Journal of Medicinal Chemistry
Article
N-(3-Aminophenyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-
= 8.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.63 (s, 2H), 7.69 (s, 1H),
7.81−7.89 (m, 2H), 8.62 (d, J = 5.5 Hz, 2H), 12.82 ppm (br s, 1H,
1
H-indole-2-carboxamide (5). 5 was synthesized as that for 4 starting
−1
from 21 and benzene-1,3-diamine. Yield 52%, mp 218−220 °C (from
disappeared on treatment with D O). IR: ν 1689, 2923, 3554 cm .
2
ethanol). 1H NMR (DMSO-d ): δ 2.29 (s, 6H), 5.21 (br, 2H,
6
Anal. (C H ClN O S (454.93)) C, H, Cl, N, S.
22 19
4
3
disappeared on treatment with D O), 6.37 (d, J = 8.6 Hz, 1H), 6.80 (d,
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-(N′-methylamino-N′-
2
J = 7.6 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 7.09 (s, 1H), 7.25 (s, 1H),
phenyl)-1H-indole-2-carbohydrazide (15). 15 was synthesized as that
7
.35 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.64 (s, 2H), 7.92
for 4 starting from 21 and 1-methyl-1-phenylhydrazine. Yield 71%, mp
1
(
s, 1H), 10.60 (br s, 1H, disappeared on treatment with D O), 13.15
200 °C dec (from ethanol). H NMR (DMSO-d ): δ 2.30 (s, 6H),
2
6
ppm (br s, 1H, disappeared on treatment with D O). IR: ν 1660, 3269
3.26 (s, 3H), 6.82 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.3 Hz, 2H), 7.23−
7.28 (m, 3H), 7.36 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.70
(s, 2H), 7.87 (s, 1H), 10.86 (s, 1H, disappeared on treatment with
D O), 13.21 ppm (br s, 1H, disappeared on treatment with D O). IR:
2
−1
cm . Anal. (C H ClN O S (453.95)) C, H, Cl, N, S.
23
20
3
3
5
-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(pyrimidin-4-yl-
methyl)-1H-indole-2-carboxamide (6). 6 was synthesized as 4
starting from 21 and pyrimidin-4-ylmethanamine. Yield 77%, mp
2
4
2
2
−1
ν 1641, 3219 cm . Anal. (C H ClN O S (467.97)) C, H, Cl, N, S.
24 22 3 3
1
25−230 °C (from ethanol). H NMR (DMSO-d ): δ 2.28 (s, 6H),
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(furan-2-ylmethyl)-
1H-indole-2-carboxamide (16). 16 was synthesized as that for 4
6
.68 (d, J = 5.5 Hz, 2H), 7.26 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.56
(
1
d, J = 8.6 Hz, 1H), 7.67 (s, 3H), 7.94 (s, 1H), 8.81 (d, J = 5.2 Hz,
H), 9.16 (s, 1H), 9.67 (br s, 1H, disappeared on treatment with
D O), 13.13 ppm (br s, 1H, disappeared on treatment with D O). IR:
starting from 21 and furan-2-ylmethanamine. Yield 42%, mp 200 °C
1
dec (from ethanol). H NMR (DMSO-d ): δ 2.29 (s, 6H), 4.58 (d, J =
6
5.4 Hz, 2H), 6.45 (s, 2H), 7.25 (s, 1H), 7.33−7.35 (m, 1H), 7.53 (d, J
2
2
−1
ν 1648, 3220 cm . Anal. (C H ClN O S (454.93)) C, H, Cl, N, S.
= 9.0 Hz, 1H), 7.59 (s, 2H), 7.65 (s, 1H), 7.93−7.95 (m, 1H), 9.42 (br
22
19
4
3
5
-Chloro-3-((2,6-dimethylphenyl)sulfonyl)-N-(pyridin-4-ylmeth-
s, 1H, disappeared on treatment with D O), 13.05 ppm (br s, 1H,
2
−1
yl)-1H-indole-2-carboxamide (9). 9 was synthesized as that for 4
starting from 22 and pyridin-4-ylmethanamine. Yield 40%, mp 230−
2
disappeared on treatment with D O)). IR: ν 1637, 3210 cm . Anal.
2
(C H ClN O S (442.92)) C, H, Cl, N, S.
22
19
2
4
1
35 °C (from ethanol). H NMR (DMSO-d ): δ 2.44 (s, 6H), 4.38 (d,
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(thiophen-2-ylmeth-
yl)-1H-indole-2-carboxamide (17). 17 was synthesized as that for 4
6
J = 5.7 Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 5.2 Hz, 2H),
7
5
1
3
.34−7.40 (m, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 8.49 (d, J =
starting from 21 and thiophen-2-ylmethanamine. Yield 73%, mp 252−
1
.0 Hz, 2H), 9.22 (br s, 1H, disappeared on treatment with D O),
255 °C (from ethanol). H NMR (DMSO-d ): δ 2.27 (s, 6H), 4.75 (d,
2
6
3.02 ppm (br s, 1H, disappeared on treatment with D O). IR: ν 1638,
J = 5.6 Hz, 2H), 7.00−7.03 (m, 1H), 7.15−7.16 (m, 1H), 7.25 (s, 1H),
7.33 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 4.9 Hz, 1H), 7.53 (d, J = 8.5 Hz,
1H), 7.58 (s, 2H), 7.95 (s, 1H) 9.51 (br s, 1H, disappeared on
2
−1
251 cm . Anal. (C H ClN O S (453.94)) C, H, Cl, N, S.
23
20
3
3
5
-Chloro-3-((2,6-dichlorophenyl)sulfonyl)-N-(pyridin-4-ylmethyl)-
1
H-indole-2-carboxamide (10). 10 was synthesized as that for 4
treatment with D O), 13.07 ppm (br s, 1H, disappeared on treatment
2
−1
starting from 23 and pyridin-4-ylmethanamine. Yield 39%, mp 210−
with D O)). IR: ν 1647, 2922, 3231 cm . Anal. (C H ClN O S
2
22 19
2
3
2
1
2
2
14 °C (from ethanol). H NMR (DMSO-d ): δ 4.48 (d, J = 5.8 Hz,
H), 7.35−7.37 (m, 3H), 7.54−7.60 (m, 4H), 7.92 (s, 1H), 8.50 (d, J
(458.98)) C, H, Cl, N, S.
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-(thiophen-2-yl)-
ethyl)-1H-indole-2-carboxamide (18). 18 was synthesized as that for
6
=
5.6 Hz, 2H), 9.32 (br s, 1H, disappeared on treatment with D O),
2
1
3.19 ppm (br s, 1H, disappeared on treatment with D O). IR: ν 1635,
4 starting from 21 and 1-(thiophen-2-yl)ethanamine. Yield 41%, mp
2
−
1
1
3
269, 3321 cm . Anal. (C H Cl N O S (494.78)) C, H, Cl, N, S.
215−217 °C (from ethanol). H NMR (DMSO-d ): δ 1.62 (d, J = 6.8
21
14
3
3
3
6
5
-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-(pyridin-4-yl)-
Hz, 3H), 2.28 (s, 6H), 5.44−5.50 (m, 1H), 7.00−7.03 (m, 1H), 7.16−
7.17 (m, 1H), 7.26 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 5.0
Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.58 (s, 2H), 7.94 (s, 1H) 9.48 (d, J
ethyl)-1H-indole-2-carboxamide (11). 11 was synthesized as that for
4
starting from 21 and 1-(pyridin-4-yl)ethanamine. Yield 71%, mp
1
2
13-216 °C (from ethanol). H NMR (DMSO-d ): δ 1.51 (d, J = 6.9
= 7.9 Hz, 1H, disappeared on treatment with D O), 13.03 ppm (br s,
6
2
−1
Hz, 3H), 2.28 (s, 6H), 5.17−5.20 (m, 1H), 7.25 (s, 1H), 7.34 (d, J =
1H, disappeared on treatment with D O)). IR: ν 1644, 3238 cm .
2
8
2
.8 Hz, 1H), 7.48 (d, J = 4.8 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.60 (s,
H), 7.92 (s, 1H), 8.55 (d, J = 4.8 Hz, 2H), 9.46 (d, J = 6.8 Hz, 1H
Anal. (C H ClN O S (473.01)) C, H, Cl, N, S.
23
21
2
3 2
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(thiophen-2-yl)-
ethyl)-1H-indole-2-carboxamide (19). 19 was synthesized as that for
disappeared on treatment with D O), 13.04 ppm (br s, 1H,
disappeared on treatment with D O). IR: ν 1658, 2923, 3312 cm .
Anal. (C H ClN O S (467.97)) C, H, Cl, N, S.
2
−1
4 starting from 21 and 2-(thiophen-2-yl)ethanamine. Yield 82%, mp
2
1
222−224 °C (from ethanol). H NMR (DMSO-d ): δ 2.31 (s, 6H),
24
22
3
3
6
5
-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-(pyridin-2-yl)-
3.09−3.17 (m, 2H), 3.58−3.68 (m, 2H), 6.96−7.00 (m, 2H), 7.26 (s,
1H), 7.32−7.39 (m, 2H), 7.52−7.57 (m, 1H), 7.62 (s, 2H), 7.93 (d, J
= 3.3 Hz, 1H), 9.17 (br s, 1H, disappeared on treatment with D O),
ethyl)-1H-indole-2-carboxamide (12). 12 was synthesized as that for
4
2
3
4
4
starting from 21 and 1-(pyridin-2-yl)ethanamine. Yield 43%, mp
2
1
22−225 °C (from ethanol). H NMR (CDCl ): δ 1.72 (d, J = 6.4 Hz,
13.05 ppm (br s, 1H, disappeared on treatment with D O)). IR: ν
3
2
−1
H), 2.29 (s, 6H), 5.41−5.44 (m, 1H), 7.15 (s, 1H), 7.21−7.35 (m,
H), 7.59 (s, 2H), 7.68 (t, J = 7.4 Hz, 1H), 8.30 (s, 1H), 8.68 (d, J =
.6 Hz, 1H), 10.28 (d, J = 6.8 Hz, 1H, disappeared on treatment with
1652, 2854, 3238 cm . Anal. (C H ClN O S (473.01)) C, H, Cl,
23 21 2 3 2
N, S.
5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(2-methyl-5-
nitro-1H-imidazol-1-yl)ethyl)-1H-indole-2-carboxamide (20). 20 was
synthesized as that for 4 starting from 21 and 2-(2-methyl-5-nitro-1H-
D O), 10.64 ppm (br s, 1H, disappeared on treatment with D O). IR:
2
2
−1
ν 1647, 3212, 3277 cm . Anal. (C H ClN O S (467.97)) C, H, Cl,
24
22
3
3
N, S.
-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-(pyridin-3-yl)-
ethyl)-1H-indole-2-carboxamide (13). 13 was synthesized as that for
imidazol-1-yl)ethanamine. Yield 78%, mp 232−234 °C (from
1
5
ethanol). H NMR (DMSO-d ): δ 2.32 (s, 6H), 2.49 (s, 3H), 3.74−
6
3.77 (m, 2H), 4.48−4.54 (m, 2H), 7.27 (s, 1H), 7.32−7.38 (m, 1H),
4
starting from 21 and 1-(pyridin-3-yl)ethanamine. Yield 40%, mp
7.52−7.56 (m, 1H), 7.63 (s, 2H), 7.92 (d, J = 3.0 Hz, 1H), 8.06 (s,
1
2
80−284 °C (from ethanol). H NMR (DMSO-d ): δ 1.54 (d, J = 6.8
1H), 9.23 (br s, 1H, disappeared on treatment with D O), 12.89 ppm
6
2
Hz, 3H), 2.28 (s, 6H), 5.22−5.27 (m, 1H), 7.24 (s, 1H), 7.30−7.34
(br s, 1H, disappeared on treatment with D O)). IR: ν 1600, 2933
2
−1
(
m, 1H), 7.37−7.41 (m, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.58 (s, 2H),
.87 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 8.49 (d, J = 4.3 Hz, 1H), 8.70
s, 1H), 9.43 (br s, 1H, disappeared on treatment with D O), 13.02
cm . Anal. (C H ClN O S (515.97)) C, H, Cl, N, S.
23 22 5 5
7
(
General Procedure for the Preparation of Derivatives 7 and
8. Example: 5-Chloro-3-((2,6-dimethylphenyl)sulfonyl)-1H-indole-2-
carboxamide (7). Ammonium hydroxide (30%, 6.5 mL) was added to
a suspension of 29 (110 mg, 0.28 mmol) in ethanol (11 mL). The
reaction mixture was stirred for 30 min at 60 °C; then, 30%
ammonium hydroxide (6.5 mL) was added again, and the reaction was
heated at 60 °C overnight. After cooling, the mixture was diluted with
water and extracted with ethyl acetate. The organic layer was washed
with brine, dried, and filtered. Removal of the solvent gave a residue
2
ppm (br s, 1H, disappeared on treatment with D O). IR: ν 1655, 2923,
2
−1
cm . Anal. (C H ClN O S (467.97)) C, H, Cl, N, S.
24
22
3
3
5
-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(N′-(pyridin-4-yl)-
amino)-1H-indole-2-carbohydrazide (14). 14 was synthesized as that
for 4 starting from 21 and 4-hydrazinylpyridine. Yield 47%, mp 231−
1
2
(
34 °C (from ethanol). H NMR (DMSO-d ): δ 2.31 (s, 6H), 5.59
6
br, 2H, disappeared on treatment with D O), 7.25 (s, 1H), 7.29 (d, J
2
I
dx.doi.org/10.1021/jm5011622 | J. Med. Chem. XXXX, XXX, XXX−XXX