Y.T. Han et al. / European Journal of Medicinal Chemistry 79 (2014) 128e142
139
120.5, 120.0, 120.0, 119.2, 119.2, 104.9, 102.6, 99.9, 68.5, 66.4, 53.2,
49.3, 46.9, 46.9, 31.2, 26.2, 24.2, 19.4, 13.9, 11.1, 10.9, 10.9; LRMS
(FAB) m/z 633 (M þ Hþ); HRMS (FAB) calcd for C36H46ClN4O4
(M þ Hþ): 633.3202; found 633.3207; HPLC (9.04 min, 99.3%).
125 MHz) d 157.8,156.8,156.0,155.8,149.1,136.4,130.3,129.8,129.8,
128.4, 128.4,127.2, 127.2, 122.3, 122.3, 120.1, 120.1, 119.2, 119.2, 114.9,
114.9, 103.0, 66.0, 51.6, 49.3, 46.8, 46.8, 32.9, 29.7, 19.9, 13.7, 10.5,
10.5; LRMS (FAB) m/z 575 (M þ Hþ); HRMS (FAB) calcd for
C
33H40ClN4O3 (M
þ
Hþ): 575.2783; found 575.2789; HPLC
4.3.12. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-5-(4-(4-
chlorophenoxy)phenyl)-1-propyl-1H-pyrazole-3-carboxamide (30)
Carboxylate 100 (12 mg, 0.03 mmol) afforded carboxamide 30
(4.45 min, 95.1%).
4.3.16. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-3-(4-
(cyclohexyloxy)phenyl)-1-methyl-1H-pyrazole-5-carboxamide (34)
Carboxylate 13a (20 mg, 0.06 mmol) afforded carboxamide 34
(23 mg, 65%) as white solid with a melting point of 118e124 ꢀC: 1H
(10 mg, 51%) as a pale yellow oil: 1H NMR (300 MHz, CD3OD)
d8.19
(d, 1H, J ¼ 8.8 Hz), 7.44 (d, 2H, J ¼ 8.6 Hz), 7.38 (d, 2H, J ¼ 9.0 Hz),
7.10 (d, 2H, J ¼ 8.8 Hz), 7.04 (d, 2H, J ¼ 9.0 Hz), 6.77 (s, 1H), 6.60e
6.49 (m, 2H), 4.16e4.05 (m, 4H), 4.00 (t, 2H, J ¼ 6.0 Hz), 2.77e2.63
(m, 6H), 1.99e1.79 (m, 6H), 1.66e1.62 (m, 2H), 1.10 (t, 6H, J ¼ 7.1 Hz),
1.03 (t, 3H, J ¼ 7.5 Hz), 0.85 (t, 3H, J ¼ 7.3 Hz); 13C NMR (CDCl3,
NMR (300 MHz, CD3OD)
d 7.69e7.62 (m, 3H), 7.04 (s, 1H), 6.93 (d,
2H, J ¼ 8.8 Hz), 6.60 (d, 1H, J ¼ 2.3 Hz), 6.52 (dd, 1H, J ¼ 2.4, 8.6 Hz),
4.35e4.32 (m,1H), 4.13 (s, 3H), 4.02 (t, 4H, J ¼ 6.0 Hz), 2.91e2.78 (m,
6H), 2.10e1.99 (m, 4H), 1.86e1.78 (m, 4H), 1.55e1.39 (m, 8H), 1.16 (t,
6H, J ¼ 7.1 Hz), 0.97 (t, 3H, J ¼ 7.3 Hz); 13C NMR (CDCl3, 75 MHz)
75 MHz) d 159.5, 157.9, 155.5, 155.0, 148.9, 146.3, 144.8, 130.6, 130.6,
130.0, 130.0, 129.2, 125.3, 121.9, 120.8, 120.8, 120.1, 118.5, 118.5,
106.6, 104.9, 100.1, 68.3, 66.6, 51.6, 49.5, 47.0, 47.0, 31.4, 26.8, 23.4,
19.4,13.9, 11.5,11.5, 11.1; LRMS (FAB) m/z 633 (M þ Hþ); HRMS (FAB)
calcd for C36H46ClN4O4 (M þ Hþ): 633.3202; found 633.3192; HPLC
(11.24 min, 97.2%).
d
157.8, 157.3, 155.9, 149.7, 148.7, 137.1, 126.7, 126.7, 125.0, 120.9,
120.4, 116.2, 116.2, 104.7, 102.2, 99.8, 75.4, 68.4, 66.2, 49.3, 46.8,
46.8, 39.3, 31.8, 31.8, 31.1, 26.0, 25.6, 23.7, 23.7, 19.4, 13.9, 10.7, 10.7;
LRMS (FAB) m/z 577 (M þ Hþ); HRMS (FAB) calcd for C34H49FN4O4
(M þ Hþ): 577.3754; found 577.3748; HPLC (4.83 min, 98.0%).
4.3.13. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-1-butyl-
5-(4-(4-chlorophenoxy)phenyl)-1H-pyrazole-3-carboxamide (31)
Carboxylate 110 (62 mg, 0.16 mmol) afforded carboxamide 31
(48 mg, 47%) as pale yellow solid with a melting point of 137e
145 ꢀC: FT-IR (thin film, neat) nmax 3383, 2959, 1677, 1536, 1484,
4.3.17. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-1-
methyl-3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxamide (35)
Carboxylate 13b (18 mg, 0.06 mmol) afforded carboxamide 35
(20 mg, 63%) as pale yellow solid with a melting point of 69e72 ꢀC:
1243 cmꢃ1
;
1H NMR (300 MHz, CD3OD)
d
8.20 (d, 1H, J ¼ 8.8 Hz),
FT-IR (thin film, neat) nmax 3425, 2960, 1676, 1528, 1439, 1240 cmꢃ1
;
7.48 (d, 2H, J ¼ 8.8 Hz), 7.39 (d, 2H, J ¼ 9.0 Hz), 7.13 (d, 2H,
J ¼ 8.6 Hz), 7.06 (d, 2H, J ¼ 9.2 Hz), 6.79 (s, 1H), 6.64 (d, 1H,
J ¼ 2.6 Hz), 6.53 (dd,1H, J ¼ 2.4, 8.8 Hz), 4.21 (t, 2H, J ¼ 7.2 Hz), 4.13e
4.06 (m, 4H), 2.89e2.74 (m, 6H), 2.06e2.01 (m, 2H), 1.86e1.81 (m,
4H), 1.70e1.62 (m, 2H), 1.30e1.25 (m, 2H), 1.14 (t, 6H, J ¼ 7.2 Hz),
1.04 (t, 3H, J ¼ 7.3 Hz), 0.87 (t, 3H, J ¼ 7.4 Hz); 13C NMR (CDCl3,
1H NMR (300 MHz, CD3OD)
d
7.77 (d, 2H, J ¼ 8.6 Hz), 7.62 (d, 1H,
J ¼ 8.8 Hz), 7.38e7.33 (m, 2H), 7.14e7.10 (m, 2H), 7.03e6.99 (m, 4H),
6.61 (d, 1H, J ¼ 2.6 Hz), 6.52 (dd, 1H, J ¼ 2.6, 8.6 Hz), 4.15 (s, 3H),
4.05e4.00 (m, 4H), 2.96e2.82 (m, 6H), 2.07e2.00 (m, 2H), 1.83e
1.73 (m, 2H), 1.56e1.44 (m, 2H), 1.17 (t, 6H, J ¼ 7.2 Hz), 0.95 (t, 3H,
J ¼ 7.4 Hz); 13C NMR (CDCl3, 125 MHz)
d 157.3, 157.2, 157.1, 156.0,
75 MHz)
d
157.2, 156.8, 155.9, 155.9, 149.1, 148.9, 137.0, 129.7, 129.7,
149.3, 148.8, 137.3, 129.8, 129.8, 127.8, 127.0, 127.0, 123.4, 120.9,
120.4, 119.1, 119.1, 119.0, 119.0, 104.8, 102.5, 99.9, 68.5, 66.3, 49.3,
46.9, 46.9, 39.4, 31.2, 26.2, 19.4, 13.9, 10.9, 10.9; LRMS (FAB) m/z 571
(M þ Hþ); HRMS (FAB) calcd for C34H43N4O4 (M þ Hþ): 571.3279;
found 571.3284; HPLC (6.02 min, 97.3%).
128.5, 128.3, 127.1, 127.1, 121.1, 120.6, 120.0, 120.0, 119.2, 119.2, 105.0,
102.6, 99.9, 68.5, 66.1, 51.5, 49.3, 46.9, 46.9, 32.9, 31.2, 25.6, 19.9,
19.4, 13.9, 13.7, 10.3, 10.3; LRMS (FAB) m/z 647 (M þ Hþ); HRMS
(FAB) calcd for C37H48ClN4O4 (M þ Hþ): 647.3359; found 647.3359;
HPLC (7.34 min, 95.8%).
4.3.18. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-1-
methyl-3-(4-(pyridin-2-yloxy)phenyl)-1H-pyrazole-5-carboxamide
(36)
4.3.14. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-1-butyl-
3-(4-(4-chlorophenoxy)phenyl)-1H-pyrazole-5-carboxamide (32)
Carboxylate 11 (33 mg, 0.08 mmol) afforded carboxamide 32
(23 mg, 44%) as white solid with a melting point of 102e107 ꢀC: FT-
IR (thin film, neat) nmax 3424, 2959, 1675, 1527, 1485, 1241 cmꢃ1; 1H
Carboxylate 7d (30 mg, 0.09 mmol) afforded carboxamide 36
(22 mg, 42%) as a colorless oil: FT-IR (thin film, neat) nmax 3423,
2957, 1674, 1528, 1429, 1244 cmꢃ1 1H NMR (300 MHz, CD3OD)
;
NMR (300 MHz, CD3OD)
d
7.82 (d, 2H, J ¼ 8.6 Hz), 7.56 (d, 1H,
d
8.15e8.13 (m, 1H), 7.87e7.78 (m, 3H), 7.62 (d, 1H, J ¼ 8.8 Hz), 7.16e
J ¼ 8.6 Hz), 7.37e7.32 (m, 2H), 7.13 (bs, 1H), 7.06e6.98 (m, 4H), 6.63
(d, 1H, J ¼ 2.6 Hz), 6.53 (dd, 1H, J ¼ 2.6, 8.8 Hz), 4.57 (t, 2H,
J ¼ 7.2 Hz), 4.06e4.01 (m, 4H), 2.76e2.62 (m, 6H), 1.95e1.74 (m,
6H), 1.55e1.45 (m, 2H), 1.40e1.32 (m, 2H), 1.12e1.06 (m, 6H), 0.98e
6.09 (m, 4H), 6.97 (d, 1H, J ¼ 8.3 Hz), 6.62 (d, 1H, J ¼ 2.6 Hz), 6.53
(dd, 1H, J ¼ 2.4, 8.6 Hz), 4.17 (s, 3H), 4.12e4.01 (m, 4H), 3.02e2.88
(m, 6H), 2.10e2.02 (m, 2H), 1.84e1.74 (m, 2H), 1.58e1.45 (m, 2H),
1.20 (t, 6H, J ¼ 7.2 Hz), 0.96 (t, 3H, J ¼ 7.4 Hz); 13C NMR (CDCl3,
0.92 (m, 6H); 13C NMR (CDCl3, 75 MHz)
d
159.5, 157.8, 155.0, 155.0,
75 MHz) d 163.7, 157.2, 155.9, 154.1, 149.3, 148.8, 147.8, 139.5, 137.3,
148.9, 146.1, 144.7, 130.6, 130.6, 129.9, 129.9, 129.1, 125.1, 122.0,
120.7, 120.7, 119.9, 118.5, 118.5, 106.5, 104.7, 99.8, 68.3, 65.9, 49.7,
49.3, 46.8, 46.8, 32.1, 31.3, 25.4, 19.7, 19.3, 13.9, 13.5, 10.2, 10.2; LRMS
(FAB) m/z 647 (M þ Hþ); HRMS (FAB) calcd for C37H48ClN4O4
(M þ Hþ): 647.3359; found 647.3364; HPLC (10.97 min, 87.8%).
129.2, 126.9, 126.9, 121.4, 121.4, 121.0, 120.5, 118.6, 111.7, 104.9, 102.7,
99.9, 68.5, 66.2, 53.0, 49.3, 46.9, 46.9, 39.4, 31.2, 19.4, 13.9, 10.6, 10.6,
LRMS (FAB) m/z 572 (M þ Hþ); HRMS (FAB) calcd for C33H42N5O4
(M þ Hþ): 572.3237; found 572.3231; HPLC (3.17 min, 97.4%).
4.3.19. N-(2-butoxy-4-(3-(diethylamino)propoxy)phenyl)-3-(4-(4-
methoxyphenoxy)phenyl)-1-methyl-1H-pyrazole-5-carboxamide
(37)
4.3.15. 1-Butyl-3-(4-(4-chlorophenoxy)phenyl)-N-(4-(3-
(diethylamino)propoxy)phenyl)-1H-pyrazole-5-carboxamide (33)
Carboxylate 11 (33 mg, 0.08 mmol) afforded carboxamide 33
Carboxylate 13c (17 mg, 0.05 mmol) afforded carboxamide 37
(21 mg, 45%) as a pale yellow oil: 1H NMR (300 MHz, CD3OD)
d 7.82
(22 mg, 76%) as white solid with a melting point of 97e100 ꢀC: 1H
(d, 2H, J ¼ 8.8 Hz), 7.58 (d, 2H, J ¼ 9.0 Hz), 7.35 (d, 2H, J ¼ 9.0 Hz),
7.21 (s, 1H), 7.06e6.93 (m, 6H), 4.57 (t, 2H, J ¼ 7.1 Hz), 4.07 (t, 2H,
J ¼ 5.8 Hz), 3.11e2.92 (m, 6H), 2.14e2.05 (m, 2H),1.90e1.80 (m, 2H),
1.42e1.20 (m, 8H), 0.95 (t, 3H, J ¼ 7.3 Hz); 13C NMR (CDCl3,
NMR (300 MHz, CD3OD)
d
7.71 (d, 2H, J ¼ 8.6 Hz), 7.64 (d, 1H,
J ¼ 8.8 Hz), 7.07 (s, 1H), 6.99e6.90 (m, 6H), 6.60 (d, 1H, J ¼ 2.4 Hz),
6.51 (dd, 1H, J ¼ 2.6, 8.8 Hz), 4.14 (s, 3H), 4.05e4.00 (m, 4H), 3.78 (s,
3H), 2.96e2.82 (m, 6H), 2.07e1.98 (m, 2H), 1.83e1.73 (m, 2H), 1.57e