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D. Yao et al. / European Journal of Medicinal Chemistry 140 (2017) 155e171
126.0, 120.9, 120.9, 118.1, 117.7, 114.6, 96.9, 44.1, 43.5, 42.2, 38.7;
HRMS (ESI)þ calculated for C21H19Cl2N4O3, [MþH]þ: m/z 445.0834,
found 445.0836; Purity: 97.1% (HPLC).
d
(ppm): 8.24 (1H, d, J ¼ 5.5 Hz),7.26 (1H, m), 7.10 (2H, d, J ¼ 1.69 Hz),
7.04 (2H, d, J ¼ 7.5 Hz), 6.78 (1H, d, J ¼ 7.5 Hz), 6.74 (1H, t,
J ¼ 15.1 Hz),6.17 (1H, d, J ¼ 5.5 Hz), 4.57 (1H, dd, J ¼ 10.7, 5.5 Hz),
3.59 (10H, m), 3.15 (1H, dd, J ¼ 15.7, 5.5 Hz); 13C NMR (100 MHz,
4.2.4.10. 2-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(4-(3,5-
dichlorophenoxy)pyrimidin-2-yl)piperazin-1-yl)-2-methylpropan-1-
one (4j). Prepared by method B, off-white solid, mp 104e107 ꢁC,
CDCl3), d(ppm): 172.5, 169.0, 161.2, 160.0, 153.3, 151.0, 135.1, 127.9,
126.8, 125.7, 124.3, 120.9, 119.8, 111.3, 96.9, 58.2, 44.7, 43.6, 43.5,
42.1; HRMS (ESI)þ calculated for C23H22Cl2N5O2, [MþH]þ: m/z
470.1151, found 470.1154; Purity: 95.4% (HPLC).
yield 83%. 1H NMR (400 MHz, CDCl3),
d(ppm): 8.16 (1H, d,
J ¼ 5.5 Hz), 7.79 (1H, s), 7.70 (2H, s), 7.22 (1H, m), 7.05 (2H, d,
J ¼ 1.7 Hz), 6.10 (1H, d, J ¼ 5.5 Hz), 1.62 (8H, m); 13C NMR (100 MHz,
4.2.4.16. (4-(4-(3,5-dichlorophenoxy)pyrimidin-2-yl)piperazin-1-
yl)(1H-pyrrol-2-yl)methanone (4p). Prepared by method B, off-
white solid, mp 198e200 ꢁC, yield 73%. 1H NMR (400 MHz,
CDCl3), d(ppm): 173.4, 168.8, 161.1, 160.0, 135.2, 149.1, 135.2, 133.0,
132.6, 132.3, 131.2, 125.6, 125.1, 124.5, 121.8, 120.8, 120.8, 96.8, 47.3,
43.3, 43.2, 42.2, 43.1, 28.3; HRMS (ESI)þ calculated for
CDCl3),
d
(ppm): 9.78 (1H, s), 8.24 (1H, d, J ¼ 5.5 Hz), 7.11 (2H, d,
C
26H23Cl2F6N4O2, [MþH]þ: m/z 607.1102, found 607.1104; Purity:
J ¼ 1.8 Hz), 6.93 (1H, m), 6.54 (1H, m), 6.26 (1H, dd, J ¼ 6.3, 2.7 Hz),
98.2% (HPLC).
6.15 (1H, d, J ¼ 5.5 Hz),3.83 (10H, m); 13C NMR (100 MHz, CDCl3),
d(ppm): 169.0, 162.0, 161.2, 160.0, 153.3, 135.1, 125.6, 124.4, 121.3,
4.2.4.11. (4-(4-(3,5-dichlorophenoxy)pyrimidin-2-yl)piperazin-1-
yl)(5-methylpyrazin-2-yl)methanone (4k). Prepared by method B,
off-white solid, mp 128e131 ꢁC, yield 79%. 1H NMR (400 MHz,
120.9, 120.9, 112.3, 110.0, 96.6, 43.6, 43.6, 43.6, 43.6; HRMS (ESI)þ
calculated for
C
19H18Cl2N5O2, [MþH]þ: m/z 418.0838, found
418.0842; Purity: 98.7% (HPLC).
CDCl3),
d
(ppm): 8.88 (1H, d, J ¼ 1.2 Hz), 8.42 (1H, s), 8.24 (1H, d,
J ¼ 5.3 Hz), 7.24 (1H, dd, J ¼ 1.8,1.9 Hz), 7.10 (2H, d, J ¼ 1.5 Hz), 6.16
(1H, d, J ¼ 5.5 Hz), 3.84 (4H, s), 3.71 (4H, d, J ¼ 10.8 Hz), 2.63 (3H, s);
4.2.5. Synthesis of compounds 5a-g
4.2.5.1. 4-(2,4-dichlorophenoxy)-2-(4-(phenylsulfonyl)piperazin-1-
yl)pyrimidine (5a). Prepared by method A, white solid, mp
13C NMR (100 MHz, CDCl3),
d(ppm): 168.9, 165.7, 161.2, 160.0, 155.1,
153.3, 145.9, 144.9, 142.2, 135.1, 125.6, 120.9, 120.9, 96.7, 46.9, 44.1,
43.5, 42.4; HRMS (ESI)þ calculated for C20H19Cl2N6O2, [MþH]þ: m/
z 445.0947, found 445.0958; Purity: 99.3% (HPLC).
147e149 ꢁC, yield 84%. 1H NMR (400 MHz, CDCl3),
d(ppm): 8.17 (1H,
d, J ¼ 5.5 Hz), 7.75 (2H, m), 7.60 (1H, m), 7.53 (2H, m), 7.24 (1H, s),
7.05 (2H, d, J ¼ 1.8 Hz), 6.09 (1H, d, J ¼ 5.5 Hz), 3.79 (4H, s), 3.02 (4H,
dd, J ¼ 5.1, 5.0 Hz); 13C NMR (100 MHz, CDCl3),
d(ppm): 168.9, 160.9,
160.0, 153.2, 135.5, 135.1, 133.0, 129.2, 129.2, 127.8, 127.8, 125.6,
4.2.4.12. (4-chloropyridin-2-yl)(4-(4-(3,5-dichlorophenoxy)pyr-
imidin-2-yl)piperazin-1-yl)methanone (4l). Prepared by method B,
off-white solid, mp 139e141 ꢁC, yield 85%. 1H NMR (400 MHz,
120.9, 120.9, 96.8, 45.8, 45.8, 43.1, 43.1; HRMS (ESI)þ calculated for
C
20H19Cl2N4O3S, [MþH]þ: m/z 465.0555, found 465.0557; Purity:
CDCl3),
d
(ppm): 8.49 (1H, d, J ¼ 5.3 Hz), 8.23 (1H, d, J ¼ 5.5 Hz), 7.72
99.2% (HPLC).
(1H, d, J ¼ 1.9 Hz), 7.37 (1H, dd, J ¼ 5.4, 2.0 Hz), 7.23 (1H, m), 7.10
(2H, d, J ¼ 1.8 Hz), 6.15 (1H, d, J ¼ 5.5 Hz), 3.83 (4H, s), 3.72 (2H, s),
4.2.5.2. 2-(4-((4-(tert-butyl)phenyl)sulfonyl)piperazin-1-yl)-4-(2,4-
3.64 (2H, m); 13C NMR (100 MHz, CDCl3),
d(ppm): 168.9, 166.4,
dichlorophenoxy)pyrimidine (5b). Prepared by method A, white
161.2, 160.0, 155.0, 153.3, 149.2, 145.4, 135.1, 125.6, 125.1, 124.8,
solid, mp 151e153 ꢁC, yield 79%. 1H NMR (400 MHz, CDCl3),
d(ppm):
120.9, 120.9, 96.7, 46.9, 44.1, 43.5, 42.4; HRMS (ESI)þ calculated for
8.17 (1H, d, J ¼ 5.5 Hz), 7.66 (2H, d, J ¼ 8.6 Hz), 7.52 (2H, d,
C
20H17Cl3N5O2, [MþH]þ: m/z 464.0448, found 464.0456; Purity:
J ¼ 8.6 Hz), 7.24 (1H, s), 7.05 (2H, d, J ¼ 1.8 Hz), 6.09 (1H, d,
96.2% (HPLC).
J ¼ 5.5 Hz), 3.79 (4H, s), 3.03 (4H, dd, J ¼ 5.1, 5.0 Hz), 1.33 (9H, s); 13
C
NMR (100 MHz, CDCl3), d(ppm): 168.9, 161.0, 160.0, 156.8, 153.2,
4.2.4.13. (4-(4-(3,5-dichlorophenoxy)pyrimidin-2-yl)piperazin-1-
yl)(quinolin-6-yl)methanone (4m). Prepared by method B, off-
white solid, mp 78e81 ꢁC, yield 70%. 1H NMR (400 MHz, CDCl3),
135.1, 132.4, 127.7, 127.7, 126.1, 126.1, 125.6, 120.9, 120.9, 96.7, 45.8,
45.8, 43.0, 43.0, 35.2, 31.1, 31.1, 31.1; HRMS (ESI)þ calculated for
C
24H27Cl2N4O3S, [MþH]þ: m/z 521.1181, found 521.1184; Purity:
d
(ppm): 8.98 (1H, dd, J ¼ 4.2, 1.6 Hz), 8.24 (1H, d, J ¼ 5.5 Hz), 8.21
96.9% (HPLC).
(1H, d, J ¼ 8.0 Hz), 8.17 (1H, d, J ¼ 8.7 Hz), 7.93 (1H, d, J ¼ 1.5 Hz), 7.74
(1H, dd, J ¼ 8.4, 1.6 Hz), 7.48 (1H, dd, J ¼ 8.3, 4.2 Hz), 7.21 (1H, m),
7.09 (2H, d, J ¼ 1.6 Hz), 6.17 (1H, d, J ¼ 5.5 Hz), 3.84 (4H, m), 3.68
4.2.5.3. 4-(2,4-dichlorophenoxy)-2-(4-((2-methoxyphenyl)sulfonyl)
piperazin-1-yl)pyrimidine (5c). Prepared by method A, white solid,
(2H, m), 3.51 (2H, m); 13C NMR (100 MHz, CDCl3),
d
(ppm): 170.0,
mp 123e126 ꢁC, yield 82%. 1H NMR (400 MHz, CDCl3),
d(ppm): 8.19
168.9, 161.2, 160.0, 153.3, 151.7, 148.5, 136.5, 135.1, 133.6, 130.1, 127.8,
127.1, 125.6, 122.0, 120.9, 120.9, 96.9, 43.7, 31.4, 30.2, 29.7; HRMS
(ESI)þ calculated for C24H20Cl2N5O2, [MþH]þ: m/z 480.0994, found
480.0997; Purity: 99.0% (HPLC).
(1H, d, J ¼ 5.5 Hz), 7.87 (1H, dd, J ¼ 7.8, 1.6 Hz), 7.51 (1H, m), 7.23
(1H, dd, J ¼ 1.8,1.7 Hz), 7.07 (2H, d, J ¼ 1.8 Hz), 7.01 (2H, m), 6.10 (1H,
d, J ¼ 5.5 Hz), 3.90 (3H s), 3.76 (4H, m), 3.25 (4H, dd, J ¼ 5.1, 5.0 Hz);
13C NMR (100 MHz, CDCl3),
d(ppm): 168.9, 161.1, 156.9, 156.9, 153.3,
135.1, 124.7, 131.8, 126.1, 125.6, 120.8, 120.8, 120.5, 112.3, 96.6, 56.0,
45.7, 45.7, 43.8, 43.8; HRMS (ESI)þ calculated for C21H21Cl2N4O4S,
[MþH]þ: m/z 495.0661, found 495.0663; Purity: 98.5% (HPLC).
4.2.4.14. 5-(4-(4-(3,5-dichlorophenoxy)pyrimidin-2-yl)piperazine-1-
carbonyl)pyrrolidin-2-one (4n). Prepared by method B, colorless oil,
yield 84%. 1H NMR (400 MHz, CDCl3),
d(ppm): 8.24 (1H, d,
J ¼ 5.4 Hz), 7.25 (1H, m), 7.10 (2H, d, J ¼ 1.8 Hz), 6.56 (1H, s), 6.18
4.2.5.4. 4-(3,5-dichlorophenoxy)-2-(4-((4-methoxyphenyl)sulfonyl)
(1H, d, J ¼ 5.5 Hz), 4.52 (1H, dd, J ¼ 7.8, 5.2 Hz), 3.69 (6H, m), 3.47
piperazin-1-yl)pyrimidine (5d). Prepared by method A, white solid,
(2H, m); 13C NMR (100 MHz, CDCl3),
d
(ppm): 178.1, 170.0, 169.0,
mp 126e128 ꢁC, yield 89%. 1H NMR (400 MHz, CDCl3),
d(ppm): 8.16
161.1, 160.0, 153.3, 135.1, 125.7, 120.9, 120.9, 97.0, 54.1, 44.6, 43.7,
43.4, 42.0, 39.4, 25.4; HRMS (ESI)þ calculated for C19H20Cl2N5O3,
[MþH]þ: m/z 436.0943, found 436.0948; Purity: 98.2% (HPLC).
(1H, d, J ¼ 5.5 Hz), 7.68 (2H, m), 7.24 (1H, s), 7.05 (2H, d, J ¼ 1.8 Hz),
6.99 (1H, m), 6.97 (1H, m), 6.09 (1H, d, J ¼ 5.5 Hz), 3.87 (3H, s), 3.78
(4H, m), 2.99 (4H, m); 13C NMR (100 MHz, CDCl3),
d(ppm): 168.9,
163.2, 160.9, 160.0, 153.3, 135.1, 130.0, 130.0, 127.0, 125.6, 120.9,
120.9, 114.3, 114.3, 96.7, 55.6, 45.8, 45.8, 43.0, 43.0; HRMS (ESI)þ
calculated for C21H21Cl2N4O4S, [MþH]þ: m/z 495.0661, found
495.0665; Purity: 98.3% (HPLC).
4.2.4.15. (4-(4-(3, 5-dichlorophenoxy) pyrimidin-2-yl) piperazin-1-
yl)(indolin-2-yl) methanone (4o). Prepared by method B, white
solid, mp 160e163 ꢁC, yield 71%. 1H NMR (400 MHz, CDCl3),