Journal of Medicinal Chemistry
Article
127.9, 126.9, 126.8, 125.0, 124.7, 123.9, 123.5, 93.4, 89.6, 70.2,
67.3, 55.9, 55.5, 52.6, 52.5, 50.4, 46.1, 43.6, 39.4, 37.7, 36.4,
30.1, 25.7; ESI MS m/z 1075.8 (M + H)+.
The resulting mixture was stirred at room temperature overnight
and then was diluted with water (10 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was resolved in MeOH (5 mL) and
treated with HCl solution (4 M in dioxane, 0.2 mL) for 10 min,
and then the solvent was removed in vacuum. Purification of
the residue by HPLC afforded 8 (97 mg, 75%). 1H NMR (300
MHz, CD3OD) δ 8.67 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 7.78−
7.70 (m, 4H), 7.62 (dd, J = 2.2, 9.2 Hz, 1H), 7.47 (t, J = 7.0 Hz,
1H), 7.24−7.21 (m, 3H), 7.12−7.01 (m, 7H), 6.94−6.88
(m, 4H), 4.35−4.28 (m, 2H), 4.07−4.06 (m, 1H), 3.54−3.34
(m, 9H), 3.20−3.11 (m, 8H), 2.84−2.80 (m, 11H), 2.19−2.15
(m, 3H), 1.71−1.66 (m, 3H); 13C NMR (75 MHz, CD3OD)
δ 165.4, 148.9, 148.1, 139.3, 138.3, 138.0, 136.1, 134.7, 134.3,
132.9, 132.4, 132.2, 131.5, 131.0, 130.8, 130.0, 129.4,
128.1, 127.8, 127.7, 127.4, 127.1, 124.8, 124.5, 123.6, 123.4,
121.9, 120.1, 119.9, 116.4, 70.2, 67.3, 55.9, 55.5, 52.4, 50.3,
46.1, 43.5, 39.4, 37.7, 36.4, 30.1, 25.7; ESI MS m/z 1091.4
(M + H)+.
(R)-4-{[4-(Dimethylamino)-1-(phenylthio)but-2-yl]-
amino}-N-(4-ethynylphenyl)-3-nitrobenzenesulfona-
mide (31). Compound 31 was prepared by a similar procedure
to that used for compound 30 in 80% yield. 1H NMR (300 MHz,
CD3OD) δ 8.43 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.38 (d, J =
8.2 Hz, 2H), 7.21−7.14 (m, 4H), 7.10−6.93 (m, 4H), 4.13−
4.12 (m, 1H), 3.44−3.37 (m, 2H), 3.26−3.14 (m, 3H), 2.88 (s,
6H), 2.30−2.21 (m, 2H); 13C NMR (75 MHz, CD3OD) δ
146.7, 138.0, 134.7, 132.9, 132.7, 130.9, 130.1, 128.7, 126.6,
126.5, 125.9, 119.6, 118.3, 114.9, 82.4, 77.3, 54.5, 51.0, 42.1,
38.0, 28.7; ESI MS m/z 526.0 (M + H)+.
4-(4-Chlorophenyl)-1-[(S)-3,4-dihydroxybutyl]-3-(3-
{[4-(4-{[(R)-4-(dimethylamino)-1-(phenylthio)but-2-yl]-
amino}-3-nitrophenylsulfonamido)phenyl]ethynyl}-
phenyl)-N-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyr-
role-2-carboxamide (10). Compound 10 was prepared from
1
31 by a similar procedure as that for 9 in 79% yield. H NMR
Ethyl 4-(4-Chlorophenyl)-3-(4-iodophenyl)-1H-pyr-
role-2-carboxylate. Compound 33 was prepared by a similar
procedure as was used to prepare 24 in 58% yield in two steps.
1H NMR (300 MHz, CCl3D) δ 9.52 (br s, 1H), 7.56 (d, J = 8.2
Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 3.0 Hz, 1H),
7.04−7.01 (m, 4H), 4.23 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CCl3D) δ 161.0, 136.8, 133.7,
132.7, 132.2, 129.6, 128.5, 127.9, 125.5, 120.4, 120.2, 92.9,
60.5, 14.1.
(300 MHz, CD3OD) δ 8.39 (d, J = 2.2 Hz, 1H), 7.63 (dd, J =
2.2, 9.0 Hz, 1H), 7.40−7.37 (m, 3H), 7.32−7.27 (m, 2H),
7.15−7.10 (m, 8H), 7.01−6.89 (m, 6H), 4.37−4.21 (m, 2H),
4.09−4.06 (m, 1H), 3.53−3.49 (m, 1H), 3.45−3.43 (m, 2H),
3.33−3.31 (m, 5H), 3.24−3.08 (m, 9H), 2.82 (s, 9H), 2.72−
2.68 (m, 2H), 2.24−1.98 (m, 3H), 1.79−1.63 (m, 3H); 13C
NMR (75 MHz, CD3OD) δ 165.4, 148.1, 139.4, 136.6, 136.2,
134.8, 134.4, 134.3, 133.7, 132.7, 132.2, 132.0, 131.5, 131.2,
130.5, 130.1, 129.8, 129.3, 128.0, 127.9, 127.4, 126.7, 125.2,
124.7, 124.6, 123.5, 121.1, 120.1, 116.3, 90.2, 90.0, 70.2, 67.3,
55.9, 55.4, 52.7, 52.3, 50.5, 46.1, 43.6, 43.5, 39.4, 37.6, 36.4,
30.1, 25.7; ESI MS m/z 1048.4 (M + H)+.
(S)-Ethyl 4-(4-Chlorophenyl)-1-[2-(2,2-dimethyl-1,3-di-
oxolan-4-yl)ethyl]-3-(4-iodophenyl)-1H-pyrrole-2-car-
boxylate (34). Compound 34 was prepared from 33 by a
1
(S)-3-(3-Azidophenyl)-4-(4-chlorophenyl)-1-[2-(2,2-di-
methyl-1,3-dioxolan-4-yl)ethyl]-N-[3-(4-methylpipera-
zin-1-yl)propyl]-1H-pyrrole-2-carboxamide (32). A mix-
ture of 26 (300 mg, 0.43 mmol), sodium azide (42 mg, 0.65
mmol), CuI (8.3 mg, 0.043 mmol), L-proline (10 mg, 0.087
mmol), and NaOH (3.5 mg, 0.087 mmol) in DMSO (4 mL) in
a sealed tube was heated to 70 °C under N2. After the reaction
was completed, the cooled mixture was partitioned between
CH2Cl2 and H2O. The organic layer was separated, and the
aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were washed with brine, dried over Mg2SO4, and
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel to afford 32 (134 mg, 51%).1H
NMR (300 MHz, CCl3D) δ 7.35−7.29 (m, 1H), 7.11 (d, J =
8.3 Hz, 2H), 6.98 (d, J = 7.7 Hz, 2H), 6.93−6.87 (m, 4H), 5.54
(br s, 1H), 4.47−4.43 (m, 1H), 4.38−4.29 (m, 1H), 4.10−4.08
(m, 1H), 4.03−3.00 (m, 1H), 3.53 (t, J = 7.3 Hz, 1H), 3.21−
3.15 (m, 2H), 2.36−1.96 (m, 15H), 1.42−1.40 (m, 5H), 1.32
(s, 3H); 13C NMR (75 MHz, CCl3D) δ 161.5, 140.6, 136.8,
132.8, 131.8, 130.2, 129.1, 128.4, 127.2, 124.1, 123.8, 122.2,
121.2, 118.1, 108.9, 73.2, 69.1, 55.7, 54.9, 52.7, 46.3, 45.8, 37.8,
35.7, 27.0, 26.1, 25.6; ESI MS m/z 606.8 (M + H)+.
4-(4-Chlorophenyl)-1-[(S)-3,4-dihydroxybutyl]-3-(3-{4-
[4-(4-{[(R)-4-(dimethylamino)-1-(phenylthio)but-2-yl]-
amino}-3-nitrophenylsulfonamido)phenyl]-1H-1,2,3-tri-
azol-1-yl}phenyl)-N-[3-(4-methylpiperazin-1-yl)propyl]-
1H-pyrrole-2-carboxamide (8). Compounds 32 (90 mg,
0.15 mmol) and 31 (78 mg, 0.15 mmol) were suspended in a
1:2 mixture of H2O and t-BuOH (9 mL), and then a solution of
CuSO4·5H2O (3.7 mg, 0.015 mmol) and (+)-sodium L-ascor-
bate (8.8 mg, 0.045 mmol) in H2O (1 mL) was added.
procedure similar to that used for 25 in 90% yield. H NMR
(300 MHz, CCl3D) δ 7.62 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.6
Hz, 2H), 7.05 (s, 1H), 6.98−6.93 (m, 4H), 4.62−4.55 (m, 1H),
4.46−4.36 (m, 1H), 4.15−4.03 (m, 4H), 3.63−3.57 (m, 1H),
2.21−2.12 (m, 1H), 2.08−1.94 (m, 1H), 1.47 (s, 3H), 1.38 (s,
3H), 0.99 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CCl3D) δ
161.2, 136.7, 135.4, 132.6, 131.9, 130.0, 129.3, 128.4, 126.4,
123.0, 119.9, 109.1, 92.3, 73.1, 69.0, 60.0, 46.8, 35.5, 27.0, 25.6,
13.7.
(S)-Ethyl 4-(4-Chlorophenyl)-1-[2-(2,2-dimethyl-1,3-di-
oxolan-4-yl)ethyl]-3-{4-[4-(4-nitrophenyl)piperazin-1-
yl]phenyl}-1H-pyrrole-2-carboxylate (35). Compound 34
(380 mg, 0.66 mmol), 1-(4-nitrophenyl)piperazine (271 mg,
1.31 mmol), CuI (12 mg, 0.066 mmol), L-proline (15 mg,
0.13 mmol), and K2CO3 (181 mg, 1.31 mmol) were dissolved
in 5 mL of DMSO. This mixture was heated to 80 °C for 2 h
under nitrogen. After the solution was cooled, saturated ammonium
chloride solution was added and the mixture was extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried over sodium sulfate, and concentrated. Purification of
the residue by flash chromatography on silica gel afforded 35
(354 mg, 82%). 1H NMR (300 MHz, CCl3D) δ 8.15 (d, J = 8.9
Hz, 2H), 7.15−7.11 (m, 4H), 7.05−7.00 (m, 3H), 6.90−6.87
(m, 4H), 4.63−4.54 (m, 1H), 4.45−4.36 (m, 1H), 4.12−4.04
(m, 4H), 3.62−3.57 (m, 5H), 3.39−3.37 (m, 4H), 2.21−2.15
(m, 1H), 2.09−2.00 (m, 1H), 1.47 (s, 3H), 1.38 (s, 3H), 1.02
(t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CCl3D) δ 161.5,
154.7, 149.4, 138.6, 133.2, 131.5, 131.1, 129.3, 128.3, 127.5,
126.4, 126.0, 123.1, 120.0, 115.3, 112.7. 109.1, 73.2, 69.1, 59.8,
48.9, 47.1, 46.9, 35.6, 27.0, 25.6, 13.8; ESI MS m/z 659.8
(M + H)+.
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dx.doi.org/10.1021/jm300178u | J. Med. Chem. 2012, 55, 4664−4682