M.M. Gamal El-Din et al. / European Journal of Medicinal Chemistry 119 (2016) 122e131
129
6.97e6.95 (m, 1H), 6.80e6.78 (m, 2H), 6.59 (t, J ¼ 5.2 Hz, 1H), 6.43
(s, 1H), 6.30 (d, J ¼ 5.2 Hz, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.34e3.12
(d, J ¼ 5.2 Hz, 1H), 7.44e7.25 (m, 10H), 7.00 (dd, J ¼ 1.2, 8.0 Hz, 1H),
6.92 (t, J ¼ 7.6 Hz,1H), 6.85e6.83 (m, 2H), 6.54 (brs,1H), 6.44 (s,1H),
(m, 4H); 13C NMR (100 MHz, DMSO-d6)
d
166.6, 159.6, 159.5, 148.1,
6.34 (d, J ¼ 5.2 Hz, 1H), 6.27 (brs, 1H), 3.66 (s, 3H), 3.42 (brs, 4H); 13
C
141.0, 140.2, 139.9, 139.6, 136.4, 131.4, 130.4, 129.9, 129.3, 128.2,
125.8, 123.0, 120.4, 119.9, 117.4, 116.4, 115.0, 112.8, 111.1, 105.7, 55.7,
55.5; MS m/z: 520.0 [Mþ1].
NMR (100 MHz, DMSO-d6) d 159.7, 159.6, 155.6, 148.2, 140.9, 140.3,
139.9, 139.6, 131.4, 130.4, 129.3, 129.1, 128.2, 125.8, 123.0, 121.5,
120.4, 118.2, 116.4, 115.0, 111.1, 105.5, 55.6, 41.9; MS m/z: 505.0
[Mþ1].
Compounds (1eeh) were prepared from 8b and appropriate
acid chloride as reported in the synthesis of 1a.
Compounds 2b,c were prepared from 8a and appropriate iso-
cyanate derivative as reported in the synthesis of 2a.
4.6.4. N-(3-((4-(3-(3-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
pyridin-2-yl)amino)-propyl)benzamide (1e)
4.7.1. 1-(2-((4-(3-(3-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
1H NMR (400 MHz, DMSO-d6)
d
8.50 (t, J ¼ 4.8 Hz, 1H), 8.09 (s,
pyridin-2-yl)amino)ethyl)-3-(3-(trifluoromethyl)phenyl)urea (2b)
1H), 7.51e7.44 (m, 3H), 7.36e7.25 (m, 6H), 6.97e6.94 (m, 1H),
6.81e6.78 (m, 2H), 6.44 (t, J ¼ 7.2 Hz, 1H), 6.34e6,30 (m, 2H), 3.63
(s, 3H), 3.31e3.29 (m, 2H), 3.29e3.25 (m, 2H), 1.69 (m, 2H); 13C
1H NMR (400 MHz, DMSO-d6)
d 8.09 (s, 1H), 7.98 (s, 1H), 7.83 (d,
J ¼ 8.0 Hz, 1H), 7.49e7.20 (m, 9H), 6.97e6.94 (m, 1H), 6.80e6.78 (m,
2H), 6.51 (brs, 1H), 6.38e6.37 (m, 2H), 6.20 (dd, J ¼ 1.2, 8.0 Hz, 1H),
3.63 (s, 3H), 3.24e3.23 (m, 4H); 13C NMR (100 MHz, DMSO-d6)
NMR (100 MHz, DMSO-d6)
d 166.6, 159.7, 159.6, 148.2, 140.9, 140.2,
139.9, 139.6, 135.1, 131.5, 131.4, 130.4, 129.3, 128.7, 128.2, 127.6,
125.8, 122.9, 120.5, 116.4, 115.0, 110.8, 105.4, 55.5, 39.2, 37.6, 29.5;
MS m/z: 504.0 [Mþ1].
d 159.6, 159.5, 155.6, 148.2, 141.9, 141.0, 140.2, 139.9, 139.6, 131.4,
130.4, 130.2, 129.7, 129.3, 128.2, 125.8, 123.0, 121.6, 120.4, 117.7,
116.4, 115.0, 114.0, 111.1, 105.5, 55.5, 41.8; MS m/z: 573.0 [Mþ1].
4.6.5. 4-Fluoro-N-(3-((4-(3-(3-methoxyphenyl)-1-phenyl-1H-
4.7.2. 1-(3,4-Dichlorophenyl)-3-(2-((4-(3-(3-methoxyphenyl)-1-
pyrazol-4-yl)pyridin-2-yl)-amino)propyl)benzamide (1f)
phenyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)ethyl)urea (2c)
1H NMR (400 MHz, DMSO-d6)
d
8.51 (s, 1H), 8.09 (s, 1H),
1H NMR (400 MHz, DMSO-d6)
d 8.56 (s, 1H), 8.13 (s, 1H), 7.87 (d,
7.93e7.90 (m, 2H), 7.83 (d, J ¼ 4.8 Hz, 1H), 7.41e7.25 (m, 8H), 6.95
(d, J ¼ 7.2 Hz, 1H), 6.81e6.78 (m, 2H), 6.43 (s, 1H), 6.34e6.30 (m,
2H), 3.62 (s, 3H), 3.33e3.31 (m, 2H), 3.17e3.15 (m, 2H),1.69 (m, 2H);
J ¼ 5.2 Hz, 1H), 7.44e7.25 (m, 10H), 7.05 (dd, J ¼ 1.2, 8.0 Hz, 1H), 6.91
(t, J ¼ 8.0 Hz, 1H), 6.85e6.83 (m, 2H), 6.54 (s, 1H), 6.44 (s, 1H), 6.34
(d, J ¼ 5.2 Hz,1H), 6.27 (s, 1H), 3.66 (s, 3H), 3.42 (br s, 4H); MS m/z:
572.9 [Mþ1].
13C NMR (100 MHz, DMSO-d6)
d 165.6, 163.0, 159.6, 148.2,
140.9,140.2, 139.9, 139.6, 131.6, 131.4, 130.4, 130.3, 130.2, 129.3,
128.2, 125.8, 122.9, 120.4, 116.4, 115.7, 115.5, 114.9, 110.8, 55.6, 39.0,
37.6, 29.4; MS m/z: 522.0 [Mþ1].
Compounds (2def) were prepared from 8b and appropriate
isocyanate derivative as reported in the synthesis of 2a.
4.7.3. 1-(3-((4-(3-(3-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
4.6.6. N-(3-((4-(3-(3-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
pyridin-2-yl)amino)propyl) -3-phenylurea (2d)
pyridin-2-yl)amino)-propyl)-3-(trifluoromethyl)benzamide (1g)
1H NMR (400 MHz, DMSO-d6)
d 8.45 (s, 1H), 8.09 (s, 1H), 7.83 (d,
1H NMR (400 MHz, DMSO-d6)
d
8.77 (s, 1H), 8.20e8.16 (m, 2H),
J ¼ 5.2 Hz, 1H), 7.41e7.21 (m, 10H), 6.98e6.95 (m, 1H), 6.87 (t,
J ¼ 8.0 Hz, 1H), 6.80e6.78 (m, 2H), 6.43 (t, J ¼ 5.6 Hz, 1H), 6.34e6.30
(m, 2H), 6.17 (t, J ¼ 5.6 Hz, 1H), 3.63 (s, 3H), 3.16e3.11 (m, 4H), 1.60
8.10 (s, 1H), 7.90 (d, J ¼ 8.0 Hz, 1H), 7.83 (d, J ¼ 5.6 Hz, 1H), 7.73 (t,
J ¼ 8.0 Hz, 1H), 7.37e7.25 (m, 6H), 6.95 (dd, J ¼ 2.0, 8.0 Hz, 1H),
6.81e6.79 (m, 2H), 6.46 (t, J ¼ 5.6 Hz, 1H), 6.35e6.31 (m, 2H), 3.63
(s, 3H), 3.37e3.33 (m, 2H), 3.20e3.18 (m, 2H),1.73 (m, 2H); 13C NMR
(m, 2H); 13C NMR (100 MHz, DMSO-d6)
d 159.7, 159.6, 155.8, 148.3,
141.1, 140.9,140.2,139.9,139.6,131.4, 130.4,129.1, 129.1, 128.2, 125.8,
123.0, 121.4, 120.5, 118.1, 116.4, 115.0, 110.8, 105.4, 55.6, 38.9, 37.4,
30.2; MS m/z: 519.1 [Mþ1].
(100 MHz, DMSO-d6)
d 165.1, 159.6, 148.2, 140.9, 140.2, 139.9, 139.6,
135.9, 131.7, 131.4, 130.4, 130.1, 129.8, 129.4, 129.3, 128.2, 125.8,
124.2, 123.2, 123.0, 120.4, 116.4, 115.0, 110.8, 105.4, 55.5, 39.0, 37.8,
29.3; MS m/z: 572.0 [Mþ1].
4.7.4. 1-(3-((4-(3-(3-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
pyridin-2-yl)amino)propyl) -3-(3-(trifluoromethyl)phenyl)urea (2e)
4.6.7. 3-Methoxy-N-(3-((4-(3-(3-methoxyphenyl)-1-phenyl-1H-
1H NMR (400 MHz, DMSO-d6)
d 8.87 (s, 1H), 8.09 (s, 1H), 7.98 (s,
pyrazol-4-yl)pyridin-2-yl)amino)propyl)benzamide (1h)
1H), 7.83 (d, J ¼ 5.6 Hz, 1H), 7.44e7.20 (m, 9H), 6.98e6.95 (m, 1H),
6.80e6.78 (m, 2H), 6.43 (d, J ¼ 5.6 Hz, 1H), 6.33e6.29 (m, 3H), 3.63
(s, 3H), 3.16e3.11 (m, 4H), 1.60 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) d 159.7, 159.6, 155.6, 148.2, 141.9, 140.9, 140.2, 139.9, 139.6, 131.4,
130.4, 130.2, 129.3, 128.2, 125.8, 123.0, 121.6, 120.5, 117.6, 116.4,
1H NMR (400 MHz, DMSO-d6)
d
8.47 (t, J ¼ 4.8 Hz, 1H), 8.09 (s,
1H), 7.82 (d, J ¼ 5.6 Hz, 1H), 7.44e7.25 (m, 9H), 7.09e7.06 (m, 1H),
6.97e6.95 (m, 1H), 6.80e6.79 (m, 2H), 6.42 (t, J ¼ 5.6 Hz, 1H),
6.33e6.30 (m, 2H), 3.79 (s, 3H), 3.63 (s, 3H), 3.29e3.28 (m, 2H),
3.17e3.15 (m, 2H), 1.69 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
115.0,114.0,110.8, 105.4, 55.6, 38.9, 37.4, 30.2; MS m/z: 587.0 [Mþ1].
d
166.6, 159.6, 148.2, 140.9, 140.2, 139.9, 139.6, 136.6, 131.4, 130.4,
129.9, 129.3, 128.2, 125.8, 123.0, 120.5, 119.8, 117.3, 116.4, 115.0,
112.8, 110.8, 105.4, 55.7, 55.6, 39.0, 37.6, 31.2, 29.5; MS m/z: 534.0
[Mþ1].
4.7.5. 1-(3,4-Dichlorophenyl)-3-(3-((4-(3-(3-methoxyphenyl)-1-
phenyl-1H-pyrazol-4-yl) pyridine-2-yl)amino)propyl)urea (2f)
1H NMR (400 MHz, DMSO-d6)
d 8.84 (s, 1H), 8.09 (s, 1H),
7.86e7.82 (m, 2H), 7.45e7.24 (m, 7H), 6.98e6.95 (m, 1H), 6.80e6.78
(m, 2H), 6.42 (t, J ¼ 5.6 Hz, 1H), 6.33e6.29 (m, 3H), 3.63 (s, 3H),
3.15e3.12 (m, 4H), 1.61 (m, 2H); 13C NMR (100 MHz, DMSO-d6)
4.7. 1-(2-((4-(3-(3-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
pyridin-2-yl)amino)ethyl)-3-phenylurea (2a)
d
159.7, 159.6, 155.4, 148.2, 141.3, 140.9, 140.2, 139.9, 139.6, 131.4,
To a solution of 8a (50 mg, 0.175 mmol) in anhydrous THF
(3 mL), phenyl isocyanate (53 mg, 0.23 mmol) was added to the
solution and the mixture was stirred overnight till completion of
the reaction. After evaporation of the solvent under reduced pres-
sure the residue was purified by column chromatography using the
appropriate ratio of ethyl acetate: methanol to yield the product as
130.9,130.4,129.3,128.2,125.8,122.9,122.6,120.5,119.1,118.1,116.4,
115.0, 110.8, 105.6, 55.6, 38.8, 37.5, 30.0; MS m/z: 589.6 [Mþ1].
4.8. N-(2-((4-(3-(3-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
pyridin-2-yl)amino) ethyl)benzamide (3a)
solid. 1H NMR (400 MHz, DMSO-d6)
d
8.56 (s, 1H), 8.13 (s, 1H), 7.87
To a solution of compound 1a (150 mg, 0.3 mmol) in methylene