J ¼ 18.2, 9.3 Hz,
1H), 1.84 (td, J ¼ 13.0, 6.8 Hz, 1H), 1.72 (p, J ¼ 6.8 Hz, 2H), resonance
N-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-
yl)acetamide (46). The reaction was carried out according to the
General acylation procedure 2, starting from 6-amino-1-methyl-
for NH missing; 13C NMR (126 MHz, DMSO‑d6)
d 171.83, 168.68,
133.78, 133.17, 126.86, 114.80, 109.52, 100.57, 60.56, 46.56, 38.22,
29.91, 25.38; HRMS (APCIþ) m/z [MþH]þ, calcd. for C13H17N4OS:
277.1123, found: 277.1127; Purity by HPLC: 98%.
1,3-dihydro-2H-benzo[d]imidazole-2-thione
0.30 mmol), HATU (136 mg, 0.36 mmol), acetic acid (17
0.36 mmol), and Et3N (50 L 0.36 mmol) to give compound 45
(22 mg, 33% yield) as a white solid. Mp.: 185 ꢀC; 1H NMR (500 MHz,
(42,
54
mg,
mL,
m
4.9. Preparation of 7-(acylamino)benzo[d]oxazole-2(3H)-thione
derivatives 65, 67, and 69
DMSO‑d6)
d
12.63 (s, 1H), 10.00 (s, 1H), 7.75 (s, 1H), 7.22 (dd, J ¼ 8.5,
1.3 Hz,1H), 7.10 (d, J ¼ 8.5 Hz,1H), 3.60 (s, 3H), 2.05 (s, 3H); 13C NMR
(126 MHz, DMSO‑d6)
d
168.47, 168.10, 134.73, 133.08, 126.48, 114.58,
N-(2-thioxo-2,3-dihydrobenzo[d]oxazol-7-yl)benzamide
(65). The reaction was carried out according to the General acyla-
tion procedure 2, starting from 7-aminobenzo[d]oxazole-2(3H)-
thione (63, 40 mg, 0.24 mmol), HATU (110 mg, 0.29 mmol), benzoic
109.51, 100.33, 29.88, 23.95; HRMS (ESIþ) m/z [MþH]þ, calcd. for
C
10H12N3OS: 222.0701, found: 222.0702; Purity by HPLC: 100%.
N-(3-methyl-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-
yl)benzamide (49). The reaction was carried out according to the
General acylation procedure 2, starting from 6-amino-1-methyl-
acid (35 mg, 0.29 mmol), and Et3N (40
compound 65 (35 mg, 54% yield) as a white solid. Mp.: 218 ꢀC; 1H
NMR (500 MHz, DMSO‑d6) 13.75 (s, 1H), 10.53 (s, 1H), 8.04e8.00
mL, 0.29 mmol) to give
1,3-dihydro-2H-benzo[d]imidazole-2-thione
0.30 mmol), HATU (136 mg, 0.36 mmol), benzoic acid (44 mg,
0.36 mmol), and Et3N (50 L, 0.36 mmol) to give compound 49
(29 mg, 34% yield) as a white solid. Mp.: 265 ꢀC; 1H NMR (500 MHz,
(42,
54
mg,
d
(m, 2H), 7.65e7.60 (m, 1H), 7.55 (dd, J ¼ 10.3, 4.7 Hz, 2H), 7.36 (dd,
m
J ¼ 8.1, 0.8 Hz, 1H), 7.29 (t, J ¼ 8.0 Hz, 1H), 7.10 (dd, J ¼ 7.8, 0.9 Hz,
1H); 13C NMR (126 MHz, DMSO‑d6)
d 179.82, 165.22, 141.69, 133.62,
DMSO‑d6)
d
12.69 (s,1H), 10.30 (s, 1H), 8.02e7.89 (m, 3H), 7.62e7.49
132.83, 131.94, 128.42, 127.85, 124.92, 121.38, 119.49, 107.41; HRMS
(ESIþ) m/z [MþH]þ, calcd. for C14H11N2O2S: 271.0541, found:
271.0538; Purity by HPLC: 100%.
(m, 4H), 7.17 (d, J ¼ 8.4 Hz, 1H), 3.64 (s, 3H); 13C NMR (126 MHz,
DMSO‑d6)
d 168.67, 165.36, 134.86, 134.43, 133.05, 131.46, 128.33,
127.53, 127.02, 116.02, 109.35, 101.75, 29.90; HRMS (APCIþ) m/z
2-(Pyridin-3-yl)-N-(2-thioxo-2,3-dihydrobenzo[d]oxazol-7-
15