Protein Farnesyltransferase Inhibitors
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 2 441
4-[N-((1-p-Nitr oben zyl-1H-im idazol-5-yl)m eth yl)am in o]-
2-p h en ylben zoylm eth ion in e (10a ) was a yellow solid (75%).
1H NMR (CD3OD): δ 8.11 (d, 2 H, J ) 9 Hz), 7.24-7.36 (m, 9
H), 7.15 (s, 1 H), 6.54 (dd, 1 H, J ) 9 and 2 Hz), 6.31 (d, 1 H,
J ) 2 Hz), 5.49 (s, 2 H), 4.40 (m, 1 H), 4.27 (s, 2 H), 3.72 (m,
1 H), 2.15 (m, 1 H), 2.05 (m, 1 H), 2.00 (s, 3 H), 1.95 (m, 1 H),
1.75 (m, 1 H). 13C NMR (CD3OD): δ 173.40, 167.27, 151.03,
149.36, 147.49, 145.40, 143.49, 142.87, 131.38, 130.04, 129.85,
129.27, 128.93, 125.61, 125.39, 115.39, 112.09, 69.29, 53.83,
44.60, 38.38, 32.42, 31.37, 26.93, 15.50. HRMS (FAB, M + H):
calcd for C29H30N5O5S 560.1961, found 560.1960.
52.30, 51.79, 48.73, 37.67, 31.77, 29.48, 25.02, 21.02, 15.52,
15.25. HRMS (FAB): calcd for C30H32N4O3S 563.1884, found
563.1884.
4-[N-((1-m -Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
n o]-2-p h en ylben zoylm eth ion in e (11c) was a yellow oily
1
solid (95%). H NMR (CD3OD): δ 8.71 (s, 1 H), 7.13-7.40 (m,
16 H), 6.55 (d, 1 H, J ) 8 Hz), 6.45 (s, 1 H), 5.47 (s, 2 H), 4.42
(m, 1 H), 4.33 (s, 2 H), 2.18 (m, 1 H), 2.06 (m, 1 H), 2.00 (s, 3
H), 1.93 (m, 1 H), 1.75 (m, 1 H). 13C NMR (CD3OD): δ 174.252,
173.302, 150.794, 143.644, 142.832, 138.561, 136.542, 132.243,
131.519, 130.295, 130.160, 129.922, 129.875, 129.624, 129.118,
128.969, 127.389, 127.260, 126.099, 115.712, 112.341, 74.603,
53.712, 51.246, 44.510, 38.510, 32.390, 31.390, 15.529. HRMS
(FAB, M + H): calcd for C29H30N4O3SCl 549.1727, found
549.1725.
4-[N-((1-p-Nitr oben zyl-1H-im idazol-5-yl)m eth yl)am in o]-
2-p h en ylben zoylm eth ion in e m eth yl ester (10b) was a
1
yellow amorphous solid (67%). H NMR (CDCl3): δ 8.04 (d, 2
H, ortho to NO2), 7.54 (s, 1 H, ortho to CONH), 7.52 (s, 1 H,
NCHN), 7.27-7.38 (m, 5 H, biphenyl aryl), 7.11 (d, 2 H, meta
to NO2), 7.04 (s, 1 H, NCHCCH2), 6.48 (dd, 1 H, para to
biphenyl), 6.29 (d, 1 H, ortho to biphenyl), 5.96 (d, 1 H, CONH),
5.30 (s, 2 H, NCH2Ar), 4.78 (t, 1 H, CH2NHAr), 4.56 (m, 1 H,
met R-CH), 4.14 (d, 2 H, CH2NHAr), 3.63 (s, 3 H, COOCH3),
2.08 (t, 2 H, CH2SCH3), 1.99 (s, 3 H, SCH3), 1.82-1.91 (m, 1
H, met CH2), 1.62-1.71 (m, 1 H, met CH2). 13C NMR (CDCl3):
δ 172.08, 168.74, 148.93, 147.46, 143.67, 141.65, 140.75,
138.94, 130.99, 129.53, 128.66, 128.53, 128.30, 127.93, 127.32,
124.08, 123.52, 113.91, 111.47, 99.66, 55.86, 52.38, 51.82,
48.06, 37.52, 31.35, 29.52, 25.04, 15.54, 15.24. LRMS (M+):
574.2. HRMS (FAB): calcd for C30H32N5O5S 574.2124, found
574.2125.
4-[N-((1-m -Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
n o]-2-p h en ylben zoylm eth ion in e m eth yl ester (11d ) was
1
a yellow oily solid (24%). H NMR (CDCl3): δ 7.62 (d, 1 H, J
) 9 Hz, Ar), 7.54 (s, 1 H, imid), 7.34-7.44 (m, 5 H, Ar), 7.20-
7.26 (m, 2 H, Ar), 7.03 (d, 2 H, J ) 12 Hz, Ar), 6.89 (d, 1 H, J
) 8 Hz, Ar), 6.52 (dd, 1 H, J ) 2 and 9 Hz, Ar), 6.37 (d, 1 H,
J ) 2 Hz, Ar), 5.82 (d, 1 H, J ) 8 Hz, amide NH), 5.14 (s, 2 H,
CH2Ar), 4.59 (m, 1 H, R-C), 4.30 (t, 1 H, J ) 6 Hz, amine NH),
4.15 (d, 2 H, J ) 6 Hz, CH2N), 2.08 (t, 2 H, J ) 8 Hz, CH2S),
2.00 (s, 3 H, SCH3), 1.84-1.92 (m, 1 H, CH2), 1.61-1.69 (m, 1
H, CH2). 13C NMR (CDCl3): δ 172.044, 168.511, 148.920,
148.837, 141.718, 140.915, 138.910, 138.107, 135.077, 131.192,
130.365, 129.432, 128.692, 128.652, 128.546, 128.448, 128.165,
127.886, 127.523, 126.799, 124.794, 123.826, 114.056, 113.519,
111.728, 53.920, 52.581, 52.319, 51.830, 49.858, 49.601, 48.298,
38.503, 38.416, 37.698, 31.757, 31.592, 29.527, 29.290, 15.277.
HRMS (FAB, M + H): calcd for C30H32N4O3SCl 563.1884,
found 563.1884.
4-[N-((1-m-Nitr oben zyl-1H-im idazol-5-yl)m eth yl)am in o]-
2-p h en ylben zoylm eth ion in e m eth yl ester (10d ) was a
1
yellow amorphous solid (66%). H NMR (CDCl3): δ 8.10 (d, 1
H, J ) 9.5 Hz, Ar), 7.87 (s, 1 H, Ar), 7.62 (s, 1 H, imid), 7.55
(d, 1 H, J ) 8 Hz, Ar), 7.47 (t, 1 H, J ) 8 Hz, Ar), 7.31-7.43
(m, 6 H, Ar), 7.08 (s, 1 H, imid), 6.49 (dd, 1 H, J ) 2 and 9.5
Hz, Ar), 6.35 (d, 1 H, J ) 2 Hz, Ar), 5.92 (d, 1H, J ) 8 Hz,
amide NH), 5.31 (s, 2 H, CH2Ar), 4.58 (m, 1 H, R-C), 4.17 (d,
2 H, J ) 5 Hz, CH2N), 3.67 (s, 3 H, COOCH3), 2.10 (t, 2 H, J
) 7 Hz, CH2S), 2.01 (s, 3 H, SCH3), 1.86-1.90 (m, 1H, CH2),
1.65-1.72 (m, 1 H, CH2). 13C NMR (CDCl3): δ 172.037,
168.603, 148.692, 148.522, 141.717, 140.794, 138.952, 138.352,
132,550, 131,054, 130.110, 130.028, 129.703, 128.668, 128.629,
128.223, 127.920, 127.837, 124.068, 123.318, 123.162, 122.272,
121.661, 113.929, 111.657, 53.888, 52.340, 51.855, 48.115,
37.654, 31.919, 31.758, 31.576, 29.646, 29.544, 29.349, 29.293,
22.683, 15.281, 14.117. HRMS (FAB, M + H): calcd for
4-[N-((1-o-Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
n o]-2-p h en ylben zoylm et h ion in e (11e) was a white solid
(90%). 1H NMR (CD3OD): δ 7.20-7.44 (m, 11 H), 7.02 (d, 1
H, J ) 6 Hz), 6.57 (d, 1 H, J ) 7 Hz), 6.44 (s, 1 H), 5.51 (s,
2H), 4.40 (m, 1 H), 4.33 (s, 2 H), 3.34 (s, 1 H), 2.17 (m, 1 H),
2.05 (m, 1 H), 1.99 (s, 3 H), 1.92 (m, 1 H), 1.76 (m, 1 H). 13C
NMR (CD3OD): δ 174.781, 173.192, 151.059, 150.973, 143.659,
143.582, 142.895, 134.832, 133.973, 131.917, 131.584, 131.497,
131.094, 130.183, 129.901, 129.863, 129.365, 128.981, 125.993,
125.749, 115.641, 112.544, 75.122, 74.652, 54.075, 53.606,
53.274, 52.568, 44.833, 44.576, 38.640, 32.619, 32.020, 31.417,
31.358, 15.600. HRMS (FAB, M + H): calcd for C29H30N4O3-
SCl, 549.1723, found 549.1725.
C
30H32N5O5S 574.2124, found 574.2125.
4-[N-((1-p-Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
4-[N-((1-o-Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
n o]-2-p h en ylben zoylm eth ion in e m eth yl ester (11f) was
a yellow oil (25%). 1H NMR (CDCl3): δ 7.63 (d, 1 H, J ) 9 Hz,
Ar), 7.52 (s, 1 H, imid), 7.34-7.44 (m, 6 H, Ar), 7.24 (t, 1 H, J
) 8 Hz, Ar), 7.15 (t, 1 H, J ) 8 Hz), 7.07 (s, 1 H, imid), 6.70 (d,
1 H, J ) 9 Hz, Ar), 6.52 (dd, 1 H, J ) 3 and 9 Hz, Ar), 6.37 (d,
1 H, J ) 3 Hz, Ar), 5.75 (d, 1 H, J ) 8 Hz, amide NH), 5.24 (s,
2 H, CH2Ar), 4.60 (m, 1 H, R-C), 4.21 (d, 2 H, J ) 5 Hz, CH2N),
4.14 (t, 1 H, J ) 5 Hz, amine NH), 3.64 (s, 3 H, COOCH3),
2.08 (t, 2 H, J ) 8 Hz, CH2S), 2.00 (s, 3 H, SCH3), 1.84-1.91
(m, 1 H, CH2), 1.62-1.69 (m, 1 H, CH2). 13C NMR (CDCl3): δ
172.059, 168.360, 148.746, 141.695, 140.980, 139.240, 133.766,
132.715, 131.274, 129.914, 129.590, 129.526, 128.738, 128.682,
127.945, 127.921, 127.532, 123.958, 114.109, 111.862, 52.323,
51.847, 46.497, 37.867, 31.714, 29.547, 15.309. HRMS (FAB,
n o]-2-p h en ylben zoylm eth ion in e (11a ) was a white amor-
1
phous solid (63%). H NMR (CDCl3/CD3OD): δ 7.27-7.37 (m,
9 H, Ar), 7.17 (s, 1 H, imid), 7.12 (d, 2 H, J ) 7 Hz, Ar), 6.53
(dd, 1 H, J ) 2 and 9 Hz, Ar), 6.39 (d, 1 H, J ) 2 Hz, Ar), 5.35
(s, 2 H, CH2Ar), 4.38 (m, 1 H, R-C), 4.24 (s, 2 H, CH2N), 2.14-
2.20 (m, 1 H, CH2S), 2.03-2.08 (m, 1 H, CH2S), 1.98 (s, 3 H,
SCH3), 1.89-1.97 (m, 1 H, CH2), 1.72-1.79 (m, 1 H, CH2). 13
C
NMR (CD3OD): δ 174.660, 173.495, 149.320, 141.890, 141.241,
137.685, 134.199, 134.073, 131.013, 129.802, 129.017, 128.830,
128.490, 128.249, 127.302, 124.927, 124.208, 123.577, 113.878,
110.744, 78.059, 73.030, 53.608, 52.619, 43.302, 36.890, 34.169,
31.011, 29.728, 29.685, 13.924. HRMS (FAB, M + H): calcd
for C29H30N4O3SCl 549.1727, found 549.1725.
4-[N-((1-p-Ch lor oben zyl-1H-im id a zol-5-yl)m eth yl)a m i-
n o]-2-p h en ylben zoylm eth ion in e m eth yl ester (11b) was
a white amorphous solid (38%). 1H NMR (CDCl3): δ 7.62 (d, 1
H, 8 Hz, ortho to CONH), 7.51 (s, 1 H, NCHN), 7.33-7.43 (m,
5 H, biphenyl aryl), 7.08 (d, 2 H, 8 Hz, meta to CH3), 6.91 (d,
2 H, 8 Hz, ortho to CH3), 6.48 (dd, 1 H, 8 and 2 Hz, para to
biphenyl), 6.30 (d, 1 H, 2 Hz, ortho to biphenyl), 5.84 (d, 1 H,
8 Hz, CONH), 5.08 (s, 2 H, NCH2Ar), 4.59 (ddd, 1 H, met
R-CH), 4.23, (t, 1 H, 5 Hz, CH2NHAr), 4.12 (d, 2 H, 5 Hz, CH2-
NHAr), 3.63 (s, 3 H, COOCH3), 2.08 (t, 2 H, 7 Hz, CH2SCH3),
2.00 (s, 3 H, SCH3), 1.84-1.91 (m, 1 H, met CH), 1.63-1.70
(m, 1 H, met CH). 13C NMR (CDCl3): 172.05, 168.52, 148.93,
141.58, 141.00, 138.01, 132.98, 131.12, 129.71, 129.44, 128.68,
127.81, 126.69, 123.50, 114.10, 111.59, 99.62, 55.82, 53.96,
M
+
H): calcd for
C30H32N4O3SCl 563.1884, found
563.1884.
4-[N-((1-p-Tolylm eth yl-1H-im idazol-5-yl)m eth yl)am in o]-
2-p h en ylben zoylm eth ion in e (12a ) was a white amorphous
solid (75%). 1H NMR (CDCl3/CD3OD): δ 7.28-7.39 (m, 8 H,
Ar), 7.09-7.14 (m, 4 H, Ar), 6.54 (dd, 1 H, J ) 2 and 9 Hz,
Ar), 6.36 (d, 1 H, J ) 2 Hz, Ar), 5.38 (s, 2 H, CH2Ar), 4.39 (m,
1 H, R-C), 4.29 (s, 2 H, CH2N), 2.27 (s, 3 H, ArCH3), 2.13-
2.21 (m, 1 H, CH2S), 2.03-2.08 (m, 1 H, CH2S), 1.99 (s, 3 H,
SCH3), 1.91-1.97 (m, 1 H, CH2), 1.73-1.78 (m, 1 H, CH2). 13
C
NMR (CD3OD): δ 175.08, 172.98, 150.86, 143.60, 142.86,
140.41, 138.61, 133.54, 133.18, 131.54, 131.39, 130.17, 129.98,
129.08, 126.60, 126.09, 126.04, 123.13, 115.76, 112.73, 74.70,