Carbonitriles as Inhibitors
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 19 4741
H), 6.67 (s, 1 H), 7.16 (d, J ) 2.27 Hz, 1 H), 7.28-7.34 (m, 1 H),
7.46 (t, J ) 8.97 Hz, 1 H), 7.56 (dd, J ) 6.69, 2.65 Hz, 1 H), 7.83
(d, J ) 2.02 Hz, 1 H), 8.38 (s, 1 H), 9.47-9.51 (m, 1 H), 12.80 (s,
1 H). HPLC method 1: 100.0%, 4.85 min. HPLC method 2: 95.5%,
6.17 min.
NaCNBH3 (22 mg, 0.35 mmol) in 9 mL of EtOH. The crude product
was purified by HPLC and lyophilized to give 39 as a yellow solid
(74 mg, 72%): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J
) 7.07 Hz, 6 H), 4.16 (d, J ) 4.55 Hz, 2 H), 6.54 (d, J ) 4.42 Hz,
1 H), 7.19 (d, J ) 2.02 Hz, 1 H), 7.26-7.34 (m, 1 H), 7.45 (t, J )
8.97 Hz, 1 H), 7.49-7.56 (m, 2 H), 7.61 (d, J ) 2.27 Hz, 1 H),
8.16 (s, 1 H), 8.39 (s, 1 H), 9.47 (s, 1 H); HRMS (ESI+) calcd for
C23H12Cl2FN6 (MH+) 469.110 50, found 469.1096. HPLC method
1: 98.8%, 4.37 min. HPLC method 2: 99.5%, 5.51 min.
8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-propyl-
1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile (40).
The imidazolecarbaldehyde 53 was prepared according to the
general procedure described above for 52. The procedure described
above for the synthesis of 12 was then followed, reacting 9c (80
mg, 0.23 mmol) with 53 (38 mg, 0.28 mmol) and NaCNBH3 (17
mg, 0.28 mmol) in 9 mL of EtOH. The crude product was purified
by HPLC and lyophilized to give 40 as a yellow solid (61 mg,
56%): 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83 (t, J ) 7.45
Hz, 3 H), 1.53 (q, 2 H), 4.15 (d, J ) 4.80 Hz, 2 H), 6.27 (s, 1 H),
6.51 (d, 2 H), 7.18 (s, 1 H), 7.25-7.32 (m, 1 H), 7.45 (t, J ) 8.97
Hz, 1 H), 7.49-7.54 (m, 2 H), 7.61 (s, 1 H), 8.16-8.20 (m, 1 H),
8.39 (s, 1 H), 9.46 (s, 1 H). HPLC method 1: 99.1%, 4.47 min.
HPLC method 2: 99.8%, 5.70 min.
8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-ethyl-1H-
imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile (41). The
imidazolecarbaldehyde 54 was prepared according to the general
procedure described above for 42a. The procedure described above
for the synthesis of 12 was then followed, reacting 9c (43 mg, 0.12
mmol) with 54 (15 mg, 0.12 mmol) and NaCNBH3 (9 mg, 0.14
mmol) in 4 mL of EtOH. The reaction was concentrated and the
residue was purified by HPLC to give 41 as a yellow solid (16
mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J )
7.58 Hz, 3 H), 2.51-2.61 (m, 2 H), 4.16 (d, J ) 4.04 Hz, 2 H),
6.54 (s, 2 H), 7.20 (s, 1 H), 7.26-7.33 (m, 1 H), 7.45 (t, J ) 9.22
Hz, 1 H), 7.50-7.63 (m, 2 H), 8.14 (s, 1 H), 8.39 (s, 1 H), 9.48 (s,
1 H); HRMS calcd for C22H17Cl2FN6 + H+, 455.094 85, found
(ESI-FTMS, [M + H]1+), 455.0945. HPLC method 1: 96.9%, 4.28
min. HPLC method 2: 97.0%, 5.31 min.
Methyl 5-[({8-Bromo-4-[(3-chloro-4-fluorophenyl)amino]-3-
cyanoquinolin-6-yl}amino)methyl]-1H-imidazole-4-carboxy-
late (42). In a microwave vial, methyl 5-hydroxymethyl-1H-
imidazole-4-carboxylate (0.20 g, 1.28 mmol) was dissolved in 2.5
mL each of CH2Cl2 and 1,4-dioxane, and activated MnO2 (0.95 g,
11 mmol) was added. The vial was heated in a microwave reactor
at 140 °C for 5 min. The contents of the vial were then rinsed into
a 1 L flask and stirred with 400 mL of MeOH for 30 min. The
suspension was then filtered to remove the deactivated MnO2, and
the filtrate was dried over anhydrous Na2SO4, filtered a second time,
and evaporated to give methyl 5-formyl-1H-imidazole-4-carboxylate
of sufficient purity to be used in the next step (163 mg, 83%
yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 8.06
(s, 1 H), 10.22 (s, 1 H), 13.76 (s, 1 H); HRMS (ESI+) calcd for
C6H7N2O3 (MH+) 155.0451, found 155.0450. The procedure
described above for the synthesis of 12 was followed, reacting 9d
(400 mg, 1.02 mmol) with methyl 5-formyl-1H-imidazole-4-
carboxylate (157 mg, 1.02 mmol) and NaCNBH3 (43 mg, 0.68
mmol) in 12 mL of THF and 4 mL of MeOH. The crude product
was purified by HPLC and lyophilized to give 42 as a bright-yellow
powder (0.18 g, 33% yield): 1H NMR (400 MHz, DMSO-d6) δ
ppm 3.76 (br s, 3 H), 4.50 (br s, 1 H), 4.62 (br s, 1 H), 6.65 (br s,
0.5 H), 6.74 (br s, 0.5 H), 7.20-7.31 (m, 2 H), 7.43 (t, J ) 9.0 Hz,
1 H), 7.50 (dd, J ) 6.4, 2.7 Hz, 1 H), 7.63-7.88 (m, 2 H), 8.39 (s,
1 H), 9.45 (br s, 1 H), 12.70 (br s, 0.5 H), 13.09 (br s, 0.5 H);
HRMS (ESI+) calcd for C22H16BrClFN6O2 (MH+) 529.0185, found
529.0186. HPLC method 1: 99.1%, 4.98 min. HPLC method 2:
98.5%, 6.63 min.
N2-{8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-
quinolin-6-yl}-N-pyridin-3-ylglycinamide (37). To a mixture of
36 (233 mg, 0.58 mmol), 3-aminopyridine (70 µL, 0.70 mmol),
and diisopropylethylamine (402 µL, 2.31 mmol) in DMF (5 mL)
was added BOP (301 mg, 0.68 mmol). After 2 h, the mixture was
1
purified by HPLC to give 37 as a tan solid (129 mg, 54%). H
NMR (400 MHz, DMSO-d6) δ ppm 4.15 (s, 2 H), 6.88 (s, 1 H),
7.17 (d, J ) 2.27 Hz, 1 H), 7.24-7.30 (m, 1 H), 7.43 (t, J ) 8.97
Hz, 1 H), 7.51 (dd, J ) 6.57, 2.53 Hz, 1 H), 7.61-7.69 (m, 2 H),
8.22-8.28 (m, 1 H), 8.41-8.46 (m, 2 H), 8.97 (s, 1 H), 9.55 (s, 1
H), 10.56 (s, 1 H); HRMS calcd for C23H15Cl2FN6O + H+,
481.074 12, found (ESI-FTMS, [M + H]1+), 481.0754. HPLC
method 1: 97.4%, 4.37 min. HPLC method 2: 100.0%, 5.24 min.
General Procedure for the Synthesis of Imidazolecarbalde-
hydes 52-54. 4-Isopropyl-1H-imidazole-5-carbaldehyde (52).
Sulfuryl chloride (5.3 mL, 9.0 g, 66 mmol) was added dropwise to
ethyl isobutyrylacetate (10.2 mL, 10.0 g, 63.2 mmol) in 50 mL of
CHCl3 at 0 °C. The mixture was heated at reflux for 2 h and
concentrated to give ethyl 2-chloro-4-methyl-3-oxopentanoate of
sufficient purity to be used directly in the next step (12.2 g, 94%
yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (dd, J ) 9.1, 6.8
Hz, 6 H), 1.30 (t, J ) 6.8 Hz, 3 H), 2.99-3.16 (m, 1 H), 4.24-
4.33 (m, 2 H), 4.92 (s, 1 H). Ethyl 2-chloro-4-methyl-3-oxopen-
tanoate (12.2 g, 63.3mol) was reacted with formamide (25 mL, 29
g, 0.63mol) and water (2.3 mL, 2.3 g, 0.13mol). The crude product
was purified by flash chromatography over silica gel (4-6% MeOH
in CH2Cl2) to give ethyl 4-isopropyl-1H-imidazole-5-carboxylate
of sufficient purity to be used in the next step (0.558 g, 4.8%
yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J ) 7.1
Hz, 6 H), 1.23-1.33 (m, 3 H), 3.44-3.57 (m, 0.35 H), 3.65-3.79
(m, 0.65 H), 4.12-4.33 (m, 2 H), 7.58 (s, 0.65 H), 7.66 (s, 0.35
H), 12.39 (br s, 0.65 H), 12.67 (br s, 0.35 H). Ethyl 4-isopropyl-
1H-imidazole-5-carboxylate (0.55 g, 3.0 mmol) in 20 mL of THF
was reduced with a 1.0 M THF solution of LiAlH4 (3.1 mL, 3.1
mmol). Workup gave (4-isopropyl-1H-imidazol-5-yl)methanol of
sufficient purity to be used directly in the next step (0.39 g, 92%
yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J ) 6.8
Hz, 6 H), 2.78-3.12 (m, 1 H), 4.33 (s, 2 H), 4.66 (br s, 1 H), 7.38
(s, 1 H), 11.66 (br s, 1 H). (4-Isopropyl-1H-imidazol-5-yl)methanol
(0.21 g, 1.55 mmol) was oxidized with activated manganese dioxide
(0.40 g, 4.64 mmol) in 5 mL of acetone. The crude product was
purified by flash chromatography over silica gel (gradient elution,
5-100% EtOAc in CH2Cl2) to give pure 52 as a pale-pink solid
(0.27 g, 37% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23
(d, J ) 6.8 Hz, 6 H), 3.41 (br s, 0.35 H), 3.53-3.68 (m, 0.65 H),
7.71 (s, 0.65 H), 7.85 (s, 0.35 H), 9.82 (s, 1 H), 12.66 (br s, 0.65
H), 12.91 (br s, 0.35 H).
8-Bromo-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(4-isopropyl-
1H-imidazol-5-yl)methyl]amino}quinoline-3-carbonitrile (38).
The procedure described above for the synthesis of 12 was followed,
reacting 9d (300 mg, 0.76 mmol) with 52 (106 mg, 0.76 mmol)
and NaCNBH3 (32 mg, 0.51 mmol) in 9 mL of THF and 3 mL of
MeOH. The crude product was purified by HPLC and lyophilized
to give 38 as a yellow solid (162 mg, 41% yield): 1H NMR (400
MHz, DMSO-d6) δ ppm 1.16 (d, J ) 6.8 Hz, 6 H), 3.09 (br s, 1
H), 4.13 (s, 2 H), 6.49 (s, 1 H), 7.21 (s, 1 H), 7.24-7.33 (m, 1 H),
7.44 (t, J ) 9.0 Hz, 1 H), 7.48-7.55 (m, 2 H), 7.83 (s, 1 H), 8.39
(s, 1 H), 9.45 (s, 1 H), 11.82 (s, 1 H); HRMS (ESI+) calcd for
C23H20BrClFN6 (MH+) 513.0600, found 513.0594. HPLC method
1: 99.3%, 4.46 min. HPLC method 2: 97.4%, 5.64 min. Anal.
(C23H20BrClFN6‚H2O): C, 51.94; H, 3.98; N, 15.80. Found: C,
51.92; H, 3.66; N, 15.35.
8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-[({4-[3-(dim-
ethylamino)propyl]-1H-imidazol-5-yl}methyl)amino]quinoline-
3-carbonitrile (43). In a 50 mL round-bottomed flask were added
56 (355 mg, 1.04 mmol), N,N-dimethylprop-2-yn-1-amine (178 mg,
2.08 mmol), dichlorobis(triphenylphosphine)palladium (85 mg, 0.12
8-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-{[(5-isopropyl-
1H-imidazol-4-yl)methyl]amino}quinoline-3-carbonitrile (39).
The procedure described above for the synthesis of 12 was followed,
reacting 9c (76 mg, 0.22 mmol) with 52 (36 mg, 0.26 mmol) and