Journal of Medicinal Chemistry
Article
J = 8.4 Hz, 2H), 7.41 (d, J = 5.5 Hz, 2H), 7.18 (d, J = 5.9 Hz, 1H),
7.10 (d, J = 8.4 Hz, 2H), 6.24 (d, J = 7.5 Hz, 1H), 4.57- 4.33 (m, 1H),
3.55−3.46 (m, 1H), 2.13−1.75 (m, 4H), 1.41 (dp, J = 23.6, 12.0 Hz,
4H). 13C NMR (100 MHz, DMSO) δ 155.06, 141.96, 131.38, 131.26,
130.39, 121.74, 117.83, 114.14, 112.59, 107.58, 103.49, 75.16, 47.96,
30.54, 30.29. 19F NMR (376 MHz, DMSO) δ −61.78, −112.16.
HRMS (ESI) m/z calcd for C20H20F4N2O2 [M + H]+, 397.15337;
found, 397.15429.
trans-1-(4-(4-Chlorophenoxy)cyclohexyl)-3-(3-(trifluoromethyl)-
phenyl)urea, I-16. Using general procedure B and employing trans-4-
(4-chlorophenoxy)cyclohexylamine 3 afforded I-16 as a white solid
(50% yield, 206 mg). mp 244 °C. RP-HPLC (C18): 0 to 100%
(ACN/water /0.1% TFA) in 25 min, tR = 19.617 min, purity = 100%.
1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.95 (s, 1H), 7.42 (d,
J = 7.9 Hz, 2H), 7.27 (dd, J = 9.0, 3.3 Hz, 2H), 7.19 (d, J = 6.8 Hz,
1H), 6.95 (dd, J = 8.7, 3.5 Hz, 2H), 6.25 (d, J = 4.0 Hz, 1H), 4.32−
4.27 (m, 1H), 3.55−3.48 (m, 1H), 2.50−1.90 (m, 4H), 1.48−1.29 (m,
4H). 13C NMR (100 MHz, DMSO) δ 156.84, 155.06, 141.96, 130.40,
129.92, 124.70, 121.73, 118.08, 117.85, 114.14, 75.13, 47.96, 30.57,
30.30. 19F NMR (376 MHz, DMSO) δ −61.79. HRMS (ESI) m/z
calcd for C20H20ClF3N2O2 [M + H]+, 413.12382; found, 413.12507.
trans-1-(4-(4-(Trifluoromethoxy)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, I-17. Using general procedure B and
employing trans-4-(4-(trifluoromethoxy)phenoxy)cyclohexylamine 5
afforded I-17 as a white solid (54% yield, 251 mg). mp 190 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
20.231 min, purity = 100%. 1H NMR (399 MHz, DMSO-d6) δ 8.66 (s,
1H), 7.96 (s, 1H), 7.46−7.41 (m, 2H), 7.39−7.04 (m, 3H), 7.01 (d, J
= 8.5 Hz, 2H), 6.25 (d, J = 7.6 Hz, 1H), 4.35−4.30 (m, 1H), 3.54−
3.49 (dd, J = 13.8, 7.3 Hz, 1H), 2.04−1.90 (m, 4H), 1.47−1.33 (m,
4H). 13C NMR (100 MHz, DMSO) δ 156.88, 155.07, 141.96, 130.36,
123.14, 121.71, 117.47, 114.14, 75.32, 47.96, 30.56, 30.30. 19F NMR
(376 MHz, DMSO) δ −57.78, −61.87. LC−MS (ESI) m/z calcd for
C21H20F6N2O3 [M + H]+, 463.13; found, 463.11.
2.01−1.76 (m, 4H), 1.63−1.21 (m, 4H). 13C NMR (100 MHz,
DMSO) δ 155.10, 142.00, 131.37, 130.40, 121.75, 120.37, 117.73,
114.23, 112.97, 75.24, 47.93, 30.48, 30.24. 19F NMR (376 MHz,
DMSO) δ −61.50, −61.77. HRMS (ESI) m/z calcd for C21H20F6N2O2
[M + H]+, 447.15017; found, 447.15145.
1-Cyclohexyl-3-(3-(trifluoromethyl)phenyl)urea, III-1. Using gen-
eral procedure B and employing cyclohexylamine afforded III-1 as a
white solid (63% yield, 180 mg). mp 180 °C. RP-HPLC (C18): 0 to
100% (ACN/water /0.1% TFA) in 25 min, tR = 16.943 min, purity =
1
98%. H NMR (399 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.95 (s, 1H),
7.42 (t, J = 7.4 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H), 6.14 (d, J = 8.3 Hz,
1H), 3.47 (m, 1H), 1.78 (d, J = 12.0 Hz, 2H), 1.62 (d, J = 13.2 Hz,
3H), 1.50 (d, J = 13.4 Hz, 1H), 1.21 (dp, J = 34.6, 12.4, 11.8 Hz, 5H).
13C NMR (100 MHz, DMSO) δ 154.92, 142.04, 130.30, 121.63,
117.73, 114.11, 48.43, 33.49, 25.85, 25.01. 19F NMR (376 MHz,
DMSO) δ −61.91. HRMS (ESI) m/z calcd for C14H 17F3N2O [M +
H]+, 287.13657; found, 287.13707.
trans-1-(4-Hydroxycyclohexyl)-3-(3-(trifluoromethyl)phenyl)urea,
III-2. Using general procedure B and employing trans-4-amino-
cyclohexanol afforded III-2 as a white solid (59% yield, 178 mg).
mp 249 °C. RP-HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in
25 min, tR = 12.467 min, purity = 100%. 1H NMR (399 MHz, DMSO-
d6) δ 8.62 (s, 1H), 7.94 (s, 1H), 7.41 (td, J = 10.8, 7.2 Hz, 2H), 7.17
(d, J = 7.1 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 4.52−4.47 (m, 1H),
3.39−3.20 (m, 2H), 1.85−1.78 (m, 4H), 1.24−1.13 (m, 4H). 13C
NMR (100 MHz, DMSO) δ 155.07, 142.01, 130.31, 130.00, 121.71,
117.79, 114.19, 68.68, 48.43, 34.45, 31.32. 19F NMR (376 MHz,
DMSO) δ −61.88. HRMS (ESI) m/z calcd for C14H17F3N2O2 [M +
H]+, 303.13149; found, 303.13204.
trans-1-(4-((4-Fluorobenzyl)oxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, III-3. Using general procedure B and
employing trans-4-((4-fluorobenzyl)oxy)cyclohexylamine 10 afforded
III-3 as a white solid (33% yield, 136 mg). mp 162 °C. RP-HPLC
(C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR = 18.230
1
min, purity = 95%. H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H),
trans-1-(4-(4-(Trifluoromethyl)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, I-18. Using general procedure B and
employing trans-4-(4-(trifluoromethyl)phenoxy)cyclohexylamine 4
afforded I-18 as a white solid (43% yield, 194 mg). mp 176 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
19.617 min, purity = 100%. 1H NMR (399 MHz, DMSO-d6) δ 8.64 (s,
1H), 7.94 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.41 (d, 2H), 7.25−7.15
(m, 1H), 7.09 (t, J = 9.3 Hz, 2H), 6.26 (d, J = 7.5 Hz, 1H), 4.58−4.31
(m, 1H), 3.72−3.39 (m, 1H), 2.25−1.73 (m, 4H), 1.53−1.29 (m, 4H).
13C NMR (100 MHz, DMSO) δ 160.97, 155.06, 141.94, 138.79,
7.93 (s, 1H), 7.41−7.39 (m, 2H), 7.34−7.30 (m, 1H), 7.18−7.09 (m,
3H), 6.14 (d, J = 7.7 Hz, 1H), 4.44 (s, 2H), 3.42 (dd, J = 12.3, 5.4 Hz,
1H), 3.49−3.36 (m, 1H), 3.35−3.33 (m, 1H), 2.09−1.71 (m, 4H),
1.24 (dq, J = 21.0, 11.0, 4H). 13C NMR (100 MHz, DMSO) δ 155.12,
142.09, 136.18, 130.36, 130.03, 129.95, 121.68, 117.71, 115.70, 115.49,
76.42, 68.94, 48.21, 30.90, 30.85. 19F NMR (376 MHz, DMSO) δ
−61.78, −116.01. LC−MS (ESI) m/z calcd for C21H22F4N2O2 [M +
H]+, 411.16; found, 411.12.
trans-1-(2-(4-(Trifluoromethyl)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, III-4. Using general procedure B and
employing trans-2-(4-(trifluoromethyl)phenoxy)cyclohexylamine 8
afforded III-4 as a white solid (79% yield, 354 mg). mp 58 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
20.047 min, purity = 97%. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (s,
1H), 7.92 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.45−7.31 (m, 2H), 7.18
(d, J = 8.4 Hz, 3H), 6.38 (d, J = 8.0 Hz, 1H), 4.70 (dt, J = 5.1, 2.58 Hz,
1H), 3.96−3.77 (m, 1H), 1.99−1.84 (m, 1H), 1.67 (q, J = 4.5, 4.0 Hz,
3H), 1.65 (dd, J = 14.5, 7.8 Hz, 1H), 1.46−1.31 (m, 3H). 13C NMR
(100 MHz, DMSO) δ 16.77, 154.70, 147.32, 141.57, 130.21, 127.36,
121.33, 116.72, 75.26, 49.83, 28.15, 27.56, 23.83, 19.91. 19F NMR (376
MHz, DMSO) δ −59.88, −61.42. HRMS (ESI) m/z calcd for
C21H20F6N2O2 [M + H]+, 447.15017; found, 447.15122.
trans-1-(3-(4-(Trifluoromethyl)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, III-5. Using general procedure B and
employing trans-3-(4-(trifluoromethyl)phenoxy)cyclohexylamine 9
afforded III-5 as a white solid (69% yield, 306 mg). mp 62 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
20.183 min, purity = 100%. 1H NMR (399 MHz, DMSO-d6) δ 8.74 (s,
1H), 7.94 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.42 (dt, J = 15.5, 8.2 Hz,
2H), 7.17 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 6.35 (d, J = 8.1
Hz, 1H), 4.80 (s, 1H), 3.90 (dp, J = 14.0, 5.4, 4.6 Hz, 1H), 2.01−1.91
(m, 1H), 1.87−1.69 (m, 2H), 1.68−1.50 (m, 4H), 1.44−1.21(m, 1H).
13C NMR (100 MHz, DMSO) δ 160.76, 155.01, 142.00, 130.33,
130.44, 127.64, 121.76, 116.00, 114.13, 75.08, 47.91, 30.53, 30.22. 19F
NMR (376 MHz, DMSO) δ −60.21, −61.78. HRMS (ESI) m/z calcd
for C21H20F6N2O2 [M + H]+, 447.15017; found, 447.15126.
trans-1-(4-(2-(Trifluoromethyl)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, I-19. Using general procedure B and
employing trans-4-(2-(trifluoromethyl)phenoxy)cyclohexylamine 6
afforded I-19 as a white solid (69% yield, 308 mg). mp 121 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
19.868 min, purity = 99%. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s,
1H), 7.96 (s, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.45−7.41 (m, 2H), 7.31
(d, J = 8.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H),
6.36 (d, J = 7.8 Hz, 1H), 4.56 (td, J = 9.4, 4.8 Hz, 1H), 3.56 (dtt, J =
15.2, 9.9, 4.9 Hz, 1H), 2.05−1.87 (m, 4H), 1.54−1.32 (m, 4H). 13C
NMR (100 MHz, DMSO) δ 154.19,153.28, 147.42, 146.89, 140.15,
132.83, 128.55, 128.14, 125.66, 119.89, 118.88, 116.01, 113.71, 112.30,
73.64, 45.71, 28.09, 27.88. 19F NMR (376 MHz, DMSO) δ −62.10,
−62.71. HRMS (ESI) m/z calcd for C21H20F6N2O2 [M + H]+,
447.15017; found, 447.15147.
trans-1-(4-(3-(Trifluoromethyl)phenoxy)cyclohexyl)-3-(3-
(trifluoromethyl)phenyl)urea, I-20. Using general procedure B and
employing trans-4-(3-(trifluoromethyl)phenoxy)cyclohexylamine 7
afforded I-20 as a white solid (59% yield, 264 mg). mp 160 °C. RP-
HPLC (C18): 0 to 100% (ACN/water /0.1% TFA) in 25 min, tR =
20.083 min, purity = 99%. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s,
1H), 7.94 (s, 1H), 7.64−7.31 (m, 3H), 7.35−7.07 (m, 4H), 6.26 (d, J
= 7.5 Hz, 1H), 4.45 (tt, J = 9.5, 4.0 Hz, 1H), 3.72−3.38 (m, 1H),
127.66, 127.75, 117.82, 116.61, 114.19, 73.09, 44.70, 36.55, 32.45,
29.33, 19.90. 19F NMR (376 MHz, DMSO) δ −60.34, −61.86. HRMS
L
dx.doi.org/10.1021/jm400793v | J. Med. Chem. XXXX, XXX, XXX−XXX