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D. Chen et al. / European Journal of Medicinal Chemistry 163 (2019) 597e609
4.32 (s, 2H), 2.44 (d, J ¼ 7.3 Hz, 2H), 2.09e1.95 (m, 1H), 0.91 (d,
J ¼ 6.6 Hz, 6H). HPLC tR ¼ 3.29 min, purity: 100%. MS (ESI): m/z 338
[MþH]þ.
was removed by vacuum and the residue was purified by sil gel
chromatography (CH2Cl2: MeOH 20:1) to get the corresponding
product.
4-(((4-Benzyl-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-
(4-fluorophenyl)benzamide (19). Using compound m12 as the acid
and 4-fluoroaniline as the amine. Yellow solid, yield 46%. 1H NMR
4-Benzyl-3-isobutyl-5-((4-methoxybenzyl)thio)-4H-1,2,4-
triazole (16). Using 1-(bromomethyl)-4-methoxybenzene as the
benzyl bromide. Yellow thick oil, yield 81%. 1H NMR (400 MHz,
Chloroform-d)
d
7.31e7.23 (m, 3H), 7.20e7.12 (m, 2H), 6.87 (dd,
(400 MHz, DMSO‑d6)
d
10.27 (s, 1H), 7.86 (d, J ¼ 8.2 Hz, 2H),
J ¼ 6.6, 2.9 Hz, 2H), 6.83e6.74 (m, 2H), 4.83 (s, 2H), 4.29 (s, 2H), 3.78
(s, 3H), 2.44 (d, J ¼ 7.2 Hz, 2H), 2.09e1.94 (m, 1H), 0.91 (d, J ¼ 6.6 Hz,
7H). HPLC tR ¼ 3.42 min, purity: 95.19%. MS (ESI): m/z 368 [MþH]þ.
4-Benzyl-3-isobutyl-5-((3-methoxybenzyl)thio)-4H-1,2,4-
7.81e7.75 (m, 2H), 7.45 (d, J ¼ 8.1 Hz, 2H), 7.36e7.25 (m, 3H), 7.19 (t,
J ¼ 8.9 Hz, 2H), 6.98 (dd, J ¼ 7.6, 1.8 Hz, 2H), 5.07 (s, 2H), 4.38 (s, 2H),
2.27 (s, 3H). HPLC tR ¼ 3.11 min, purity: 95.25%. MS (ESI): m/z 433
[MþH]þ.
triazole (17). Using 1-(bromomethyl)-3-methoxybenzene as the
4-(((4-benzyl-5-ethyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-(4-
fluorophenyl)benzamide (20). Using compound m13 as the acid
and 4-fluoroaniline as the amine. White solid, yield 53%. 1H NMR
benzyl bromide. Yellow thick oil, yield 90%. 1H NMR (400 MHz,
Chloroform-d) d 7.32e7.27 (m, 4H), 6.92e6.77 (m, 5H), 4.83 (s, 2H),
4.30 (s, 2H), 3.75 (s, 3H), 2.45 (d, J ¼ 7.1 Hz, 2H), 2.07e1.95 (m, 1H),
(400 MHz, DMSO‑d6)
d
10.26 (s, 1H), 7.87 (d, J ¼ 8.3 Hz, 2H),
0.91 (d, J ¼ 6.6 Hz, 6H). 13C NMR (126 MHz, DMSO)
d
159.67, 155.57,
7.82e7.73 (m, 2H), 7.45 (d, J ¼ 8.3 Hz, 2H), 7.35e7.25 (m, 3H), 7.19 (t,
J ¼ 8.9 Hz, 2H), 6.99e6.92 (m, 2H), 5.07 (s, 2H), 4.39 (s, 2H), 2.59 (q,
J ¼ 7.5 Hz, 2H), 1.12 (t, J ¼ 7.5 Hz, 3H). 13C NMR (126 MHz, DMSO)
149.05, 139.15, 136.22, 129.97, 129.22, 128.22, 126.79, 121.53, 114.84,
113.54, 55.44, 46.53, 38.07, 33.65, 26.99. HPLC tR ¼ 3.30 min, purity:
100%. MS (ESI): m/z 368 [MþH]þ.
d
165.51, 157.35, 149.00, 141.61, 136.07, 134.23, 129.38, 129.28,
4-(((4-Benzyl-5-isobutyl-4H-1,2,4-triazol-3-yl)thio)methyl)
benzamide (18). Using 4-(bromomethyl)benzamide as the benzyl
bromide. White wax, yield 71%. 1H NMR (400 MHz, Chloroform-d)
128.23,126.91,122.66,115.73,115.56, 46.55, 37.18,18.62,11.56. HPLC
tR ¼ 3.27 min, purity: 100%. MS (ESI): m/z 447 [MþH]þ.
4-(((4-benzyl-5-isobutyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-
(4-fluorophenyl)benzamide (21). Using compound m14 as the acid
and 4-fluoroaniline as the amine. Off-white solid, yield 48%. 1H
d
7.77e7.69 (m, 2H), 7.38e7.33 (m, 2H), 7.31e7.27 (m, 3H), 6.87 (m,
2H), 6.38e6.32 (m, 1H), 5.81 (s, 1H), 4.87 (s, 2H), 4.35 (s, 2H), 2.44
(d, J ¼ 7.3 Hz, 2H), 2.09e1.93 (m, 1H), 0.90 (d, J ¼ 6.7 Hz, 6H). 13C
NMR (400 MHz, DMSO‑d6)
d
10.26 (s, 1H), 7.86 (d, J ¼ 8.2 Hz, 2H),
NMR (126 MHz, DMSO)
d
167.91, 155.62, 148.84, 141.08, 136.17,
7.83e7.73 (m, 2H), 7.43 (d, J ¼ 8.2 Hz, 2H), 7.36e7.23 (m, 3H), 7.19 (t,
J ¼ 8.9 Hz, 2H), 6.98e6.90 (m, 2H), 5.06 (s, 2H), 4.38 (s, 2H), 2.47 (d,
J ¼ 7.2 Hz, 2H), 1.95e1.79 (m, 1H), 0.83 (d, J ¼ 6.6 Hz, 6H). 13C NMR
133.77, 129.21, 128.22, 128.06, 126.78, 46.58, 37.48, 33.63, 26.96,
22.55. HPLC tR ¼ 2.79 min, purity: 98.11%. MS (ESI): m/z 381
[MþH]þ.
(126 MHz, DMSO)
d 165.47, 159.70, 157.79, 155.67, 148.83, 141.58,
4-(((4-Benzyl-5-methyl-4H-1,2,4-triazol-3-yl)thio)methyl)ben-
zoic acid (m12). The intermediate m9 was prepared using general
procedure A by compound m7 coupling with ethyl 4-(bromo-
methyl)benzoate. The crude product was dissolved in MeOH: H2O
(3:1) 4 mL and added LiOH 800 mg. The mixture was stirred at 60 ꢀC
for 5 h and then overnight at room temperature. The reaction was
diluted with water and washed with ethyl acetate. The aqueous
layer was adjusted to pH3 by 1N HCl and extracted with ethyl ac-
etate. The organic layer was washed with brine, dried with Na2SO4,
concentrated to get the product as pale yellow solid 582 mg, total
136.17, 135.92, 134.19, 129.37, 129.24, 128.25, 128.22, 126.80, 122.68,
122.61, 115.73, 115.56, 46.60, 37.35, 33.62, 26.98, 22.56. HPLC
tR ¼ 3.37 min, purity: 97.71%. MS (ESI): m/z 475 [MþH]þ. HRMS
(ESIþ) calcd for C27H28FN4OS [MþH] 475.1962, found 475.1976.
4-(((4-benzyl-5-isobutyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-
phenylbenzamide (22). Using compound m14 as the acid and ani-
line as the amine. White solid, yield 50%. 1H NMR (400 MHz,
DMSO‑d6)
d
10.20 (s, 1H), 7.87 (d, J ¼ 8.5 Hz, 2H), 7.76 (d, J ¼ 8.1 Hz,
2H), 7.43 (d, J ¼ 8.1 Hz, 2H), 7.38e7.26 (m, 5H), 7.10 (t, J ¼ 7.6 Hz,1H),
6.94 (d, J ¼ 6.8 Hz, 2H), 5.05 (s, 2H), 4.38 (s, 2H), 2.47 (d, J ¼ 7.1 Hz,
2H), 1.93e1.83 (m, 1H), 0.83 (d, J ¼ 6.5 Hz, 6H). HPLC tR ¼ 3.35 min,
purity: 98.92%. MS (ESI): m/z 457 [MþH]þ. HRMS (ESIþ) calcd for
yield 70%. 1H NMR (400 MHz, DMSO‑d6)
d 12.97e12.88 (m, 1H), 7.86
(d, J ¼ 8.0 Hz, 2H), 7.41 (d, J ¼ 8.0 Hz, 2H), 7.30 (d, J ¼ 6.2 Hz, 3H),
7.00e6.93 (m, 2H), 5.06 (s, 2H), 4.37 (s, 2H), 2.25 (d, J ¼ 7.1 Hz, 3H).
MS (ESI): m/z 340 [MþH]þ.
C
27H29N4OS [MþH] 457.2057, found 457.2055.
4-(((4-benzyl-5-isobutyl-4H-1,2,4-triazol-3-yl)thio)methyl)-N-
4-(((4-Benzyl-5-ethyl-4H-1,2,4-triazol-3-yl)thio)methyl)ben-
zoic acid (m13). Prepared by the same method of compound m12
starting with compound m8. White solid, yield 56%. 1H NMR
(4-(dimethylamino)phenyl)benzamide (23). Using compound m14
as the acid and N1,N1-dimethylbenzene-1,4-diamine as the amine.
Brown solid, yield 78%. 1H NMR (400 MHz, DMSO‑d6)
d 9.94 (s, 1H),
(400 MHz, DMSO‑d6)
d
12.97 (s, 1H), 7.89e7.82 (m, 2H), 7.44e7.37
7.85 (d, J ¼ 8.2 Hz, 2H), 7.56 (d, J ¼ 9.0 Hz, 2H), 7.40 (d, J ¼ 8.1 Hz,
2H), 7.36e7.23 (m, 3H), 6.97e6.90 (m, 2H), 6.72 (d, J ¼ 9.1 Hz, 2H),
5.05 (s, 2H), 4.37 (s, 2H), 2.87 (s, 6H), 2.47 (d, J ¼ 7.2 Hz, 2H),
1.93e1.79 (m, 1H), 0.83 (d, J ¼ 6.6 Hz, 6H). 13C NMR (126 MHz,
(m, 2H), 7.35e7.23 (m, 3H), 6.98e6.90 (m, 2H), 5.05 (s, 2H), 4.38 (s,
2H), 2.59 (q, J ¼ 7.5 Hz, 2H), 1.12 (t, J ¼ 7.5 Hz, 3H). MS (ESI): m/z 354
[MþH]þ.
4-(((4-Benzyl-5-isobutyl-4H-1,2,4-triazol-3-yl)thio)methyl)
benzoic acid (m14). Prepared by the same method of compound
m12 starting with compound 13. Pale yellow solid, yield 86%. 1H
DMSO) d 164.73, 155.66, 148.86, 147.79, 141.07, 136.19, 134.65,
129.27, 129.24, 128.25, 128.06, 126.80, 122.30, 112.91, 46.60, 40.93,
37.43, 33.63, 26.98, 22.57. HPLC tR ¼ 2.82 min, purity: 99.36%. MS
(ESI): m/z 500 [MþH]þ. HRMS (ESIþ) calcd for C29H33N5NaOS
[MþNa] 522.2298, found 522.2297.
NMR (400 MHz, DMSO‑d6)
d 7.88e7.80 (m, 2H), 7.42e7.34 (m, 2H),
7.34e7.22 (m, 3H), 6.95e6.88 (m, 2H), 5.02 (s, 2H), 4.36 (s, 2H), 2.46
(d, J ¼ 7.2 Hz, 2H), 1.93e1.78 (m, 1H), 0.82 (d, J ¼ 6.6 Hz, 6H). 13C
N-([1,10-biphenyl]-4-yl)-4-(((4-benzyl-5-isobutyl-4H-1,2,4-
triazol-3-yl)thio)methyl)benzamide (24). Using compound m14 as
the acid and [1,10-biphenyl]-4-amine as the amine. Yellow solid,
NMR (126 MHz, DMSO)
d 167.49, 155.66, 148.71, 142.87, 136.17,
130.37, 129.87, 129.50, 129.20, 128.22, 126.77, 46.55, 37.53, 33.60,
26.99, 22.53. MS (ESI): m/z 382 [MþH]þ. HRMS (ESIþ) calcd for
yield 54%. 1H NMR (400 MHz, DMSO‑d6)
d 10.31 (s, 1H), 7.93e7.84
C
21H24N3O2S [MþH] 382.1584, found 382.1573.
(m, 4H), 7.72e7.64 (m, 4H), 7.50e7.41 (m, 4H), 7.39e7.23 (m, 4H),
6.98e6.91 (m, 2H), 5.06 (s, 2H), 4.39 (s, 2H), 2.48 (d, J ¼ 7.2 Hz, 2H),
1.95e1.81 (m, 1H), 0.84 (d, J ¼ 6.6 Hz, 6H). 13C NMR (126 MHz,
General procedure B for compounds 19e32. The acids (m12-
m14, 1 eq.), amines (2 eq.), 1-Ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (1 eq.) and 4-dimethylaminopyridine
(0.1 eq.) were dissolved in N,N-dimethylformamide and the
mixture was stirred at room temperature overnight. The solvent
DMSO)
d 165.58, 155.68, 148.84, 141.59, 140.15, 139.09, 136.18,
135.75,134.32,129.38,129.25,128.28,127.54,127.26,126.80,126.75,
121.11, 46.61, 37.36, 33.62, 26.98, 22.57. HPLC tR ¼ 3.79 min, purity: