A.Z. Abdelazem et al. / European Journal of Medicinal Chemistry 90 (2015) 195e208
203
52e54 ꢀC; 1H NMR (CDCl3)
d
1.70e1.76 (m, 4H), 2.39 (s, 3H),
123.49, 131.99, 133.44, 134.37, 139.93, 148.32, 150.89, 159.75, 162.12,
162.72.
3.51e3.54 (m, 2H), 3.74 (t, J ¼ 6 Hz, 2H), 3.86 (s, 3H), 5.82 (s, 1H),
5.99 (s, 1H), 6.68 (s, 1H), 6.81 (s, 1H), 7.20 (s, 1H), 7.26 (s, 1H),
7.37e7.42 (m, 1H), 8.28 (d, J ¼ 8.0 Hz, 1H), 8.69 (d, J ¼ 1.2 Hz, 1H),
4.5.2. 3-(6-(3-(3-Methoxy-5-methylphenyl)-1H-pyrazol-4-yl)-2-
(pyridin-3-yl)pyrimidin-4-yl)amino) propan-1-ol (5b)
9.21 (s, 1H) 15.49 (s, 1H); 13C NMR (CDCl3)
d 21.48, 21.60, 25.97,
26.18, 29.90, 30.03, 41.22, 41.51, 48.12, 55.35, 55.44, 62.15, 62.41,
93.52, 102.66, 106.33, 108.33, 110.41, 117.16, 119.32, 120.61, 122.36,
123.51, 133.09, 134.41, 134.53, 137.34, 137.72, 139.49, 139.87, 148.37,
148.54, 150.99, 151.07, 159.76, 161.34, 162.75, 164.32, 165.52, 195.95.
Flash column chromatography was carried out using (ethyl
acetate-methanol, 10:1, v/v). Yield (148 mg, 71%); mp 70e72 ꢀC; 1H
NMR (CDCl3)
d 1.80e1.84 (m, 2H), 2.33 (s, 3H), 3.67e3.74 (m 7H),
5.72 (s, 1H), 6.81 (s, 1H), 6.91 (s, 1H), 6.92 (s, 1H), 6.96 (s, 1H),
7.33e7.36 (dd, J ¼ 4.8, 7.6 Hz,1H), 8.10 (d, J ¼ 8.0 Hz,1H), 8.19 (s,1H),
8.64 (d, J ¼ 1.6, 4.8 Hz, 1H), 8.89 (d, J ¼ 1.2 Hz, 1H); 13C NMR (CDCl3)
4.4.4. 2-(6-(2-Morpholinoethylamino)-1-(3-methoxy-5-
d
21.49, 32.86, 37.66, 55.31, 58.89, 104.29, 111.71, 115.53, 117.78,
methylphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)ethanone (4d)
Flash column chromatography was carried out using (ethyl
acetate-methanol,10:1, v/v) to give the title compound as a mixture
of keto/enol tautomers. Yield: (317 mg, 71%); mp 72e74 ꢀC; 1H NMR
122.14, 123.59, 133.13, 134.37, 139.91, 148.25, 151.03, 159.72, 160.99,
162.35, 162.93.
4.5.3. 4-(6-(3-(3-Methoxy-5-methylphenyl)-1H-pyrazol-4-yl)-2-
(pyridin-3-yl)pyrimidin-4-yl)amino) butan-1-ol (5c)
(CDCl3)
d 2.36 (s, 3H), 2.50 (m 4H), 2.65 (m 2H), 3.59 (m 2H), 3.74
(m, 4H), 3.82 (s, 3H), 5.88 (s, 1H), 5.99 (s, 1H), 6.70 (s, 1H), 6.80 (s,
Flash column chromatography was carried out using
(dichloromethane-methanol, 20:1, v/v). Yield (159 mg, 74%); mp
1H), 7.20 (s, 1H), 7.39e7.40 (m, 1H), 8.29 (d, J ¼ 8.0 Hz, 1H), 8.67 (d,
J ¼ 3.6 Hz, 1H), 9.21 (s, 1H), 15.38 (s, 1H); 13C NMR (CDCl3)
d 21.48,
79e81 ꢀC; 1H NMR (CDCl3)
d 1.71e1.78 (m, 4H), 2.40 (s, 3H),
21.58, 22.96, 23.83, 28.79, 30.52, 37.70, 37.74, 38.73, 48.06, 53.37,
53.40, 55.33, 55.41, 57.33, 66.75, 66.80, 66.97, 93.71, 102.98, 106.41,
108.16, 110.51, 117.14, 119.22, 120.40, 122.30, 123.43, 123.46, 128.76,
130.34, 133.24, 134.34, 134.5, 137.23, 137.84, 139.48, 139.82, 148.44,
148.57, 151.06, 151.14, 159.77, 162.73, 165.47, 196.09.
3.57e3.59 (m 2H), 3.75 (t, J ¼ 6 Hz, 2H), 3.81 (s, 3H), 6.87 (s, 1H),
6.94 (s, 1H), 6.97 (s, 1H), 7.00 (s, 1H), 7.39 (ddd, J ¼ 0.8, 4.8, 8.0 Hz,
1H), 8.17 (dt, J ¼ 1.6, 8.0 Hz,1H), 8.36 (s, 1H), 8.68 (dd, J ¼ 1.6, 4.8 Hz,
1H), 8.97 (d, J ¼ 2.0 Hz, 1H); 13C NMR (CDCl3)
d 21.53, 26.14, 29.94,
41.21, 55.40, 62.52, 103.64, 111.70, 115.77, 122.09, 123.56, 131.87,
132.94, 134.47, 140.13, 148.40, 151.24, 159.83, 160.78, 163.54.
4.4.5. 2-(6-(3-Morpholinopropylamino)-1-(3-methoxy-5-
methylphenyl)-2-(pyridin-3-yl)pyrimidin-4-yl)ethanone (4e)
Flash column chromatography was carried out using (ethyl
acetate-methanol, 3:1, v/v) to give the title compound as a mixture
of keto/enol tautomers (1:2.2). Yield: (244 mg, 53%); mp 79e80 ꢀC;
4.5.4. 6-(3-(3-Methoxy-5-methylphenyl)-1H-pyrazol-4-yl)-N-(2-
morpholinoethyl)-2-(pyridin-3-yl) pyrimidin-4-amine (5d)
Flash column chromatography was carried out using (ethyl
acetate-methanol, 2:1, v/v). Yield (146 mg, 62%); mp 87e88 ꢀC; 1H
1H NMR (CDCl3)
d
1.70e1.87 (m, J ¼ 6.8, 13.2 Hz, 2H), 2.41 (s, 3H),
NMR (CDCl3) d 2.35 (s, 3H), 2.63 (m, 4H), 2.72 (m, 2H), 3.66 (m, 2H),
2.51e2.62 (m, 6H), 3.62e3.66 (m, 2H), 3.82e3.83 (m, 4H), 3.88 (s,
3H), 6.02 (s, 1H), 6.48 (s, 1H), 6.73 (s, 1H), 6.83 (s, 1H), 7.22 (s, 1H),
7.41e7.43 (m, 1H), 8.32 (d, J ¼ 1.6 Hz, 1H), 8.71 (dd, J ¼ 1.6, 4.8 Hz,
3.76 (s, 3H), 3.80 (t, J ¼ 4.4 Hz, 4H), 5.90 (s, 1H), 6.82 (s, 1H), 6.93 (s,
1H), 6.97 (s, 1H), 6.99 (s, 1H), 7.35 (ddd, J ¼ 0.8, 4.8, 8.0 Hz, 1H), 8.15
(dt, J ¼ 1.6, 8.0 Hz, 2H), 8.20 (s, 1H), 8.65 (dd, J ¼ 1.6, 4.8 Hz,1H), 8.97
1H), 9.24 (s, 1H) 15.48 (s, 1H); 13C NMR (CDCl3)
d 21.50, 21.61, 25.14,
(d, J ¼ 1.6 Hz,1H); 13C NMR (CDCl3)
d 21.15, 37.67, 53.74, 55.31, 57.03,
67.34, 104.08, 111.76, 115.51, 118.01, 122.14, 123.47, 132.05, 133.51,
134.90, 139.86, 148.28, 150.84, 159.72, 161.19, 162.69.
25.73, 29.70, 30.94, 40.43, 41.13, 53.66, 53.74, 55.36, 55.43, 57.11,
57.47, 66.85, 67.01, 93.69, 102.63, 106.22, 108.20, 110.39, 117.08,
119.25, 120.57, 122.38, 123.44, 123.48, 133.26, 134.31, 134.44, 137.23,
137.72, 139.49, 139.83, 148.45, 148.58, 151.04, 151.12, 159.75, 159.82,
162.82, 164.64, 165.59, 195.98.
4.5.5. 6-(3-(3-Methoxy-5-methylphenyl)-1H-pyrazol-4-yl)-N-(3-
morpholinopropyl)-2-(pyridin-3-yl)pyrimidin-4-amine (5e)
Flash column chromatography was carried out using (ethyl
acetate-methanol, 2:1, v/v). Yield (167 mg, 69%); mp 62e64 ꢀC; 1H
4.5. General procedure for the synthesis of compounds 5aee
NMR (CDCl3)
d 1.86e1.89 (m, 2H), 2.37 (s, 3H), 2.54e2.56 (m, 6H),
A mixture of compound 4aee (0.5 mmol) and dimethylforma-
mide dimethyl acetal (3.5 mmol) was heated to 90 ꢀC for 2 h and
allowed to cool to ambient temperature. The excess reagent was
evaporated and the residue was dissolved in 10 mL of absolute
ethanol, then hydrazine hydrate (3.5 mmol) was added. The
mixture was stirred at ambient temperature for 12 h. The solution
was concentrated in vacuo. The residue was diluted with water and
extracted with ethyl acetate. The combined organic layer was
washed with brine, dried over anhydrous MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography us-
ing the proper mobile phase.
3.58 (m, 2H), 3.78e3.80 (m, 7H), 5.99 (s, 1H), 6.84 (s, 1H), 6.94 (s,
1H), 6.95 (s, 1H), 7.00 (s, 1H), 7.36 (ddd, J ¼ 0.8, 4.8, 8.0 Hz, 1H), 8.16
(dt, J ¼ 1.6, 8.0 Hz, 1H), 8.19 (s, 1H), 8.65 (dd, J ¼ 1.6, 4.8 Hz, 1H), 8.97
(d, J ¼ 1.2 Hz, 1H); 13C NMR (CDCl3)
d 21.53, 25.87, 40.29, 53.64,
55.34, 57.08, 66.78, 103.92, 111.69, 115.59, 118.54, 122.12, 123.48,
132.05, 133.51, 134.29, 139.93, 148.27, 150.82, 153.98, 159.74, 161.08,
162.89.
4.6. General procedure for the synthesis of compounds 6aee
In a vial capped with a rubber septum, a mixture of compound
5aee (0.35 mmol) and cesium carbonate (1.05 mmol) was purged
with nitrogen gas with 5 min. Then 5 mL anhydrous dime-
thylformamide was injected into the vial, and the vial was once
again bubbled with nitrogen for 5 min and left under nitrogen using
nitrogen balloon. Then iodoacetonitrile (0.7 mmol) was injected
and the reaction mixture was left for stirring at ambient temper-
ature for 16 h. The reaction mixture was quenched by water
(10 mL), and then extracted with ethyl acetate (2 ꢁ 10 mL). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4 and concentrated in vacuo. The residue was
4.5.1. N-isobutyl-6-(3-(3-methoxy-5-methylphenyl)-1H-pyrazol-4-
yl)-2-(pyridin-3-yl)pyrimidin-4-amine (5a)
Flash column chromatography was carried out using
(dichloromethane-methanol, 20:1, v/v). Yield (122 mg, 59%); mp
67e68 ꢀC; 1H NMR (CDCl3)
d
0.99 (d, J ¼ 6.8 Hz, 6H), 1.92e1.95 (m,
1H), 2.34 (s, 3H), 3.31 (m, 2H), 3.74 (s, 3H), 6.81 (s, 1H), 6.93 (s, 1H),
6.95 (s, 1H), 6.99 (s, 1H), 7.33e7.36 (m, 1H), 8.14 (s, 1H), 8.17 (s, 1H),
8.63 (dd, J ¼ 1.6, 4.8 Hz,1H), 8.98 (d, J ¼ 1.6 Hz,1H); 13C NMR (CDCl3)
d
20.32, 21.51, 28.51, 49.07, 55.32, 103.77, 111.63, 115.67, 122.10,