Protein Farnesyltransferase Inhibitors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3711
N-[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-
tetrahydroquinolin-3-yl]-4-fluoro-benzenesulfonamide 1H
NMR (500 MHz, CD3OD) δ 8.35 (s, 1H), 7.95-7.93 (m, 2H),
7.46 (s, 1H), 7.39 (d, J ) 8.5 Hz, 1H), 7.35 (t, J ) 8.0 Hz, 2H),
7.24 (s, 1H), 6.82 (d, J ) 8.5 Hz, 1H), 4.82 (d, J ) 17.0 Hz,
1H), 4.65 (d, J ) 17.0 Hz, 1H), 3.95-3.85 (m, 4H), 3.69-3.65
(m, 1H), 3.55-3.45 (m, 1H), 2.97-2.96 (m, 1H), 2.71-2.61 (m,
1H), MS (EI) m/z 426.12 (M+).
7.33 (d, J ) 8.5 Hz, 1H), 7.28-7.18 (m, 4H), 7.12 (s, 1H), 6.70
(d, J ) 8.5 Hz, 1H), 4.57-4.38 (m, 5H), 3.81 (s, 3H), 3.78 (s,
3H), 3.45 (d, J ) 10 Hz, 1H), 3.25-3.20 (m, 1H), 3.02-2.97
(m, 1H), 2.89 (d, J ) 13.5, 1H), 2.22 (s, 3H), MS (EI) m/z 516.61
(M+).
4-{[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-
1,2,3,4-tetrahydroquinolin-3-yl]-(1-methyl-1H-imidazole-
4-sulfonyl)amino]methyl}-piperidine-1-carboxylic Acid
tert-Butyl Ester (4g). 1H NMR (500 MHz, CD3OD) δ 8.94 (s,
1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.36 (d, J ) 8.7
Hz, 1H), 7.29 (s, 1H), 6.75 (d, J ) 8.5 Hz, 1H), 4.77 (d, J )
16.7 Hz, 1H), 4.65 (d, J ) 16.7 Hz, 1H), 4.42-4.31 (m, 1H),
4.17-4.01 (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.65-3.45 (m,
3H), 3.25-2.95 (m, 3H) 2.85-2.68 (m, 1H), 1.95-1.68 (m, 3H),
1.47 (s, 9H), 1.20-0.98 (m, 2H), MS (EI) m/z 609.5 (M+).
1-Methyl-1H-imidazole-4-sulfonic Acid (1-Bromonaph-
thalen-2-ylmethyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-
ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]amide (4h). 1H
NMR (500 MHz, CD3OD) δ 8.85 (s, 1H), 8.30-8.20 (m, 1H),
7.98-7.74 (m, 3H), 7.71-7.48 (m, 6H), 7.25-7.18 (m, 2H), 6.62
(d, J ) 8.5 Hz, 1H), 4.80-4.38 (m, 5H), 4.12 (m, 1H), 3.81 (s,
3H), 3.78 (s, 3H), 3.45 (m, 1H), 3.25-3.20 (m, 1H), 3.02-2.97
(m, 2H), MS (EI) m/z 632.21 (M+).
Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imi-
dazol-4-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-pyri-
din-2-ylmethylamide (4i). 1H NMR (300 MHz, CD3OD) δ
8.91 (s, 1H), 8.76 (d, J ) 4.8 Hz, 1H), 8.54 (d, J ) 5.1 Hz, 1H),
7.98-8.15 (m, 3H), 7.83 (d, J ) 7.8 Hz, 1H), 7.71 (ddd, J )
1.2, 4.5, 7.2 Hz, 1H), 7.55-7.59 (m, 1H), 7.31-7.33 (m, 2H),
7.22 (s, 1H), 6.72 (d, J ) 8.7 Hz, 1H), 4.82 (d, J ) 17.7 Hz,
1H), 4.76 (d, J ) 17.7 Hz, 1H), 4.54-4.65 (m, 3H), 3.86 (s,
3H), 3.45-3.56 (m, 2H), 3.13 (dd, J ) 10.2, 15.6 Hz, 1H), 2.93
(dd, J ) 4.2, 16.2 Hz, 1H); MS (EI) m/z 500.3 (M+)
General Procedure for N-Alkylation. To a suspension
of the reductive amination product (5 mmol) and Cs2CO3 (9.8
mmol) in dry DMF (5 mL) was added the appropriate alkyl
halide (5.4 mmol), and the mixture was stirred at room-
temperature overnight under argon. After addition of water
(20 mL), the solution was extracted with ethyl acetate (3 ×
20 mL). The organic layer was extracted with brine (3 × 10
mL). The combine organic layers were dried over MgSO4 and
evaporated under reduce pressure. The residue was purified
by RP HPLC. Appropriate fractions were collected, and the
pure product was obtained as the trifluoroacetate salt.
[[6-Cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-
tetrahydroquinolin-3-yl]-(1-methyl-1H-imidazole-4-sul-
1
fonyl)-amino]-acetic Acid tert-Butyl Ester (4a). H NMR
(300 MHz, CDCl3) δ 8.66 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H),
7.38 (d, J ) 8.5 Hz, 1H), 7.16 (s, 1H), 7.12 (s, 1H), 6.65 (d, J
) 8.6 Hz, 1H), 4.71 (d, J ) 16.8 Hz, 1H), 4.68 (d, J ) 16.8 Hz,
1H), 4.50-4.34 (m, 2H), 3.96 (d, J ) 17.3 Hz, 1H), 3.90 (s,
3H), 3.81 (s, 3H), 3.44-3.55 (m, 2H), 3.12 (dd, J ) 11.5, 15.2
Hz, 1H) 2.81 (dd, J ) 3.2, 15.1 Hz, 1H), 1.35 (s, 9H); high-
resolution mass spectroscopy (FAB+) m/z calcd for C25H32O4N7S
(MH+) 526.2237 obsd 526.2241.
1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-
methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquin-
olin-3-yl]-(2-methylallyl)amide (4b). 1H NMR (300 MHz,
CDCl3) δ 8.63 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.40-7.35 (m,
2H), 7.14 (s, 1H), 6.68 (d, J ) 8.6 Hz, 1H), 5.05-4.95 (m, 1H),
4.92-4.85 (m, 1H), 4.74 (d, J ) 16.7 Hz, 1H), 4.67 (d, J ) 16.5
Hz, 1H), 4.48-4.21 (m, 2H), 3.99 (d, J ) 17.3 Hz, 1H), 3.92 (s,
3H), 3.85 (s, 3H), 3.53-3.41 (m, 2H), 3.09 (dd, J ) 11.4, 15.1
Hz, 1H) 2.9 (dd, J ) 3.1, 15.0 Hz, 1H), 1.81 (s, 3H); high-
resolution mass spectroscopy (FAB+) m/z calcd for C23H28O2N7S
(MH+) 466.2025 obsd 466.2029.
1-Methyl-1H-imidazole-4-sulfonic Acid (2-Bromoallyl)-
[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tet-
rahydroquinolin-3-yl]amide (4c). 1H NMR (300 MHz,
CDCl3) δ 8.64 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.41-7.36 (m,
2H), 7.15 (s, 1H), 6.70 (d, J ) 8.6 Hz, 1H), 6.08-6.02 (m, 1H),
5.70-5.60 (m, 1H), 4.67 (d, J ) 16.5 Hz, 1H), 4.58-4.2 (m,
2H), 3.92 (s, 3H), 3.89 (m, 1H), 3.85 (s, 3H), 3.53-3.41 (m, 2H),
3.09 (dd, J ) 11.4, 15.1 Hz, 1H) 2.9 (dd, J ) 3.1, 15.0 Hz, 1H)
MS (EI) m/z 531.41 (M+).
N-tert-Butyl-2-[[6-cyano-1-(3-methyl-3H-imidazol-4-yl-
methyl)-1,2,3,4-tetrahydroquinolin-3-yl]-(1-methyl-1H-
imidazole-4-sulfonyl)amino]acetamide (4d). 1H NMR (500
MHz, CD3OD) δ 8.94 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.43 (s,
1H), 7.39 (d, J ) 8.7 Hz, 1H), 7.29 (s, 1H), 6.83 (d, J ) 8.5 Hz,
1H), 4.80 (d, J ) 16.7 Hz, 1H), 4.68 (d, J ) 16.7 Hz, 1H), 4.32-
4.41 (m, 1H), 4.01 (d, J ) 17.3 Hz, 1H), 3.96 (d, J ) 17.4 Hz,
1H), 3.85 (s, 3H), 3.65 (s, 3H), 3.57-3.51 (m, 2H), 3.13 (dd, J
) 12, 15.1 Hz, 1H) 2.85 (dd, J ) 3.3, 15.3 Hz, 1H), 1.37 (s,
9H); high-resolution mass spectroscopy (FAB+) m/z calcd for
C25H33O4N8S (MH+) 525.2396 obsd 525.2397.
Pyridine-2-sulfonic Acid [6-Cyano-1-(3-methyl-3H-imi-
dazol-4-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-(5-meth-
1
yl-3-phenylisoxazol-4-ylmethyl)amide (4j). H NMR (300
MHz, CD3OD) δ 8.93 (s, 1H), 8.71 (d, J ) 7.2 Hz, 1H), 8.05
(td, J ) 1.8, 7.5 Hz, 1H), 7.93-8.00 (m, 1H), 7.66 (ddd, J )
1.2, 4.8, 7.5 Hz, 1H), 7.40-7.51 (m, 5 H), 7.39 (dd, J ) 1.5, 8.4
Hz, 1H), 7.33 (s, 1H), 7.02 (s, 1H), 6.80 (d, J ) 9.7 Hz, 1H),
4.49-4.73 (m, 4H), 4.03-4.21 (m, 1H), 3.85 (s, 3H), 3.28-3.47
(m, 2H), 2.85-2.91 (m, 1H), 2.64 (s, 3H), 2.46-2.53 (m, 1H);
MS (EI) m/z 580.4 (M+).
Pyridine-2-sulfonic Acid (1-Bromonaphthalen-2-ylm-
ethyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-
1,2,3,4-tetrahydroquinolin-3-yl]amide (4k). 1H NMR (300
MHz, CDCl3) δ 8.79 (d, J ) 7.2 Hz, 1H), 8.27-8.28 (m, 2H),
8.00-8.06 (m, 2 H), 7.85-7.93 (m, 3H), 7.62-7.68 (m, 3 H),
7.30-7.33 (m, 1H), 7.19 (s, 1H), 7.13 (s, 1H), 6.51 (d, J ) 8.7
Hz, 1H), 4.96 (d, J ) 17.1 Hz, 1H), 4.88 (d, J ) 17.1 Hz, 1H),
4.47-4.50 (m, 1H), 4.31 (d, J ) 15.9 Hz, 1H), 4.19 (d, J ) 15.9
Hz, 1H), 3.50 (s, 3H), 3.15-3.21 (m, 2H), 2.89-2.94 (m, 2H).
MS (EI) m/z 627.5 (M+).
Pyridine-2-sulfonicAcid(6-Chlorobenzo[1,2,5]thiadiazol-
5-ylmethyl)-[6-cyano-1-(3-methyl-3H-imidazol-4-ylmethyl)-
1
1,2,3,4-tetrahydroquinolin-3-yl]amide (4l). H NMR (300
MHz, CDCl3) δ 8.75 (d, J ) 7.2 Hz, 1H), 8.64 (s, 1H), 8.30 (s,
1H), 8.19 (s, 1H), 7.95-8.03 (m, 2H), 7.61-7.63 (m, 1H), 7.20
(s, 1H), 7.18 (m, 2H), 6.43 (d, J ) 8.5 Hz, 1H), 4.75 (s, 2H),
4.64-4.68 (m, 1H), 4. 48 (d, J ) 16.5 Hz, 1H), 4.35 (d, J )
16.5 Hz, 1H), 3.81 (s, 3H), 3.62-3.66 (m, 1H), 3.38-3.46 (m,
1H), 2.98-3.01 (m, 2H); MS (EI) m/z 591.4.
1-Methyl-1H-imidazole-4-sulfonic Acid Benzyl-[6-cy-
ano-1-(3-methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahy-
N-tert-Butyl-2-[[6-isocyano-1-(3-methyl-3H-imidazol-4-
ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-(pyridine-2-
sulfonyl)amino]acetamide (4m). 1H NMR (300 MHz, CD3-
OD) δ 8.93 (s, 1H), 8.71 (d, J ) 7.2 Hz, 1H), 8.05 (td, J ) 1.8,
7.5 Hz, 1H), 8.01-8.02 (m, 1H), 7.66 (ddd, J ) 1.2, 4.8, 7.5
Hz, 1H), 7.43 (s, 1H), 7.39 (dd, J ) 1.5, 8.4 Hz, 1H), 7.33 (s,
1H), 6.80 (d, J ) 9.7 Hz, 1H), 4.81 (d, J ) 16.8 Hz, 1H), 4.68
(d, J ) 16.8 Hz, 1H), 4.32-4.44 (m, 1H), 4.00 (d, J ) 17.4 Hz,
1H), 3.95 (d, J ) 17.4 Hz, 1H), 3.90 (s, 3H), 3.46-3.59 (m,
2H), 3.13 (dd, J ) 12, 15.3 Hz, 1H) 2.85 (dd, J ) 3.3, 15.3 Hz,
1H), 1.32 (s, 9H); high-resolution mass spectroscopy (FAB+)
m/z calcd for C26H32O3N7S (MH+) 522.2287 obsd 522.2275.
1
droquinolin-3-yl]amide (4e). H NMR (300 MHz, CD3OD)
δ 8.85 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.45-7.21 (m, 6H),
7.14 (s, 1H), 6.72 (d, J ) 8.6 Hz, 1H), 4.70-4.25 (m, 5H), 4.00
(d, J ) 17.3 Hz, 1H), 3.72 (s, 3H), 3.65 (s, 3H), 3.53-3.41 (m,
1H), 3.08 (dd, J ) 11.5, 15.2 Hz, 1H) 2.85 (dd, J ) 3.0, 15.1
Hz, 1H); high-resolution mass spectroscopy (FAB+) m/z calcd
for C26H28O2N7S (MH+) 502.2055 obsd 502.2022.
1-Methyl-1H-imidazole-4-sulfonic Acid [6-Cyano-1-(3-
methyl-3H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydroquin-
olin-3-yl]-(2-methylbenzyl)amide (4f). 1H NMR (500 MHz,
CD3OD) δ 8.89 (s, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H),