Journal of Medicinal Chemistry
Article
Acid (22b). Intermediate 22b was prepared in 70% yield from 21b
using a similar procedure as that for 22a. 1H NMR (300 MHz, CCl3D)
δ 8.13 (d. J = 9.2, 2H), 7.28 (d, J = 8.2, 2H), 7.12 (d, J = 8.3, 2H), 7.05
(t, J = 7.8, 1H), 6.83 (d, J = 9.3, 2H), 6.73−6.66 (m, 3H), 3.85 (q, J =
7.1, 2H), 3.46−3.45 (m, 4H), 3.17−3.15 (m, 4H), 2.64 (s, 3H), 1.18
(t, J = 7.0, 3H); 13C NMR (75 MHz, CCl3D) δ 170.8, 154.8, 149.4,
138.4, 137.1, 135.7, 133.8, 132.7, 130.6, 130.3, 128.6, 128.1, 126.0,
124.7, 123.2, 119.9, 114.2, 112.6, 109.9, 48.9, 46.7, 39.2, 16.0, 12.0. ESI
MS: m/z 545.5 (M + H)+.
3H), 7.10−7.01 (m, 3H), 6.95 (d, J = 8.8, 2H), 6.81 (d, J = 8.9, 2H),
6.71−6.63 (m, 3H), 4.43−4.34 (m, 1H), 3.18−3.10 (m, 8H), 2.73 (s,
3H), 1.45 (d, J = 7.0, 6H); 13C NMR (75 MHz, CCl3D) δ 169.7,
150.1, 149.9, 137.2, 137.0, 136.9, 136.5, 136.4, 135.9, 134.4, 134.3,
133.8, 133.1, 131.3, 130.8, 128.3, 128.1, 126.5, 125.9, 125.5, 124.6,
123.1, 119.6, 119.3, 116.6, 114.4, 110.8, 49.3, 48.8, 48.7, 22.2, 13.5. ESI
MS: m/z 754.2 (M + Na)+.
(R)-5-(4-Chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-
(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-
phenyl)piperazin-1-yl)phenyl)-1,2-dimethyl-1H-pyrrole-3-car-
boxylic Acid (12). DIEA (70 μL, 0.4 mmol) was added to a solution
of 23a (158 mg, 0.22 mmol) and (R)-N1,N1-dimethyl-4-phenylthio)-
butane-1,3-diamine (51 mg, 0.22 mmol) in DMF. The solution was
stirred overnight and concentrated. The residue was purified by HPLC
to afford 12 (145 mg, 71%). 1H NMR (300 MHz, CD3OD) δ 8.30 (d,
J = 2.2 Hz, 1H), 7.59 (dd, J = 2.2, 9.2, 1H), 7.26−7.23 (m, 2H), 7.18−
7.13 (m, 3H), 7.09−6.88 (m, 13H), 4.10−4.07 (m, 1H), 3.40 (s, 3H),
3.36−3.29 (m, 9H), 3.21−3.15 (m, 3H), 2.83 (s, 6H), 2.58 (s, 3H),
2.26−2.10 (m, 2H); 13C NMR (75 MHz, CD3OD), δ 169.1, 148.5,
148.0, 146.9, 139.0, 138.4, 136.2, 134.8, 134.4, 134.0, 132.3, 132.2,
132.1, 131.9, 131.6, 130.1, 129.6, 129.5, 129.0, 128.0, 127.9, 127.6,
124.8, 124.3, 122.9, 118.9, 117.2, 116.2, 111.5, 55.9, 53.2, 52.4, 50.1,
43.5, 39.5, 32.2, 30.1, 12.1. ESI MS: m/z 908.9 (M + H)+ .
5-(4-Chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-
nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic
Acid (22c). Intermediate 22c was prepared from 21c in 73% yield by a
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similar procedure as that for compound 22a. H NMR (300 MHz,
CCl3D) δ 11.8 (br, 1H), 8.13 (d, J = 9.1, 2H), 7.27 (d, J = 8.6, 2H),
7.10 (d, J = 8.2, 2H), 7.03 (t, J = 8.2, 1H), 6.83 (d, J = 9.2, 2H), 6.67−
6.53 (m, 3H), 4.44−4.35 (m, 1H), 3.46 (br, 4H), 3.14 (br, 4H), 2.73
(s, 3H), 1.45 (d, J = 7.0, 6H); 13C NMR (75 MHz, CCl3D), δ 170.9,
154.8, 149.4, 138.4, 137.0, 136.0, 133.8, 133.1, 131.4, 130.8, 128.4,
128.0, 126.0, 124.6, 123.2, 119.8, 114.1, 112.6, 110.9, 48.9, 48.8, 46.7,
22.3, 13.5. ESI MS: m/z 559.6 (M + H)+.
5-(4-Chlorophenyl)-1-cyclopropyl-2-methyl-4-(3-(4-(4-
nitrophenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic
Acid (22d). Intermediate 22d was prepared from 21d in 76% yield by
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a similar procedure as that for compound 22a. H NMR (300 MHz,
(R)-5-(4-Chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-
(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-
phenyl)piperazin-1-yl)phenyl)-1-ethyl-2-methyl-1H-pyrrole-3-
carboxylic Acid (14). Compound 14 was prepared from 23b in 81%
CCl3D) δ 8.13 (d, J = 9.3, 2H), 7.22 (d, J = 8.4, 2H), 7.12−7.05 (m,
3H), 6.83 (d, J = 8.4, 2H), 6.74−6.70 (m, 2H), 6.64 (d, J = 7.5, 1H),
3.48−3.45 (m, 4H), 3.18−3.15 (m, 5H), 2.70 (s, 3H), 0.93−0.86 (m,
2H), 0.56−0.53 (m, 2H); 13C NMR (75 MHz, CCl3D) δ 170.2, 154.8,
149.6, 140.6, 138.4, 135.8, 132.9, 132.0, 131.5, 131.0, 128.2, 128.1,
125.9, 123.9, 123.3, 120.0, 114.4, 112.6, 110.1, 48.9, 46.7, 27.3, 13.2,
9.7. ESI MS: m/z 557.9 (M + H)+.
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yield using a similar procedure as that for compound 12. H NMR
(300 MHz, CD3OD) δ 8.24 (d, J = 2.1, 1H), 7.54 (dd, J = 2.1, 9.1,
1H), 7.20 (d, J = 8.4, 2H), 7.12−6.85 (m, 16H), 4.06−4.03 (m, 1H),
3.80 (q, J = 7.1, 2H), 3.28−3.24 (m, 9H), 3.16−3.09 (m, 3H), 2.78 (s,
6H), 2.54 (s, 3H), 2.22−2.06 (m, 2H), 1.03 (t, J = 7.1, 3H); 13C NMR
(75 MHz, CD3OD) δ 169.1, 148.1, 148.0, 145.9, 139.1, 137.4, 136.2,
135.1, 134.4, 134.3, 132.6, 132.1, 132.0, 131.7, 131.6, 130.1, 129.64,
129.58, 128.0, 127.9, 127.4, 125.1, 124.1, 123.1, 119.0, 117.5, 116.4,
111.7, 55.9, 53.6, 52.4, 50.0, 43.5, 40.2, 39.5, 30.1, 16.2, 12.0. ESI MS:
m/z 922.6 (M + H)+.
5 - ( 4 - C h l o r o p h e n y l ) - 4 - ( 3 - ( 4 - ( 4 - ( 4 - fl u o r o - 3 -
nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1,2-di-
methyl-1H-pyrrole-3-carboxylic Acid (23a). To a solution of
compound 22a (1.2 g, 2.3 mmol) in a mixture of CH2Cl2 (10 mL) and
MeOH (10 mL) was added 10% Pd−C (120 mg). The solution was
stirred under 1 atm of H2 at room temperature for 0.5 h before
filtering through Celite and being concentrated. The resulting aniline
was used in the next step without purification. To this aniline in
pyridine (20 mL), 4-fluoro-3-nitrobenzene-1-sulfonyl chloride (0.54 g,
2.3 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30
min. The pyridine was removed under vacuum and the residue was
purified by flash chromatography on silica gel (3:2 ethyl acetate/
(R)-5-(4-Chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-
(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)-
phenyl)piperazin-1-yl)phenyl)-1-isopropyl-2-methyl-1H-pyr-
role-3-carboxylic Acid (15). Compound 15 was prepared from 22c
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in 79% yield using a similar procedure as that for 12. H NMR (300
MHz, CD3OD) δ 8.29 (d, J = 2.2, 1H), 7.60 (dd, J = 2.2, 9.2, 1H),
7.26−6.90 (m, 18H), 4.41−4.36 (m, 1H), 4.10−4.08 (m, 1H), 3.38−
3.31 (m, 9H), 3.21−3.15 (m, 3H), 2.83 (s, 6H), 2.68 (s, 3H), 2.24−
2.14 (m, 2H), 1.39 (d, J = 7.1, 6H); 13C NMR (75 MHz, CD3OD) δ
169.2, 148.2, 148.0, 145.8, 139.4, 137.1, 136.2, 135.2, 134.8, 134.4,
132.9, 132.6, 132.2, 132.1, 131.6, 130.1, 129.9, 129.6, 129.4, 128.0,
127.9, 127.6, 125.1. 124.2, 122.9, 119.0, 117.5, 116.2, 112.8, 55.9, 53.8,
52.4, 50.3, 50.0, 43.5, 39.5, 30.1, 22.5, 13.5. ESI MS: m/z 936.8 (M +
H)+.
(R)-5-(4-Chlorophenyl)-1-cyclopropyl-4-(3-(4-(4-(4-((4-(dime-
t h y la m in o ) - 1 - ( p h e n yl th i o ) bu ta n - 2 - yl ) am i n o ) - 3 -
nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-2-
methyl-1H-pyrrole-3-carboxylic Acid (16). Compound 16 was
prepared from 22d in 78% yield by a similar procedure as that for
compound 12. 1H NMR (300 MHz, CD3OD) δ 8.29 (d, J = 2.3, 1H),
7.60 (dd, J = 2.3, 9.2, 1H), 7.24−6.91 (m, 18H), 4.12−4.07 (m, 1H),
3.39−3.31 (m, 9H), 3.24−3.14 (m, 4H), 2.83 (s, 6H), 2.67 (s, 3H),
2.24−2.15 (m, 2H), 0.89−0.82 (m, 2H), 0.50−0.44 (m, 2H); 13C
NMR (75 MHz, CD3OD) δ 169.0, 148.5, 147.9, 140.8, 139.0, 136.2,
134.4, 134.1, 133.6, 132.8, 132.7, 132.3, 131.6, 130.1, 129.6, 129.1,
128.0, 127.9, 127.7, 124.5, 124.3, 122.9, 118.9, 117.3, 116.2, 112.0,
55.9, 53.2, 52.4, 50.1, 43.5, 39.6, 30.1, 28.3, 13.2, 10.3. ESI MS: m/z
935.3 (M + H)+.
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hexane) to give 23a (1.18 g, 74% in two steps). H NMR (300 MHz,
CCl3D) δ 8.43 (dd, J = 2.1, 6.7, 1H), 7.89−7.86 (m, 1H), 7.33 (d, J =
9.6, 1H), 7.25 (d, J = 8.4, 2H), 7.16 (br, 1H), 7.08−7.05 (m, 3H), 6.80
(d, J = 8.9, 2H), 6.73 (s, 2H), 6.66 (d, J = 7.4, 1H), 3.44 (s, 3H), 3.17−
3.11 (m, 8H), 2.64 (s, 3H); 13C NMR (75 MHz, CCl3D/CD3OD =
5:1) δ 167.7, 149.8, 149.5, 137.0, 136.7, 136.6, 135.9, 134.2, 134.1,
133.3, 132.3, 130.4, 130.3, 128.3, 127.9, 127.5, 125.6, 124.6, 124.1,
123.3, 119.7, 119.3, 119.0, 116.7, 114.5, 110.2, 49.7, 48.1, 31.7, 11.8.
ESI MS: m/z 704.6 (M + H)+.
5-(4-Chlorophenyl)-1-ethyl-4-(3-(4-(4-(4-fluoro-3-
nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-2-
methyl-1H-pyrrole-3-carboxylic Acid (23b). Intermediate 23b
was prepared from 22b in 67% yield in two steps using a similar
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procedure as that for 23a. H NMR (300 MHz, CCl3D) δ 8.44 (dd, J
= 2.2, 6.8, 1H), 7.89−7.86 (m, 1H), 7.34−7.25 (m, 3H), 7.11 (d, J =
8.4, 2H), 7.04 (t, J = 8.0, 1H), 6.95 (d, J = 8.9, 2H), 6.80 (d, J = 8.9,
2H), 6.72−6.64 (m, 3H), 3.85 (q, J = 7.1, 2H), 3.18−3.10 (m, 8H),
2.65 (s, 3H), 1.18 (t, J = 7.1, 3H); 13C NMR (75 MHz, CCl3D) δ
169.8, 150.1, 149.9, 137.14, 137.07, 136.4, 135.7, 134.4, 134.3, 133.8,
132.7, 130.6, 130.3, 128.5, 128.1, 126.5, 125.9, 125.5, 124.7, 123.1,
119.8, 119.6, 119.3, 116.6, 114.4, 109.8, 49.3, 48.7, 39.2, 16.0, 12.0. ESI
MS: m/z 740.3 (M + Na)+.
5-(4-Chlorophenyl)-4-(3-iodophenyl)-1,2-dimethyl-N-(3-(4-
methylpiperazin-1-yl)propyl)-1H-pyrrole-3-carboxamide (24).
A solution of 21a (1.0 g, 2.2 mmol), 1-(3-aminopropyl)-4-
methylpiperazine (0.52 g, 3.3 mmol), EDCI (0.64 g, 3.3 mmol),
HOBt (0.43 g, 3.3 mmol), and N,N-diisopropylethylamine (0.77 mL,
4.4 mmol) in CH2Cl2 (15 mL) was stirred for 8 h and then
5 - ( 4 - C h l o r o p h e n y l ) - 4 - ( 3 - ( 4 - ( 4 - ( 4 - fl u o r o - 3 -
nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-iso-
propyl-2-methyl-1H-pyrrole-3-carboxylic Acid (23c). Intermedi-
ate 23c was prepared in 71% yield in two steps using a similar
procedure as that for 23a. H NMR (300 MHz, CCl3D) δ 8.45 (dd, J
= 2.1, 6.7, 1H), 7.90−7.85 (m, 1H), 7.39 (br, 1H), 7.34−7.23 (m,
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dx.doi.org/10.1021/jm300608w | J. Med. Chem. XXXX, XXX, XXX−XXX