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M. Xin et al. / European Journal of Medicinal Chemistry 110 (2016) 115e125
5.1.10. 4-((5-Fluoro-4-(4-trifluoromethoxyphenyl)pyrimidin-2-yl)
amino)-N-(2-methyl-5-((4-methyl-1-piperazinyl)methyl)phenyl)
benzamide (12ae)
(580 mg, 91%) as a yellow solid, MS (ESI) m/z: [MþH]þ ¼ 513.2. 1H
NMR (400 M, DMSO-d6) d 10.12 (s, 1H, CONH), 9.76 (s, 1H, NH), 8.67
(d, 1H, J ¼ 5.2 Hz, ArH), 8.35 (d, 2H, J ¼ 8.4 Hz, ArH), 7.99 (s, 4H,
ArH), 7.59 (m, 3H, ArH), 7.45 (s, 1H, ArH), 7.30 (d, 1H, J ¼ 7.6 Hz,
ArH), 7.24 (d, 1H, J ¼ 8.0 Hz, ArH), 4.77 (s, 2H, ArCH2Cl), 2.25 (s, 3H,
ArCH3) ppm.
Similar procedure of 12aa was performed to give compound
12ae (67 mg, 74%) as a yellow solid, MS (ESI) m/z: [MþH]þ ¼ 595.3.
1H NMR (400 M, DMSO-d6)
d 10.20 (s, 1H, CONH), 9.70 (s, 1H, NH),
8.76 (d, 1H, J ¼ 3.2 Hz, ArH), 8.22 (d, 2H, J ¼ 8.8 Hz, ArH), 7.99 (d, 2H,
J ¼ 8.8 Hz, ArH), 7.93 (d, 2H, J ¼ 8.8 Hz, ArH), 7.63 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.27 (s, 1H, ArH), 7.22 (d, 1H, J ¼ 7.6 Hz, ArH), 7.08 (d, 1H,
J ¼ 7.6 Hz, ArH), 3.43 (s, 2H, ArCH2N), 2.48e2.30 (m, 8H, piperazine-
H), 2.21 (s, 3H, ArCH3), 2.20 (s, 3H, NCH3) ppm. 13C NMR (100 M,
5.1.17. N-(5-((Dimethylamino)methyl)-2-methylphenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (12ba)
Similar procedure of 12aa was performed to give compound
12ba (25 mg, 49%) as a white solid, MS (ESI) m/z: [MþH]þ ¼ 522.2.
DMSO-d6)
d 164.72, 156.12, 151.56, 150.00, 149.72, 149.63, 149.04,
1H NMR (400 M, DMSO-d6)
d 10.10 (s, 1H, CONH), 9.69 (s, 1H, NH),
148.08, 147.83, 143.45, 136.44, 135.87, 132.17, 130.97, 130.91, 129.98,
128.50, 126.92, 126.88, 126.28, 121.27, 121.15, 118.72, 117.37, 61.51,
54.46, 52.13, 45.34, 17.66. HPLC: 98.21%.
8.67 (d, 1H, J ¼ 5.2 Hz, ArH), 8.35 (d, 2H, J ¼ 8.4 Hz, ArH), 7.99 (s, 4H,
ArH), 7.59 (m, 3H, ArH), 7.30 (s, 1H, ArH), 7.22 (d, 1H, J ¼ 7.6 Hz,
ArH), 7.09 (d, 1H, J ¼ 7.6 Hz, ArH), 3.40 (s, 2H, ArCH2N), 2.23 (s, 3H,
ArCH3), 2.18 (s, 6H, N(CH3)2) ppm. 13C NMR (100 M, DMSO-d6)
5.1.11. 4-((5-Fluoro-4-(4-trifluoromethoxyphenyl)pyrimidin-2-yl)
amino)-N-(2-methyl-5-((4-morpholinyl)methyl)phenyl)benzamide
(12af)
d
164.77, 162.33, 159.88, 159.43, 150.20, 143.53, 136.45, 135.67,
132.14, 129.98, 129.11, 128.44, 126.92, 126.83, 126.14, 121.24, 118.74,
117.79, 108.81, 62.82, 44.79, 17.66. HPLC: 94.74%.
Similar procedure of 12aa was performed to give compound
12af (50 mg, 91%) as a yellow solid, MS (ESI) m/z: [MþH]þ ¼ 582.2.
1H NMR (400 M, DMSO-d6)
d
10.21 (s, 1H, CONH), 9.72 (s, 1H, NH),
5.1.18. N-(5-(Diethylamino)methyl)-2-methylphenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (12bb)
Similar procedure of 12aa was performed to give compound
12bb (41 mg, 76%) as a white solid, MS (ESI) m/z: [MþH]þ ¼ 550.3.
8.76 (d, 1H, J ¼ 3.2 Hz, ArH), 8.22 (d, 2H, J ¼ 8.8 Hz, ArH), 7.99 (d, 2H,
J ¼ 8.4 Hz, ArH), 7.93 (d, 2H, J ¼ 8.4 Hz, ArH), 7.63 (d, 2H, J ¼ 8.4 Hz,
ArH), 7.29 (s, 1H, ArH), 7.23 (d, 1H, J ¼ 7.6 Hz, ArH), 7.11 (d, 1H,
J ¼ 7.6 Hz, ArH), 3.65e3.50 (m, 4H, morpholine-H), 3.44 (s, 2H,
ArCH2N), 2.44e2.32 (m, 4H, morpholine-H), 2.22 (s, 3H, ArCH3)
1H NMR (400 M, DMSO-d6)
d 10.10 (s, 1H, CONH), 9.70 (s, 1H, NH),
8.67 (d, 1H, J ¼ 4.8 Hz, ArH), 8.35 (d, 2H, J ¼ 8.8 Hz, ArH), 7.99 (s, 4H,
ArH), 7.59 (m, 3H, ArH), 7.30 (s, 1H, ArH), 7.21 (d, 1H, J ¼ 8.0 Hz,
ArH), 7.10 (d, 1H, J ¼ 7.6 Hz, ArH), 3.51 (s, 2H, ArCH2N), 2.51e2.40
(m, 4H, N(CH2)2), 2.22 (s, 3H, ArCH3), 1.05e0.94 (m, 6H, (CH3)2)
ppm. 13C NMR (100 M, DMSO-d6)
d 164.75, 156.10, 151.55, 150.00,
149.72, 149.63, 149.03, 148.06, 147.81, 143.45, 136.44, 135.48, 132.25,
132.14, 132.08, 130.96, 130.90, 130.01, 128.50, 126.98, 126.90, 126.39,
121.27, 121.14, 118.71, 117.37, 66.14, 62.00, 53.08, 17.65. HPLC: 98.11%.
ppm. 13C NMR (100 M, DMSO-d6)
d 164.75, 162.32, 159.88, 159.42,
150.20, 143.52, 136.42, 135.67, 131.86, 129.89, 129.11, 128.45, 126.92,
126.60, 125.97, 121.29, 121.24, 118.74, 117.78, 108.79, 56.43, 46.03,
17.66, 11.58. HPLC: 96.85%.
5.1.12. 2-Chloro-4-(4-trifluoromethoxyphenyl)pyrimidine (7b)
It was prepared according to the method we recently described
[10], as a white solid (0.3 g, 66%), MS (ESI) m/z: [MþH]þ ¼ 275.0. 1H
NMR (400 M, CDCl3)
d
8.68 (d, 1H, J ¼ 5.2 Hz, ArH), 8.16 (d, 2H,
5.1.19. N-(2-Methyl-5-((1-pyrrolidinyl)methyl)phenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (12bc)
Similar procedure of 12aa was performed to give compound
12bc (47 mg, 88%) as a white solid, MS (ESI) m/z: [MþH]þ ¼ 548.2.
J ¼ 8.4 Hz, ArH), 7.64 (d, 1H, J ¼ 5.2 Hz, ArH), 7.37 (d, 2H, J ¼ 8.8 Hz,
ArH) ppm.
5.1.13. Methyl 4-((4-(4-trifluoromethoxyphenyl)pyrimidin-2-yl)
amino)benzoate (8b)
1H NMR (400 M, DMSO-d6)
d 10.10 (s, 1H, CONH), 9.71 (s, 1H, NH),
8.67 (d, 1H, J ¼ 5.2 Hz, ArH), 8.35 (d, 2H, J ¼ 8.4 Hz, ArH), 8.00 (s, 4H,
ArH), 7.59 (m, 3H, ArH), 7.30 (s, 1H, ArH), 7.21 (d, 1H, J ¼ 7.6 Hz,
ArH), 7.10 (d, 1H, J ¼ 7.6 Hz, ArH), 3.56 (s, 2H, ArCH2N), 2.38e2.29
(m, 4H, piperidine-H), 2.22 (s, 3H, ArCH3), 1.52e1.44 (m, 4H,
piperidine-H), 1.42e1.35 (m, 2H, piperidine-H) ppm. 13C NMR
It was prepared according to the method we recently reported
[10], as a white solid (0.69 g, 88%), MS (ESI) m/z: [MþH]þ ¼ 390.1.
5.1.14. 4-((4-(4-Trifluoromethoxyphenyl)pyrimidin-2-yl)amino)
benzoic acid (9b)
(100 M, DMSO-d6)
d 164.80, 162.33, 159.87, 159.42, 150.20, 143.52,
It was synthesized as we recently described [10], as a white
137.16, 136.40, 135.65, 131.92, 129.94, 128.45, 126.91, 126.51, 125.84,
121.29, 121.23, 118.74, 117.79, 108.79, 59.12, 53.41, 23.08, 17.64.
HPLC: 94.74%.
product (0.64 g, 95%), MS (ESI) m/z: [MþH]þ ¼ 376.1. 1H NMR
(400 M, DMSO-d6)
d 12.51 (s, 1H, COOH), 10.13 (s, 1H, NH), 8.66 (d,
1H, J ¼ 5.2 Hz, ArH), 8.34 (d, 2H, J ¼ 8.4 Hz, ArH), 7.98e7.87 (m, 4H,
ArH), 7.64e7.54 (m, 3H, ArH) ppm.
5.1.20. N-(2-Methyl-5-((1-piperidyl)methyl)phenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (12bd)
Similar procedure of 12aa was performed to give compound
12bd (51 mg, 93%) as a white solid, MS (ESI) m/z: [MþH]þ ¼ 562.3.
5.1.15. N-(5-(Hydroxymethyl)-2-methylphenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (10b)
Similar procedure of 10a was performed to give compound 10b
(611 mg, 73%) as a white solid, MS (ESI) m/z: [MþH]þ ¼ 495.2. 1H
1H NMR (400 M, DMSO-d6)
d 10.10 (s, 1H, CONH), 9.71 (s, 1H, NH),
NMR (400 M, DMSO-d6)
d
10.11 (s, 1H, CONH), 9.70 (s, 1H, NH), 8.67
8.67 (d, 1H, J ¼ 4.8 Hz, ArH), 8.35 (d, 2H, J ¼ 8.4 Hz, ArH), 7.99 (s, 4H,
ArH), 7.58 (m, 3H, ArH), 7.27 (s, 1H, ArH), 7.21 (d, 1H, J ¼ 7.6 Hz,
ArH), 7.08 (d, 1H, J ¼ 8.0 Hz, ArH), 3.40 (s, 2H, ArCH2N), 2.38e2.28
(m, 4H, piperidine-H), 2.22 (s, 3H, ArCH3), 1.54e1.45 (m, 4H,
piperidine-H), 1.43e1.30 (m, 2H, piperidine-H) ppm. 13C NMR
(d, 1H, J ¼ 5.2 Hz, ArH), 8.35 (d, 2H, J ¼ 8.4 Hz, ArH), 7.98 (s, 4H,
ArH), 7.59 (m, 3H, ArH), 7.30 (s, 1H, ArH), 7.22 (d, 1H, J ¼ 7.6 Hz,
ArH), 7.11 (d, 1H, J ¼ 7.6 Hz, ArH), 5.18 (s, 1H, OH), 4.49 (d, 2H,
J ¼ 5.2 Hz, ArCH2O), 2.22 (s, 3H, ArCH3) ppm.
(100 M, DMSO-d6)
d 164.77, 162.33, 159.88, 159.41, 150.20, 143.53,
5.1.16. N-(5-(Chloromethyl)-2-methylphenyl)-4-((4-(4-
trifluoromethoxyphenyl)pyrimidin-2-yl)amino)benzamide (11b)
Similar procedure of 11a was performed to give compound 11b
136.40, 132.04,129.90,129.10,128.45,126.90,126.86,126.25,121.29,
121.23, 118.74, 117.79, 108.79, 62.41, 53.80, 25.49, 23.96,17.66. HPLC:
97.72%.