Rational Design of Substituted Diarylureas
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7763
(2H, ddd, J ) 8.1, 2.0, 0.9 Hz), 7.57 (2H, d, J ) 7.8 Hz), 7.41
(2H, t, J ) 7.9 Hz) ppm. 13C NMR (100 MHz, DMSO- d6) δ 167.2,
152.5, 139.8, 131.3, 129.0, 122.8, 122.5, 119.0 ppm. HRMS m/z
calcd C15H12N2O5 [M + H]+ 301.0819, found 301.0807.
4,4′-Ureylenedibenzoic Acid (7l). Following method 7, 6l (3.12
g, 7.558 mmol) was deprotected to yield a fine white powder (2.15
g, 7.172 mmol, 95%). Mp >350 °C [lit. >400 °C]. 1H NMR (400
MHz, DMSO) δ 12.62 (2H, s), 9.21 (2H, s), 7.88 (4H, d, J ) 8.7
Hz), 7.58 (4H, d, J ) 8.7 Hz) ppm. 13C NMR (100 MHz, DMSO-
d6) δ 166.9, 151.9, 143.6, 130.5, 123.9, 117.3 ppm. HRMS m/z
calcd C15H12N2O5 [M + H]+ 301.0819, found 301.0817.
111.2, 53.3, 51.4, 35.9, 23.1 ppm. HRMS m/z calcd C41H46N8O5
[M + H]+ 731.3664, found 731.3651.
1,3-Bis(3-(3-(4-(pyrrolidin-1-yl)butanamido)phenylcarbam-
oyl)phenyl)urea (9f). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3f (494.2 mg, 1.998 mmol) to yield a white
solid (189.6 mg, 0.249 mmol, 50%). HPLC (method A) 96%, tR )
1
19.56 min. Mp 234-236 °C. H NMR (400 MHz, DMSO- d6) δ
10.26 (2H, s), 9.94 (2H, s), 9.01 (2H, s), 8.11 (2H, s), 7.99 (2H, s),
7.72 (2H, d, J ) 8.0 Hz), 7.57 (2H, d, J ) 7.6 Hz), 7.43 (4H, m),
7.37 (2H, d, J ) 7.9 Hz), 7.25 (2H, t, J ) 8.1 Hz), 2.48 (12H, m),
2.37 (4H, t, J ) 7.3 Hz), 1.77 (4H, m), 1.69 (8H, m) ppm. 13C
NMR (100 MHz, DMSO- d6) δ 171.0, 165.5, 152.5, 139.6, 139.4,
139.3, 135.7, 128.6, 128.5, 121.2, 120.9, 117.7, 115.1, 114.5, 111.3,
54.9, 53.4, 34.2, 24.1, 23.0 ppm. HRMS m/z calcd C43H50N8O5 [M
+ H]+ 759.3977, found 759.3942.
1,3-Bis(3-(4-(2-(pyrrolidin-1-yl)acetamido)phenylcarbam-
oyl)phenyl)urea (9a). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3a (438.1 mg, 1.998 mmol) to yield a
pale-brown solid (333.0 mg, 0.474 mmol, 95%), which was purified
by semiprep HPLC (method F). HPLC (method A) 97%, tR ) 17.69
1,3-Bis(3-(4-(3-(dimethylamino)propanamido)phenylcarbamoyl)-
phenyl)urea (9g). Following method 8, 7k (100.0 mg, 0.333 mmol)
was reacted with 3g (276.1 mg, 1.333 mmol) to yield a white solid
(222.8 mg, 0.328 mmol, 99%), which was purified by filtration from
boiling MeOH (2 mL). HPLC (method C) 95%, tR ) 17.28 min.
1
min. Mp 286-288 °C. H NMR (400 MHz, DMSO- d6) δ 10.20
(2H, s), 9.73 (2H, s), 8.98 (2H, s), 7.98 (2H, s), 7.70 (6H, d, J )
8.9 Hz), 7.61 (4H, d, J ) 8.9 Hz), 7.56 (2H, d, J ) 7.8 Hz), 7.44
(2H, t, J ) 7.9 Hz), 3.32 (4H, s), 2.67 (8H, m), 1.77 (8H, m) ppm.
13C NMR (100 MHz, DMSO- d6) δ 167.9, 165.2, 152.4, 139.7,
135.7, 134.6, 134.3, 128.6, 121.1, 120.8, 120.6, 119.6, 117.6, 59.0,
53.7, 23.3 ppm. HRMS m/z calcd C39H42N8O5 [M + H]+ 703.3351,
found 703.3386.
1
Mp 322 -324 °C. H NMR (400 MHz, DMSO- d6) δ 10.18 (2H,
s), 10.00 (2H, s), 8.94 (2H, s), 7.98 (2H, s), 7.70 (6H, m), 7.56
(6H, m), 7.44 (2H, t, J ) 7.9 Hz), 2.57 (4H, t, J ) 7.0 Hz), 2.44
(4H, t, J ) 6.9 Hz), 2.19 (12H, s) ppm. 13C NMR (100 MHz,
DMSO- d6) δ 169.9, 165.3, 152.5, 139.7, 135.8, 135.1, 134.4, 128.8,
121.2, 120.9, 120.7, 119.2, 117.7, 55.1, 44.9, 34.7 ppm. HRMS
m/z calcd C37H42N8O5 [M + H]+ 679.3351, found 679.3334.
1,3-Bis(3-(4-(3-(piperidin-1-yl)propanamido)phenylcarbam-
oyl)phenyl)urea (9h). Following method 8, 7k (100.0 mg, 0.333
mmol) was reacted with 3h (329.8 mg, 1.333 mmol) to yield a
white solid (221.1 mg, 0.291 mmol, 87%), which was purified by
filtration from boiling MeOH (2 mL). HPLC (method C) 100%, tR
1,3-Bis(3-(4-(3-(pyrrolidin-1-yl)propanamido)phenylcarbam-
oyl)phenyl)urea (9b). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3b (466.2 mg, 1.998 mmol) to yield a
white solid (346.0 mg, 0.473 mmol, 95%). HPLC (method A) 98%,
1
tR ) 19.00 min. Mp 330 °C dec. H NMR (400 MHz, DMSO-d6)
δ 10.18 (2H, s), 10.05 (2H, s), 8.95 (2H, s), 7.97 (2H, s), 7.70
(6H, m), 7.55 (6H, m), 7.44 (2H, t, J ) 7.9 Hz), 2.75 (4H, t, J )
7.1 Hz), 2.50 (12H, m), 1.70 (8H, m) ppm. 13C NMR (100 MHz,
DMSO- d6) δ 169.6, 165.2, 152.4, 139.6, 135.7, 135.0, 134.3, 128.7,
121.1, 120.8, 120.7, 119.1, 117.6, 53.3, 51.4, 35.7, 23.0 ppm.
HRMS m/z calcd C41H46N8O5 [M + H]+ 731.3664, found 731.3690.
1,3-Bis(3-(4-(4-(pyrrolidin-1-yl)butanamido)phenylcarbam-
oyl)phenyl)urea (9c). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3c (494.2 mg, 1.998 mmol) to yield a white
solid (344.8 mg, 0.454 mmol, 91%). HPLC (method A) 96%, tR )
1
) 18.71 min. Mp 322-324 °C. H NMR (400 MHz, DMSO- d6)
δ 10.18 (2H, s), 10.14 (2H, s), 8.95 (2H, s), 7.97 (2H, s), 7.70
(6H, m), 7.55 (6H, m), 7.44 (2H, t, J ) 7.9 Hz), 2.60 (4H, t, J )
7.0 Hz), 2.45 (4H, t, J ) 7.0 Hz), 2.39 (8H, m), 1.51 (8H, m), 1.40
(4H, m) ppm. 13C NMR (100 MHz, DMSO- d6) δ 167.0, 165.3,
152.5, 139.7, 135.8, 135.1, 134.4, 128.7, 121.2, 120.9, 120.8, 119.2,
117.7, 54.4, 53.6, 34.0, 25.6, 24.0 ppm. HRMS m/z calcd
C43H50N8O5 [M + 2H]+2 380.2025, found 380.2018.
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19.86 min. Mp 239-241 °C. H NMR (400 MHz, DMSO- d6) δ
10.20 (2H, s), 9.89 (2H, s), 9.00 (2H, s), 7.99 (2H, s), 7.70 (6H,
m), 7.57 (6H, m), 7.44 (2H, t, J ) 7.9 Hz), 2.50 (12H, m), 2.35
(4H, t, J ) 7.4 Hz), 1.77 (4H, m), 1.70 (8H, m) ppm. 13C NMR
(100 MHz, DMSO- d6) δ 170.7, 165.2, 152.4, 139.7, 135.7, 135.1,
134.2, 128.6, 121.1, 120.8, 120.6, 119.1, 117.6, 54.9, 53.4, 45.7,
34.1, 23.0 ppm. HRMS m/z calcd C43H50N8O5 [M + H]+ 759.3977,
found 759.3940.
1,3-Bis(3-(4-(3-(morpholino)propanamido)phenylcarbamoyl)phenyl)-
urea (9i). Following method 8, 7k (100.0 mg, 0.333 mmol) was
reacted with 3i (332.4 mg, 1.333 mmol) to yield a pale-purple solid
(239.2 mg, 0.314 mmol, 94%), which was purified by filtration from
boiling MeOH (2 mL). HPLC (method C) 97%, tR ) 17.20 min.
1
Mp 313-315 °C. H NMR (400 MHz, DMSO- d6) δ 10.19 (2H,
s), 10.00 (2H, s), 8.92 (2H, s), 7.98 (2H, s), 7.70 (6H, m), 7.56
(6H, m), 7.44 (2H, t, J ) 7.9 Hz), 3.59 (8H, t, J ) 4.5 Hz), 2.64
(4H, t, J ) 7.0 Hz), 2.48 (4H, t, J ) 7.1 Hz), 2.42 (8H, m) ppm.
13C NMR (100 MHz, DMSO- d6) δ 169.8, 165.3, 152.5, 139.7,
135.8, 135.1, 134.4, 128.8, 121.2, 120.9, 120.8, 119.2, 117.7, 66.2,
54.2, 53.0, 33.8 ppm. HRMS m/z calcd C41H46N8O7 [M + H]+
763.3562, found 763.3539.
1,3-Bis(3-(3-(2-(pyrrolidin-1-yl)acetamido)phenylcarbam-
oyl)phenyl)urea (9d). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3c (438.1 mg, 1.998 mmol) to yield a pale-
yellow solid (310.1 mg, 0.441 mmol, 88%). HPLC (method A)
1
91%, tR ) 18.69 min. Mp 154-157 °C. H NMR (400 MHz,
DMSO- d6) δ 10.27 (2H, s), 9.78 (2H, s), 8.96 (2H, s), 8.12 (2H,
s), 7.79 (2H, s), 7.71 (2H, d, J ) 8.0 Hz), 7.57 (2H, d, J ) 7.7
Hz), 7.44 (4H, m), 7.38 (2H, d, J ) 8.3 Hz), 7.26 (2H, t, J ) 8.0
Hz), 3.31 (4H, s), 2.65 (8H, m), 1.76 (8H, m) ppm. 13C NMR (100
MHz, DMSO- d6) δ 168.3, 165.6, 152.6, 139.7, 139.4, 138.8, 135.8,
128.8, 128.7, 121.3, 121.0, 117.8, 115.7, 115.0, 111.8, 59.2, 53.7,
23.4 ppm. HRMS m/z calcd C39H42N8O5 [M + H]+ 703.3351, found
703.3344.
1,3-Bis(4-(4-(2-(pyrrolidin-1-yl)acetamido)phenylcarbam-
oyl)phenyl)urea (10a). Following method 8, 7l (150.0 mg, 0.500
mmol) was reacted with 3a (438.1 mg, 1.998 mmol) to yield a
dark-brown solid (325.3 mg, 0.463 mmol, 93%), which was purified
by semiprep HPLC (method F). HPLC (method A, 280nm) 98%,
1
tR ) 19.23 min. Mp 296-298 °C. H NMR (400 MHz, DMSO-
d6) δ 10.04 (2H, s), 9.65 (2H, s), 9.14 (2H, s), 7.94 (4H, d, J ) 8.8
Hz), 7.69 (4H, d, J ) 9.0 Hz), 7.61 (4H, d, J ) 8.8 Hz), 7.60 (4H,
d, J ) 9.0 Hz), 3.25 (4H, s), 2.61 (8H, m), 1.76 (8H, m) ppm.
HRMS m/z calcd C39H42N8O5 [M + H]+ 703.3351, found 703.3353.
1,3-Bis(4-(4-(3-(pyrrolidin-1-yl)propanamido)phenylcarbam-
oyl)phenyl)urea (10b). Following method 8, 7l (150.0 mg, 0.500
mmol) was reacted with 3b (466.2 mg, 1.998 mmol) to yield an
off-white solid (298.6 mg, 0.409 mmol, 82%). HPLC (method A,
1,3-Bis(3-(3-(3-(pyrrolidin-1-yl)propanamido)phenylcarbam-
oyl)phenyl)urea (9e). Following method 8, 7k (150.0 mg, 0.500
mmol) was reacted with 3e (466.2 mg, 1.998 mmol) to yield a pale-
yellow solid (292.4 mg, 0.400 mmol, 80%). HPLC (method A)
1
93%, tR ) 19.39 min. Mp 160 - 163 °C. H NMR (400 MHz,
DMSO- d6) δ 10.26 (2H, s), 10.13 (2H, s), 9.00 (2H, s), 8.10 (2H,
s), 7.98 (2H, s), 7.72 (2H, d, J ) 7.9 Hz), 7.57 (2H, d, J ) 7.7
Hz), 7.44 (4H, m), 7.38 (2H, d, J ) 7.9 Hz), 7.25 (2H, t, J ) 7.7
Hz), 2.72 (4H, t, J ) 6.9 Hz), 2.49 (12H, m), 1.70 (8H, m) ppm.
13C NMR (100 MHz, DMSO- d6) δ 170.0, 165.5, 152.6, 139.6,
139.3, 139.3, 135.7, 128.6, 128.5, 121.2, 120.9, 117.7, 115.2, 114.5,
1
280nm) 99%, tR ) 18.65 min. Mp 299-301 °C. H NMR (400
MHz, DMSO- d6) δ 10.04 (4H, s), 9.15 (2H, s), 7.94 (4H, d, J )
8.6 Hz), 7.69 (4H, d, J ) 8.8 Hz), 7.62 (4H, d, J ) 8.6 Hz), 7.55
(4H, d, J ) 8.8 Hz), 2.77 (4H, t, J ) 6.4 Hz), 2.50 (12H, m), 1.72