4180
W.-H. Lin et al. / Bioorg. Med. Chem. 19 (2011) 4173–4182
found: 547.1 (M+H+); HRMS (FAB) calcd for C28H30N6O4S:
546.2049; found: 546.2056.
532.1 (M+H+); HRMS (FAB) calcd for C28H29N5O4S: 531.1940;
found: 531.1944.
5.2.15. N1-(3-3-[(Ethylsulfonyl)amino]phenyl-1H-5-pyrazolyl)-
4-(4-methylpiperazino) benzamide (8m)
5.2.22. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-4-(2-morpholinoethoxy)benzamide (8t)
Mp 256–258 °C. 1H NMR (300 MHz, DMSO-d6): d 12.61 (s, 1H),
10.56 (s, 1H), 9.90 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.47 (d,
J = 7.8 Hz, 1H), 7.52–7.39 (m, 2H), 7.17 (d, J = 6.9 Hz, 1H), 6.98 (d,
J = 7.8 Hz, 1H), 3.29 (d, J = 4.5 Hz, 4H), 3.16–3.14 (m, 2H), 2.44 (t,
J = 4.5 Hz, 4H), 2.22 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); MS (ES+) m/z
calcd for C23H28N6O3S: 468.6; found: 491.9 (M+Na), 469.1 (M+H+).
Mp 106–107 °C. 1H NMR (400 MHz, DMSO-d6): d 12.92 (s, 1H),
10.73 (s, 1H), 10.41 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.79 (d,
J = 6.8 Hz, 2H), 7.63–7.55 (m, 3H), 7.43–7.37 (m, 2H), 7.30 (t,
J = 8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 4.17 (t,
J = 5.6 Hz, 2H), 3.58 (t, J = 4.8 Hz, 4H), 2.71 (t, J = 5.6 Hz, 2H), 2.48
(t, J = 4.8 Hz, 4H); MS (ES+) m/z calcd for C28H29N5O5S: 547.63;
found: 548.2 (M+H+).
5.2.16. N1-(3-3-[(Propylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-4-(4-methylpiperazino) benzamide (8n)
5.2.23. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-4-(morpholinomethyl)benzamide (8u)
Mp 228–230 °C. 1H NMR (300 MHz, DMSO-d6): d 12.92 (s, 1H),
10.57 (s, 1H), 9.90 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.52–7.40 (m,
3H), 7.17 (d, J = 7.5 Hz, 1H), 7.00–6.97 (m, 3H), 3.29 (t, J = 4.8 Hz,
4H), 3.12 (t, J = 7.5 Hz, 2H), 2.44 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H),
1.71 (qt, J = 7.5, 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H); MS (ES+) m/z
calcd for C24H30N6O3S: 482.59; found: 483.1 (M+H+); HRMS (FAB)
calcd for C24H30N6O3S: 482.2100; found: 482.2103.
Mp 06–108 °C. 1H NMR (400 MHz, DMSO-d6): d 12.99 (s, 1H),
10.91 (s, 1H), 10.45 (s, 1H), 8.02 (d, J = 5.6 Hz, 2H), 7.80 (d,
J = 6.8 Hz, 2H), 7.63–7.53 (m, 4H), 7.43 (d, J = 8.0 Hz, 1H), 7.35–
7.28 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 3.63 (br s, 6H),
2.41 (br s, 4H); MS (ES+) m/z calcd for C27H27N5O4S: 517.60; found:
518.1 (M+H+); HRMS (FAB) calcd for C27H27N5O4S: 517.1784;
found: 517.1793.
5.2.17. N1-(3-3-[(Isopropylsulfonyl)amino]phenyl-1H-5-pyrazol
yl)-4-(4-methylpiperazino) benzamide (8o)
5.2.24. N1-3-[3-(Benzoylamino)phenyl]-1H-5-pyrazolyl-4-(4-
methylpiperazino)benzamide (9)
Mp 170–172 °C. 1H NMR (300 MHz, DMSO-d6): d 10.56 (s, 1H),
9.87 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.54–
7.37 (m, 2H), 7.19 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.29
(t, J = 4.8 Hz, 4H), 2.44 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.81 (s, 1H),
1.27 (s, 3H), 1.25 (s, 3H); MS (ES+) m/z calcd for C24H30N6O3S:
482.6; found: 505.1 (M+Na), 483.1 (M+H+).
Mp 197–200 °C. 1H NMR (300 MHz, DMSO-d6): d 12.88 (s, 1H),
10.62(s, 1H) 10.34 (s, 1H), 8.20 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H),
7.93 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.63–7.40 (m, 5H),
6.98 (d, J = 8.7 Hz, 1H), 3.28 (t, J = 4.8 Hz, 4H), 2.43 (t, J = 4.8 Hz,
4H), 2.21 (s, 3H); MS (ES+) m/z calcd for C28H28N6O2: 480.22;
found: 481.3 (M+H+).
5.2.18. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-3-(4-methylpiperazino) benzamide (8p)
5.2.25. N1-(3-{3-[(Anilinocarbonyl)amino]phenyl}-1H-5-pyrazo
lyl)-4-(4-methylpiperazino) benzamide (10)
Mp 104–105 °C. 1H NMR (400 MHz, DMSO-d6): d 12.96 (s, 1H),
10.86 (s, 1H), 10.43 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.62- 7.53 (m,
4H), 7.43–7.39 (m, 3H), 7.34–7.28 (m, 2H), 7.12 (d, J = 6.4 Hz,
1H), 7.05 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 3.23 (t, J = 4.8 Hz, 4H),
2.48 (t, J = 4.8 Hz, 4H), 2.24 (s, 3H); MS (ES+) m/z calcd for
1H NMR (300 MHz, DMSO-d6): d 12.85 (s, 1H), 10.57 (s, 1H),
8.81 (d, J = 10.8 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H), 7.48
(d, J = 7.8 Hz, 2H), 7.35–7.24 (m, 5H), 6.99–6.94 (m, 3H), 3.28 (t,
J = 4.8 Hz, 4H), 2.44 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H); MS (ES+) m/z
calcd for C28H29N7O2: 495.24; found: 496.3 (M+H+).
C
C
27H28N6O3S: 516.62; found: 517.1 (M+H+); HRMS (FAB) calcd for
27H28N6O3S: 516.1944; found: 516.1952.
5.3. General procedure for the preparation of compound 12
5.2.19. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-3-morpholino benzamide (8q)
To a solution of 5a (1.0 equiv) and 4,6-dichloro-2-methylpyrim-
idine (1.5 equiv) in DMF at room temperature was added hydrogen
chloride solution (4.0 M in dioxane, 1.6 equiv) and the resultant
mixture was stirred at 80 °C for 4 h. After cooling to room temper-
ature, the solvent was evaporated in vacuo to give a viscous resi-
due, which was partitioned between EtOAc and 1 N NaHCO3. The
organic layer was separated, dried over MgSO4 and concentrated
in vacuo. Purification by flash column chromatography (eluted
with CH2Cl2/CH3OH) yielded compounds 11. Only one of 11 is se-
lected to show its NMR spectrum and Mass.
1H NMR (400 MHz, DMSO-d6): d 12.96 (s, 1H), 10.87 (s, 1H),
10.42 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.63- 7.53 (m, 4H), 7.46–
7.41 (m, 3H), 7.35 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.15
(d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.92 (br s, 1H), 3.77 (t,
J = 4.8 Hz, 4H), 3.20 (t, J = 4.8 Hz, 4H); MS (ES+) m/z calcd for
C
26H25N5O4S: 503.57; found: 504.0 (M+H+).
5.2.20. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-4-morpholino benzamide (8r)
Mp 257–260 °C. 1H NMR (300 MHz, DMSO-d6): d 12.86 (s, 1H),
10.59 (s, 1H), 10.39 (s, 1H), 7.94 (d, J = 10.8 Hz, 2H), 7.79 (d,
J = 11.2 Hz, 2H), 7.63–7.52 (m, 3H), 7.45–7.40 (m, 2H), 7.29 (t,
J = 10.0 Hz, 1H), 7.02 (t, J = 12.0 Hz, 3H), 6.87 (br s, 1H), 3.74 (t,
J = 6.0 Hz, 4H), 3.26 (t, J = 6.0 Hz, 4H); MS (ES+) m/z calcd for
5.3.1. N-(6-Chloro-2-methyl-4-pyrimidinyl)-N-[5-(3-nitrophen
yl)-1H-3-pyrazolyl]amine (11)
Mp 238–240 °C. 1H NMR (400 MHz, DMSO-d6): d 13.21(s, 1H),
10.34(s, 1H) 10.34 (s, 1H), 8.58 (s, 1H), 8.18 (d, J = 7.2 Hz, 2H),
7.74 (t, J = 8.0 Hz, 1H), 6.85 (br s, 1H), 2.46 (s, 3H); MS (ES+) m/z
calcd for C14H11ClN6O2: 330.06; found: 331.1 (M+H+).
C
26H25N5O4S: 503.57; found: 504.0 (M+H+).
5.2.21. N1-(3-3-[(Phenylsulfonyl)amino]phenyl-1H-5-pyrazolyl)
-4-(2-tetrahydro-1H-1-pyrrolylethoxy)benzamide (8s)
To a solution of 11 (1.0 equiv) in pyridine at room temperature
was added 1° or 2° amines (2.0 equiv) and the resultant mixture
was stirred at 80 °C for 2 h. After cooling to room temperature,
the reaction mixture was evaporated to dryness and the residue
suspended in 1 N NaHCO3. The suspension was vigorously stirred
at room temperature for 1 h, and the resultant solid was collected
by filtration and dried in vacuo to yield crude products which were
Mp 238–240 °C. 1H NMR (300 MHz, DMSO-d6): d 10.87 (s, 1H),
10.46 (s, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 6.9 Hz, 2H), 7.61-
7.41 (m, 4H), 7.31–7.26 (m, 2H), 7.12–7.03 (m, 3H), 6.78 (s, 1H),
4.43 (t, J = 4.8 Hz, 2H), 3.59 (br, 4H), 3.14–3.04 (m, 2H), 2.00–1.86
(m, 4H); MS (ES+) m/z calcd for C28H29N5O4S: 531.63; found: