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R.D. Jadhav et al. / European Journal of Medicinal Chemistry 54 (2012) 324e342
isocyanate to afford the title compound (65.8 mg, 26.8%) as an off
white solid.
(85.5 mg, 0.55 mmol, 1.1 equiv) as the substituted isocyanate to
afford the title compound (62.4 mg, 27.2%) as an off white solid.
1H NMR (300 MHz, DMSO-d6)
d
12.88 (bs, 1H), 9.15 (s, 1H), 9.11
1H NMR (300 MHz, DMSO-d6)
d 12.81 (bs, 1H), 9.28 (s, 1H), 8.94
(s, 1H), 8.95 (d, J ¼ 8.1 Hz, 1H), 8.02 (bs, 1H), 7.85 (d, J ¼ 8.7 Hz, 2H),
7.59 (s, 1H), 7.64 (d, J ¼ 8.7 Hz, 2H), 7.59 (m, 2H), 7.33 (d, J ¼ 7.2 Hz,
1H), 4.29 (t, J ¼ 7.8 Hz,1H), 2.25 (m,1H), 0.97 (d, J ¼ 6.6 Hz, 3H), 0.96
(d, J ¼ 8.1 Hz, 1H), 8.58 (s, 1H), 8.09 (m, 1H), 7.84 (d, J ¼ 8.7 Hz, 2H),
7.67 (s,1H), 7.60 (d, J ¼ 8.1 Hz, 2H), 7.34 (m,1H), 7.04 (m,1H), 4.28 (t,
J ¼ 6.9 Hz,1H), 2.19 (t, J ¼ 6.9 Hz,1H), 0.96 (d, J ¼ 6.6 Hz, 6H), 0.95 (d,
(d, J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d
172.8, 163.9,
J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d 173.2, 164.3, 163.0,
162.7, 156.7, 152.9, 142.2, 140.9, 130.3, 129.9, 128.1 (2C), 126.5, 123.0,
122.4, 121.9, 121.4, 119.1 (2C), 105.2, 58.6, 30.0, 19.8, 19.2; MS (ESIþ)
m/z 491 (M þ H)þ; mp 232e235 ꢁC; HPLC retention time e
3.783 min, purity e 99.80% (Method A).
161.7, 161.2, 157.0, 153.1, 142.6, 128.5 (2C), 124.8, 123.2, 119.2 (2C),
112.2, 111.9, 105.6, 104.8, 58.9, 30.4, 20.1, 19.6; MS (ESIþ) m/z 459
[M þ H]þ; mp 252e254 ꢁC; HPLC retention time e 3.086 min,
purity e 95.64% (Method A).
6.1.12.5. 2-(3-(4-(3-(3,4-Dimethylphenyl)ureido)phenyl)isoxazole-5-
carboxamido)-3-methyl butanoic acid (34a). Prepared as described
above in the general procedure using 3,4-dimethylphenyl isocya-
nate (81 mg, 0.55 mmol, 1.1 equiv) as the substituted isocyanate to
afford the title compound (145.8 mg, 64.8%) as an off white solid.
6.1.12.9. 2-(3-(4-(3-(4-Fluorophenyl)ureido)phenyl)isoxazole-5-car-
boxamido)-3-methylbutanoic acid (38a). Prepared as described
above in the general procedure using 4-fluorophenyl isocyanate
(75.5 mg, 0.55 mmol, 1.1 equiv) as the substituted isocyanate to
afford the title compound (77.6 mg, 35.2%) as an off white solid.
1H NMR (300 MHz, DMSO-d6)
d
12.79 (s, 1H), 8.95 (d, J ¼ 7.2 Hz,
1H NMR (300 MHz, DMSO-d6)
d 12.82 (bs, 1H), 8.96 (s, 1H), 8.95
1H), 8.62 (s, 1H), 7.85 (d, J ¼ 8.7 Hz, 2H), 7.69 (s, 1H), 7.63 (d,
J ¼ 8.7 Hz, 2H), 7.25 (s, 1H), 7.22e7.12 (m, 2H), 7.05 (s, 1H), 4.31 (t,
J ¼ 7.8 Hz, 1H), 2.25 (m, 7H), 0.99 (d, J ¼ 6.6 Hz, 3H), 0.97 (d,
(d, J ¼ 8.4 Hz, 1H), 8.79 (s, 1H), 7.84 (d, J ¼ 8.7 Hz, 2H), 7.68 (s, 1H),
7.61 (d, J ¼ 8.7 Hz, 2H), 7.49 (m, 2H), 7.15 (t, J ¼ 9.0 Hz, 2H), 4.29 (t,
J ¼ 7.5 Hz, 1H), 2.21 (m, 1H), 0.97 (d, J ¼ 6.6 Hz, 3H), 0.96 (d,
J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d
172.8, 163.8, 162.6,
J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d 172.8, 163.8, 162.6,
156.5, 152.8, 142.6, 137.6, 136.8, 130.1, 129.7, 127.9, 121.1, 120.1, 119.9,
118.6,116.4,116.1,105.1, 58.5, 59.9, 20.1,19.6,19.1,18.9; MS (ESIꢀ) m/
z 449 (M ꢀ H)ꢀ, (ESIþ) m/z 451 (M þ H)þ; mp 190e192 ꢁC; HPLC
retention time e 3.550 min, purity e 95.31% (Method A).
156.8, 156.6, 152.9, 142.4, 136.2, 127.9 (2C), 121.4, 120.7, 120.6, 118.8
(2C), 115.9, 115.7, 105.1, 58.5, 29.8, 19.6, 19.1; MS (ESIþ) m/z 458
(M þ H)þ; mp 248e251 ꢁC; HPLC retention time e 3.092 min, purity
e 98.15% (Method A).
6.1.12.6. 2-(3-(4-(3-(4-Chloro-2-phenoxyphenyl)ureido)phenyl)iso-
xazole-5-carboxamido)-3-methylbutanoic acid (35a). Prepared as
described above in the general procedure using 4-chloro-2-
phenoxyphenyl isocyanate (135 mg, 0.55 mmol, 1.1 equiv) as the
substituted isocyanate to afford the title compound (177.4 mg,
64.7%) as an off white solid.
6.1.12.10. 3-Methyl-2-(3-(4-(3-p-tolylureido)phenyl)isoxazole-5-car-
boxamido)butanoic acid (39a). Prepared as described above in the
general procedure using 4-methylphenyl isocyanate (73 mg,
0.55 mmol, 1.1 equiv) as the substituted isocyanate to afford the
title compound (93.4 mg, 42.8%) as an off white solid.
1H NMR (300 MHz, DMSO-d6)
d
12.81 (bs,1H), 8.95 (d, J ¼ 8.4 Hz,
1H NMR (300 MHz, DMSO-d6)
d
9.79 (s, 1H), 8.87 (s, 1H), 8.39 (d,
1H), 8.91 (s, 1H), 8.64 (s, 1H), 7.83 (d, J ¼ 8.7 Hz, 2H), 7.68 (s, 1H),
7.61 (d, J ¼ 7.8 Hz, 2H), 7.35 (d, J ¼ 8.1 Hz, 2H), 7.09 (d, J ¼ 8.1 Hz, 2H),
4.29 (q, J ¼ 7.2 Hz, 1H), 2.23 (s, 3H), 2.19 (m, 1H), 0.97 (d, J ¼ 6.6 Hz,
J ¼ 1.8 Hz, 1H), 8.20 (m, 1H), 7.88 (d, J ¼ 8.4 Hz, 2H), 7.67 (s, 1H), 7.62
(d, J ¼ 8.4 Hz, 2H), 7.46 (t, J ¼ 7.5 Hz, 2H), 7.21 (t, J ¼ 6.9 Hz, 1H), 7.10
(d, J ¼ 8.1 Hz, 2H), 7.02 (dd, J ¼ 2.1, 6.3 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz,
1H), 4.09 (t, J ¼ 7.8 Hz, 1H), 2.28 (m, 1H), 0.92e0.84 (d, J ¼ 6.3 Hz,
3H), 0.95 (d, J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d 172.9,
163.9, 162.7, 156.7, 152.9, 142.6, 137.4, 131.5, 129.8 (2C), 128.0 (2C),
121.4, 119.0 (2C), 118.8 (2C), 105.2, 58.6, 29.9, 20.9, 19.8, 19.2; MS
(ESIþ) m/z 437 (M þ H)þ; mp 224e226 ꢁC; HPLC retention time e
3.203 min, purity e 95.84% (Method A).
6H); 13C NMR (75 MHz, DMSO-d6)
d 173.1, 164.4, 162.7, 156.8, 155.6,
152.7, 144.7, 142.1, 132.8, 130.6 (2C), 128.0 (2C), 127.7, 124.4, 122.2,
121.7, 119.9, 119.5, 119.1 (2C), 118.7 (2C), 104.7, 59.4, 30.9, 20.0, 18.8;
MS (ESIꢀ) m/z 547 [M ꢀ H]ꢀ, (ESIþ) m/z 549 (M þ H)þ; mp
250e252 ꢁC; HPLC retention time e 4.623 min, purity e 99.66%
(Method A).
6.1.12.11. 2-(3-(4-(3-(4-Methoxyphenyl)ureido)phenyl)isoxazole-5-
carboxamido)-3-methylbutanoic acid (40a). Prepared as described
above in the general procedure using 4-methoxyphenyl isocyanate
(82 mg, 0.55 mmol,1.1 equiv) as the substituted isocyanate to afford
the title compound (70.7 mg, 31.2%) as an off white solid.
6.1.12.7. 2-(3-(4-(3-(4-Chloro-2-fluorophenyl)ureido)phenyl)isoxazole-
5-carboxamido)-3-methylbutanoic acid (36a). Prepared as des-
cribed above in the general procedure using 4-chloro-2-fluo-
rophenyl isocyanate (94.5 mg, 0.55 mmol, 1.1 equiv) as the
substituted isocyanate to afford the title compound (158.6 mg,
66.9%) as an off white solid.
1H NMR (300 MHz, DMSO-d6)
d 12.61 (bs, 1H), 9.01 (s, 1H), 8.93
(d, J ¼ 8.1 Hz, 1H), 8.69 (s, 1H), 7.82 (d, J ¼ 8.7 Hz, 2H), 7.68 (s, 1H),
7.61 (d, J ¼ 8.7 Hz, 2H), 7.38 (d, J ¼ 8.7 Hz, 2H), 6.88 (d, J ¼ 8.7 Hz,
2H), 4.29 (t, J ¼ 7.2 Hz, 1H), 3.70 (s, 3H), 2.23 (m, 1H), 0.97 (d,
J ¼ 6.6 Hz, 3H), 0.96 (d, J ¼ 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
1H NMR (300 MHz, DMSO-d6)
d 12.85 (s, 1H), 9.38 (s, 1H), 8.97
(d, J ¼ 9.9 Hz, 1H), 8.75 (s, 1H), 8.21 (t, J ¼ 8.7, 9.0 Hz, 1H), 7.87 (d,
J ¼ 8.7 Hz, 2H), 7.70 (s, 1H), 7.64 (d, J ¼ 8.7 Hz, 2H), 7.50 (dd, J ¼ 1.8,
8.7 Hz, 1H), 7.27 (d, J ¼ 8.7 Hz, 1H), 4.31 (t, J ¼ 7.2 Hz, 1H), 2.27 (m,
1H), 0.99 (d, J ¼ 6.6 Hz, 3H), 0.97 (d, J ¼ 6.6 Hz, 3H); 13C NMR
d 172.9,163.9, 162.7,156.6, 155.2,153.1, 142.8, 133.1,128.0 (2C),121.3,
120.7 (2C), 118.7 (2C), 114.6 (2C), 105.2, 58.7, 55.7, 30.6, 19.8,
19.2; MS (ESIþ) m/z 453 [M þ H]þ; mp 220e222 ꢁC; HPLC retention
time e 2.750 min, purity e 95.57% (Method A).
(75 MHz, DMSO-d6)
d 172.8, 163.8, 162.5, 156.5, 152.3, 150.7, 141.9,
128.0 (2C), 127.0, 125.9, 125.1, 121.9, 118.7 (2C), 116.3, 115.9, 105.1,
58.5, 29.9, 19.6, 19.1; MS (ESIꢀ) m/z 473 (M ꢀ H)ꢀ, (ESIþ) m/z
475 (M þ H)þ; mp 245e247 ꢁC; HPLC retention time e 3.750 min,
purity e 95.42% (Method A).
6.1.12.12. 2-(3-(4-(3-(2-Fluorophenyl)ureido)phenyl)isoxazole-5-car-
boxamido)-3-methylbutanoic acid (41a). Prepared as described
above in the general procedure using 2-fluorophenyl isocyanate
(75.5 mg, 0.55 mmol, 1.1 equiv) as the substituted isocyanate to
afford the title compound (116.8 mg, 53.1%) as an off white solid.
6.1.12.8. 2-(3-(4-(3-(2,4-Difluorophenyl)ureido)phenyl)isoxazole-5-
carboxamido)-3-methylbutanoic acid (37a). Prepared as described
above in the general procedure using 2,4-difluorophenyl isocyanate
1H NMR (300 MHz, DMSO-d6)
d 12.84 (bs, 1H), 9.34 (s, 1H), 8.96
(d, J ¼ 8.1 Hz, 1H), 8.64 (s, 1H), 8.133 (t, 1H), 7.85 (d, J ¼ 8.4 Hz, 2H),
7.69 (s, 1H), 7.62 (d, J ¼ 8.7 Hz, 2H), 7.24 (m, 1H), 7.14 (m, 1H), 7.03