R. Xu et al. / Bioorg. Med. Chem. 14 (2006) 3285–3299
3297
1
Compound 33: H NMR (300 MHz, CDCl3) d 10.7 (s,
(m, 7H), 1.32 (m, 2H), 1.00 (dd, J = 9.3, 4.9 Hz, 1H),
0.76 (t, J = 5.5 Hz, 1H). LCMS: 513.1, tR = 5.16 min.
(M+H+), >99% purity; HRMS (FAB) m/z 513.1828
(M+ H+), calcd for C27H31Cl2N4O2: 513.1819.
1H), 7.40–7.76 (m, 6H), 7.06 (t, J = 9.3 Hz, 1H), 4.48
(m, 1H), 4.29 (m, 1H), 1.16–3.12 (m, 18H), 1.14(s,
3H). LCMS: 533.1, tR = 5.23 min. (M+H+), >99% puri-
ty; HRMS (FAB) m/z 533.2547 (M+H+), calcd for
C28H33F4N4O2: 533.2534. Compound 34: 1H NMR
(300 MHz, CDCl3) d 10.7 (s, 1H), 7.4–7.8 (m, 6H),
7.06 (t, J = 9.3 Hz, 1H), 4.54 (m, 1H), 4.14 (m, 1H),
1.60–3.50 (m, 18H), 1.31 (s, 3H). LCMS: 533.1,
tR = 5.26 min. (M+H+), >99% purity; HRMS (FAB)
m/z 533.2547 (M+H+), calcd for C28H33F4N4O2:
533.2534.
5.1.29. N-[trans-6-(3-Cyanophenyl)bicyclo[4.1.0]hept-3-
yl]-N0-(3, 5-dichloro-phenyl)-N-[2-[3(R)-hydroxy-1-pyrro-
1
lidinyl]ethyl]urea (38). H NMR (300 MHz, CDCl3) d
10.82 (d, J = 6.0 Hz, 1H), 7.33–7.55 (m, 6H), 6.89 (t,
J = 1.9 Hz, 1H), 4.54 (m, 1H), 4.18 (m, 1H), 3.23 (m,
2H), 3.08 (m, 1H), 2.72–2.92 (m, 4H), 2.54 (m, 1H),
1.82–2.42 (m, 5H), 1.58 (m, 2H), 1.31 (m, 2 H), 0.99
(dd, J = 9.3, 4.9 Hz, 1H), 0.75 (t, J = 5.5 Hz, 1H).
LCMS: 513.1, tR = 5.26 min. (M+H+), >99% purity;
HRMS (FAB) m/z 513.1816 (M+H+), calcd for
C27H31Cl2N4O2: 513.1819.
5.1.26. N-[trans-6-(3-Cyanophenyl)bicyclo[4.1.0]hept-3-yl]-
N0-(3-chloro-4-fluorophenyl)-N-[2-[3(R)-hydroxy-1-pyrro-
lidinyl]ethyl]urea (35). Compound 25 (1.4 g, 6.6 mmol),
2-[3-(R)-hydroxy-1-pyrrolidinyl]ethylamine
(1.3 g,
10 mmol), and Ti(O-i-Pr)4 were stirred at room temper-
ature overnight. NaBH4 (0.5 g, 13 mmol) was added and
the reaction mixture was stirred at room temperature for
2 h. One hundred milliliters of 2 N HCl solution was
added and the aqueous layer was washed with CH2Cl2
twice (50 ml each). Two hundred milliliters of CH2Cl2
was added to the aqueous layer and pH of the two layer
solution was adjusted to 14 by adding 50% NaOH solu-
tion. The white precipitate was filtered and discarded.
The organic layer of the filtrate was separated, washed
with 50 ml brine, dried over Na2SO4, and concentrated.
The residue (1.5 g, 4.6 mmol) was dissolved in 40 ml dry
CH2Cl2 and 3-chloro-4-fluorophenyl isocyanate (1 g,
5.8 mmol) was added. The reaction mixture was stirred
at room temperature for 2 h. The solvent was removed
and the residue was purified by column using EtOAc/
7N NH3 in MeOH (99/1) as the eluent. After the cis iso-
mer came off the column completely, the trans isomer
was collected as the major product (1.0 g, 44%). 1H
NMR (300 MHz, CDCl3) d 10.55 (s, 1H), 7.62–7.68
(m, 2H), 7.25–7.55 (m, 4H), 6.97 (t, J = 8.8 Hz, 1H),
4.52 (m, 1H), 4.19 (m, 1H), 3.25 (m, 2H), 3.07 (m,
1H), 2.73–2.91 (m, 4H), 2.54 (m, 1H), 1.50–2.40 (m,
7H), 1.32 (m, 2H), 0.99 (dd, J = 9.3, 4.9 Hz, 1H), 0.76
(t, J = 4.9 Hz, 1H). LCMS: 497.1, tR = 5.11 min.
(M+H+), >99% purity; HRMS (FAB) m/z 497.2125
(M+ H+), calcd for C27H31ClFN4O2: 497.2114.
5.1.30. N-[trans-6-(4-cyanophenyl)bicyclo[4.1.0]hept-3-yl]-
N0-(3-chloro-4-fluorophenyl)-N-[2-[3(R)-hydroxy-1-pyrro-
lidinyl]ethyl]urea (39). 1H NMR (300 MHz, CDCl3) d
10.57 (s, 1H), 7.64 (dt, J = 7.1, 2.7 Hz, 1H), 7.56 (d,
J = 8.2 Hz, 2H), 7.34 (m, 3H), 6.95 (t, J = 8.8 Hz, 1H),
4.54 (m, 1H), 4.20 (m, 1H), 3.26 (m, 2H), 3.09 (m, 1H),
2.74–2.92 (m, 4H), 2.55 (m, 1H), 2.03–2.45 (m, 4H),
1.20–1.94 (m, 5H), 1.02 (dd, J = 9.3, 4.9 Hz, 1H), 0.79
(t, J = 5.4 Hz, 1H). LCMS: 497.1, tR = 5.28 min.
(M+H+), 100% purity; HRMS (FAB) m/z 497.2139
(M+H+), calcd for C27H31ClFN4O2: 497.2114.
5.1.31. N-[trans-6-[3-(Thiomethoxy)phenyl]bicyclo[4.1.0]-
hept-3-yl]-N0-(3-chloro-4-fluorophenyl)-N-[3-(1-pyrrolidi-
nyl)propyl]urea (40). 1H NMR (300 MHz, CDCl3) d 9.69
(s, 1H), 7.53 (m, 1H), 7.31 (m, 1H), 7.20 (m, 2H), 7.03
(m, 3H), 3.95 (m, 1H), 3.35 (m, 2H), 2.64 (m, 6H),
2.47(s, 3H), 2.30 (m, 2H), 2.08 (m, 1H), 1.74–1.94 (m,
7H), 1.60 (m, 2H), 1.28 (m, 1H), 0.97 (dd, J = 9.3,
4.9 Hz, 1H), 0.79 (t, J = 5.5 Hz, 1H). LCMS: 516.1,
tR = 5.66 min. (M+H+), 97% purity; HRMS (FAB) m/
z
516.2246.
516.2248 (M+H+), calcd for C28H36ClFN3OS:
5.1.32. N-[trans-6-(3-Fluorophenyl)bicyclo[4.1.0]hept-3-yl]-
N0-(3-chloro-4-fluorophenyl)-N-[2-[3(S)-hydroxy-1-pyrro-
1
lidinyl]ethyl]urea (41). H NMR (300 MHz, CDCl3) d
10.43 (s, 1H), 7.66 (m, 1H), 7.12–7.36 (m, 3H), 6.92–
7.07 (m, 3H), 4.53 (m, 1H), 4.27 (m, 1H), 3.27 (m,
2H), 3.10 (m, 1H), 2.76–2.93 (m, 4H), 2.57 (m, 1H),
1.82–2.44 (m, 8 H), 1.20–1.62 (m, 2H), 0.97 (dd,
J = 9.3, 4.9 Hz, 1H), 0.68 (t, J = 4.9 Hz, 1H). LCMS:
490.3, tR = 4.87 min. (M+H+), 95% purity; HRMS
(FAB) m/z 490.2080 (M+H+), calcd for C26H31
ClF2N4O2: 490.2067.
5.1.27. N-[trans-6-(3-Cyanophenyl)bicyclo[4.1.0]hept-3-
yl]-N0-(4-fluoro-3-trifluoromethylphenyl)-N-[2-[3(R)-hy-
droxy-1-pyrrolidinyl]ethyl]urea
(36).
1H
NMR
(300 MHz, CDCl3) d 10.75 (d, J = 6.6 Hz, 1H), 7.66–
7.74 (m, 2H), 7.33–7.55 (m, 4H), 7.04 (t, J = 9.9 Hz,
1H), 4.51 (m, 1H), 4.21 (m, 1H), 3.26 (m, 2H), 3.09
(m, 1H), 2.70–2.91 (m, 4H), 2.53 (m, 1H), 1.50–2.60
(m, 7H), 1.32 (m, 2H), 1.00 (dd, J = 9.3, 5.4 Hz, 1H),
0.76 (t, J = 4.9 Hz, 1H). LCMS: 531.1, tR = 5.16 min.
(M+H+), >99% purity; HRMS (FAB) m/z 531.2373
(M+H+), calcd for C28H31F4N4O2: 531.2378.
5.1.33. N-[3-trans-4-[[[(3-Chloro-4-fluorophenyl)amino]car-
bonyl][2-(1-pyrrolidinyl)ethyl]amino]bicyclo[4.1.0]hept-1-
yl]phenyl]acetamide (42). 1H NMR (300 MHz, CDCl3) d
11.03 (s, 1H), 7.40–7.51(m, 2H), 7.12–7.32 (m, 3H), 6.96–
7.04 (m, 2H), 4.22 (m, 1H), 3.25 (m, 2H), 2.72 (m, 6H),
2.00–2.4(m, 2H), 2.19 (s, 3H), 1.90 (m, 4H), 1.60 (m,
4H), 1.25 (m, 1H), 1.00 (dd, J = 4.4, 9.3 Hz, 1H), 0.64 (t,
J = 5.5 Hz, 1H). LCMS: 513.1, tR = 5.18 min. (M+H+),
95% purity; HRMS (FAB) m/z 513.2440 (M+H+), calcd
for C28H35ClFN4O2: 513.2427.
5.1.28. N-[trans-6-(3-Cyanophenyl)bicyclo[4.1.0]hept-3-
yl]-N0-(3,4-dichloro-phenyl)-N-[2-[3(R)-hydroxy-1-pyrro-
1
lidinyl]ethyl]urea (37). H NMR (300 MHz, CDCl3) d
10.70 (s, 1H), 7.70 (t, J = 2.4 Hz, 1H), 7.23–7.56 (m,
6H), 4.53 (m, 1H), 4.20 (m, 1H), 3.24 (m, 2H), 3.08
(m, 1H), 2.74–2.91 (m, 4H), 2.54 (m, 1H), 1.50-2.42