88
C. Han et al. / European Journal of Medicinal Chemistry 66 (2013) 82e90
NMR (75 MHz, DMSO-d6):
d
164.19, 163.99, 158.48, 157.72, 151.02,
(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (10a). The title com-
pound was obtained starting from 9a. As a yellow solid, 55% yield.
M.p. 77e79 ꢀC. Analytical data for 10a: 1H NMR (300 MHz, CDCl3),
150.13, 148.24, 144.68, 136.96, 129.91, 122.82, 122.23, 121.46, 119.60,
106.41, 103.93, 99.87, 63.49, 55.85, 50.76, 50.33, 45.69, 42.01; ESI-
MS: m/z 496.3 [M þ H]þ, 518.3 [M þ Na]þ; ESI-HRMS (m/z):
[M þ H]þ calcd for C25H26ClN5O4 496.1746; obsd 496.1762.
d
2.26 (m, 2H), 2.45 (s, 3H), 2.77 (m, 4H), 2.91 (t, J ¼ 6.8 Hz, 2H), 3.18
(m, 4H), 3.82 (s, 3H), 4.49 (t, J ¼ 5.6 Hz, 2H), 6.18 (d, J ¼ 8.3 Hz, 1H),
6.46 (d, J ¼ 2.1 Hz,1H), 7.15 (d, J ¼ 8.4 Hz, 2H), 7.31 (d, J ¼ 8.3 Hz, 2H),
7.52e7.55 (brs, 1H), 7.63 (t, J ¼ 7.9 Hz, 2H), 7.73e7.79 (t, J ¼ 7.3 Hz,
2H), 8.09 (d, J ¼ 7.5 Hz, 2H), 8.24 (s, 1H); 13C NMR (75 MHz, CDCl3):
5.1.5.6. (3-((5-Chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)
phenyl)amino)pyrimidin-4-yl)oxy)phenyl)methanol (9f). The title
compound was obtained starting from 5d and 8a. As a white solid,
92% yield. M.p. 213e215 ꢀC. Analytical data for 9f: 1H NMR
d
164.02, 158.37, 157.12, 157.01, 150.44, 148.29, 146.61, 137.58, 137.30,
135.19, 129.22, 128.95, 128.02, 121.80, 121.54, 118.68, 110.07, 107.66,
100.14, 69.90, 55.14, 54.30, 49.05, 44.96, 30.61, 29.70; ESI-MS: m/z
708.0 [M þ H]þ; ESI-HRMS (m/z): [M þ H]þ calcd for C33H34ClN7O7S
708.2007; obsd 708.2014.
(500 MHz, CDCl3): d 2.88 (s, 3H), 3.14 (m, 2H), 3.46 (m, 2H), 3.51 (m,
2H), 3.58 (m, 2H), 3.82 (s, 3H), 4.72 (s, 2H), 6.32 (d, J ¼ 7.4 Hz, 1H),
6.53 (s, 1H), 7.11 (d, J ¼ 7.7 Hz, 1H), 7.17 (s, 1H), 7.41 (d, J ¼ 7.7 Hz,
1H), 7.46 (t, J ¼ 8.0 Hz, 1H), 7.51 (s, 1H), 7.90 (s, 1H), 8.23 (s, 1H); 13C
NMR (75 MHz, DMSO-d6):
d
163.92, 158.42, 157.81, 151.78, 151.23,
5.1.6.2. 4-(4-((5-Chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)
phenyl)amino)pyrimidin-4-yl)oxy)phenethoxy)-3-(phenylsulfonyl)-
1,2,5-oxadiazole-2-oxide (10b). The title compound was obtained
starting from 9b. As a yellow solid, 67% yield. M.p. 88e90 ꢀC.
147.28, 129.55, 128.12, 127.52, 122.99, 121.03, 120.13, 119.38, 109.01,
103.86, 101.01, 63.26, 55.59, 54.97, 48.86, 45.93; ESI-MS: m/z 456.3
[M þ H]þ; ESI-HRMS (m/z): [M þ H]þ calcd for C23H26ClN5O3
456.1797; obsd 456.1800.
Analytical data for 10b: 1H NMR (300 MHz, CDCl3):
d 2.37 (s, 3H),
2.61 (m, 4H), 3.10 (m, 4H), 3.27 (t, J ¼ 6.6 Hz, 2H), 3.79 (s, 3H), 4.68
(t, J ¼ 6.6 Hz, 2H), 6.18 (d, J ¼ 7.2 Hz, 1H), 6.44 (d, J ¼ 1.5 Hz, 1H), 7.21
(d, J ¼ 8.4 Hz, 2H), 7.41 (d, J ¼ 8.1 Hz, 3H), 7.54 (t, J ¼ 4.8 Hz, 2H), 7.69
(d, J ¼ 7.5 Hz, 2H), 7.93 (d, J ¼ 7.8 Hz, 2H), 8.25 (s, 1H); 13C NMR
5.1.5.7. 1-(4-((5-Chloro-4-(3-(hydroxymethyl)phenoxy)pyrimidin-2-
yl)amino)-3-methoxyphenyl)piperidin-4-ol (9g). The title com-
pound was obtained starting from 5d and 8b. As a pale yellow solid,
90% yield. M.p. 183e185 ꢀC. Analytical data for 9g: 1H NMR
(75 MHz, CDCl3):
d 163.95, 158.36, 157.22, 157.01, 151.02, 148.30,
(500 MHz, CDCl3):
d
1.71 (m, 2H), 2.02 (m, 2H), 2.85 (m, 2H), 3.42
146.70, 137.50, 135.12, 133.51, 129.71, 129.19, 127.88, 127.28, 121.89,
121.40, 118.75, 109.88, 107.26, 99.88, 71.05, 55.07, 54.57, 49.49,
45.52, 33.86; ESI-MS: m/z 694.3 [M þ H]þ; ESI-HRMS (m/z):
[M þ H]þ calcd for C32H32ClN7O7S 694.1851; obsd 694.1858.
(m, 2H), 3.81 (s, 3H), 3.84 (m, 1H), 4.73 (s, 2H), 6.21 (s, 1H), 6.49 (s,
1H), 7.14 (d, J ¼ 7.7 Hz, 1H), 7.22 (s, 1H), 7.34 (d, J ¼ 7.6 Hz, 1H), 7.42
(s, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.53 (brs, 1H), 8.22 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d 163.68, 158.02, 157.39, 152.22, 151.15, 146.98,
129.47, 128.04, 127.52, 122.98, 121.09, 120.04, 119.40, 108.59, 104.87,
99.98, 66.98, 62.77, 55.45, 48.73, 33.80; ESI-MS: m/z 457.2 [M þ H]þ,
479.2 [M þ Na]þ; ESI-HRMS (m/z): [M þ H]þ calcd for C23H25ClN4O4
457.1637; obsd 457.1646.
5.1.6.3. 4-((4-((5-Chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)
phenyl)amino)pyrimidin-4-yl)oxy)benzyl)oxy)-3-(phenylsulfonyl)-
1,2,5-oxadiazole-2-oxide (10c). The title compound was obtained
starting from 9c. As a yellow solid, 87% yield. M.p. 195e197 ꢀC.
Analytical data for 10c: 1H NMR (300 MHz, CDCl3),
d 2.34 (s, 3H),
5.1.5.8. 1-(4-(4-((5-Chloro-4-(3-(hydroxymethyl)phenoxy)pyr-
imidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)prop-2-en-1-
one (9h). The title compound was obtained starting from 5d and
8c. As a pale yellow solid, 85% yield. M.p. 178e180 ꢀC. Analytical
2.56 (t, J ¼ 4.8 Hz, 4H), 3.11 (t, J ¼ 4.62 Hz, 4H), 3.81 (s, 3H), 5.52 (s,
2H), 6.26 (d, J ¼ 8.79 Hz, 1H), 6.47 (d, J ¼ 2.31 Hz, 1H), 7.29 (d,
J ¼ 8.49 Hz, 2H), 7.40 (s, 1H), 7.52e7.60 (m, 4H), 7.73 (m, 2H), 8.04
(d, J ¼ 7.41 Hz, 2H), 8.29 (s, 1H); 13C NMR (75 MHz, CDCl3):
d 163.68,
data for 9h: 1H NMR (500 MHz, CDCl3):
d
3.11 (m, 4H), 3.77 (m, 2H),
159.51, 158.15, 157.33, 157.03, 152.48, 148.33, 146.82, 137.47, 135.17,
130.61, 129.19, 128.90, 128.07, 122.04, 121.01, 118.87, 110.07, 107.40,
99.71, 71.54, 55.10, 54.55, 49.38, 45.52; ESI-MS: m/z 680.1 [M þ H]þ;
ESI-HRMS (m/z): [M þ H]þ calcd for C31H30ClN7O7S 680.1694; obsd
680.1706.
3.83 (s, 3H), 3.89 (m, 2H), 4.74 (s, 2H), 5.75 (dd, J ¼ 1.8, 10.6 Hz, 1H),
6.27 (s, 1H), 6.33 (dd, J ¼ 1.7, 16.8 Hz, 1H), 6.54 (s, 1H), 6.59 (dd,
J ¼ 10.6, 16.8 Hz, 1H), 7.14 (d, J ¼ 7.8 Hz, 1H), 7.22 (s, 1H), 7.35 (d,
J ¼ 7.6 Hz, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.52 (s, 1H), 7.60 (s, 1H), 8.24
(s, 1H); 13C NMR (75 MHz, DMSO-d6):
d 164.18, 163.72, 158.12,
157.71, 151.90, 151.15, 147.18, 144.68, 129.25, 128.04, 127.52, 123.45,
122.74, 120.84, 119.94, 119.40, 107.59, 104.26, 100.93, 62.27, 55.58,
50.01, 49.39, 44.64, 41.06; ESI-MS: m/z 496.3 [M þ H]þ, 518.3
[M þ Na]þ; ESI-HRMS (m/z): [M þ H]þ calcd for C25H26ClN5O4
496.1746; obsd 496.1762.
5.1.6.4. 4-(4-((5-Chloro-2-((4-(4-hydroxypiperidin-1-yl)-2-
methoxyphenyl)amino)pyrimidin-4-yl)oxy)benzyl)-3-(phenyl-
sulfonyl)-1,2,5-oxadiazole-2-oxide (10d). The title compound was
obtained starting from 9d. As a yellow solid, 82% yield. M.p. 155e
157 ꢀC. Analytical data for 10d: 1H NMR (300 MHz, CDCl3),
d 1.68 (q,
J ¼ 9 Hz, 2H), 1.99 (q, J ¼ 9.4 Hz, 2H), 2.84 (t, J ¼ 8.1 Hz, 2H), 3.43 (t,
J ¼ 6.5 Hz, 2H), 3.81 (s, 4H), 5.52 (s, 2H), 6.27 (d, J ¼ 8.79 Hz, 1H),
6.50 (d, J ¼ 2.31 Hz, 1H), 7.29 (d, J ¼ 8.49 Hz, 2H), 7.43 (s, 1H), 7.52e
7.62 (m, 4H), 7.73 (m, 2H), 8.04 (d, J ¼ 7.41 Hz, 2H), 8.26 (s, 1H); 13C
5.1.6. General procedure for the preparation of 10aeh
Compounds 9aeh (0.34 mmol) were dissolved in 10 mL of
anhydrous THF, to which 65% NaH (25 mg, 0.68 mmol) was slowly
added under stirring at 0 ꢀC. Subsequently, 3,4-bis(phenylsulfonyl)-
1,2,5-oxadiazole-2-oxide (11) (249 mg, 0.68 mmol) was added, and
the obtained mixture was allowed to stir for 0.5 h at room tem-
perature. 15 mL of H2O was added to the mixture. The organic layer
was separated, then the water layer was extracted with CH2Cl2
(10 mL ꢃ 2). The combined organic layer was washed with water
and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by column chromatography
(MeOH/CH2Cl2 1:25 v/v) to give the title compounds.
NMR (75 MHz, CDCl3):
d 157.35, 157.03, 152.51, 148.26, 146.92,
135.16, 130.60, 129.18, 128.88, 128.08, 122.06, 120.94, 118.78, 107.84,
100.44, 71.54, 67.13, 55.09, 47.72, 33.77; ESI-MS: m/z 681.4
[M þ H]þ; ESI-HRMS (m/z): [M þ Na]þ calcd for C31H29ClN6O8S
703.1354; obsd 703.1361.
5.1.6.5. 4-(4-((2-((4-(4-Acryloylpiperazin-1-yl)-2-methoxyphenyl)
amino)-5-chloropyrimidin-4-yl)oxy)benzyl)-3-(phenylsulfonyl)-
1,2,5-oxadiazole-2-oxide (10e). The title compound was obtained
starting from 9e. As a yellow solid, 83% yield. M.p. 162e164 ꢀC.
5.1.6.1. 4-(3-(4-((5-Chloro-2-((2-methoxy-4-(4-methylpiperazin-1-
yl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)propoxy)-3-
Analytical data for 10e: 1H NMR (300 MHz, CDCl3),
d
3.08 (m, 4H),
3.71 (brs, 2H), 3.83 (s, 5H), 5.53 (s, 2H), 5.73 (d, J ¼ 10.32 Hz, 1H),