Aurora A and B Kinase Inhibitors
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 965
raphy, eluting with CH2Cl2:MeOH, NH3 (3 N) (95:5) to give 18
(120 mg, 39%): 1H NMR (DMSO-d6, TFA) δ 2.29 (t, 2H), 3.17
(t, 2H), 3.36 (t, 2H), 3.55 (d, 1H), 3.69 (t, 2H), 3.96 (s, 3H), 4.04
(d, 2H), 4.27 (t, 2H), 7.22 (m, 3H), 7.74 (m, 2H), 7.82 (s, 1H),
8.07 (s, 1H), 8.76 (s, 1H); MS ESI+ m/z 522.1 (M + H)+. Anal.
(C26H28FN7O4‚1.8H2O) C, H, N.
Methyl (2-Amino-1,3-oxazol-5-yl)acetate (19). Methyl 3-bromo-
4-oxobutanoate (3 g, 15.4 mmol) in DMF (10 mL) was reacted
with urea (1.25 g, 20.9 mmol) at 110 °C for 30 min. The solvent
was evaporated and the residual oil was purified by silica gel
chromatography, eluting with CH2Cl2:MeOH, NH3 (7 N) (99:1 to
97.5:2.5) to give oxazole 19 as an oil (774 mg, 48%): 1H NMR
(DMSO-d6) δ 3.64 (s, 3H), 3.66 (s, 2H), 6.48 (s, 1H), 6.49 (s, 2H);
MS ESI+ m/z 157.3 (M + H)+.
Methyl (2-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazo-
lin-4-yl]amino}-1,3-oxazol-5-yl)acetate (23). Amidine 7 (500 mg,
1.4 mmol) in AcOH (1.2 mL) was heated with stirring with
aminooxazole 1948 (237 mg, 1.52 mmol) at 135 °C under argon
for 30 min. The solvent was evaporated, and the residual oil was
purified by silica gel chromatography, eluting with CH2Cl2:MeOH,
NH3 (7 N) (99:1 to 97.5:2.5) to give ester 23 as a yellow solid
(464 mg, 73%): 1H NMR (DMSO-d6, TFA) δ 2.28 (m, 2H), 3.15
(m, 2H), 3.36 (m, 2H), 3.55 (m, 2H), 3.67 (m, 2H), 3.7 (s, 3H),
3.97 (s, 2H), 4 (s, 3H), 4.02 (m, 2H), 4.3 (m, 2H), 7.34 (s, 1H),
7.42 (s, 1H), 7.77 (s, 1H), 8.89 (s, 1H); MS ESI+ m/z 458.6 (M +
H)+.
N-(3-Fluorophenyl)-2-(2-{[6-methoxy-7-(3-morpholin-4-yl-
propoxy)quinazolin-4-yl]amino}-1,3-oxazol-5-yl)acetamide (24).
Step 1. Quinazoline ester 23 (300 mg, 0.66 mmol) in solution in
MeOH (7.5 mL) was saponified with NaOH (2 N, 7.5 mL) at 80
°C for 2 h. The MeOH was evaporated and the residue was treated
with HCl (6 N, 6 mL). This was purified by chromatography over
a Waters macroporous copolymer, Oasis, eluting successively with
H2O and H2O:MeOH (1:1) to give (2-{[6-methoxy-7-(3-morpholin-
4-ylpropoxy)quinazolin-4-yl]amino}-1,3-oxazol-5-yl)acetic acid as
a yellow solid (273 mg, 94%): 1H NMR (DMSO-d6, TFA) δ 2.29
(m, 2H), 3.16 (m, 2H), 3.35 (m, 2H), 3.54 (m, 2H), 3.68 (m, 2H),
3.85 (s, 2H), 3.98 (s, 3H), 4.03 (m, 2H), 4.29 (m, 2H), 7.33 (s,
1H), 7.39 (s, 1H), 7.77 (s, 1H), 8.88 (s, 1H); MS ESI+ m/z 444.6
(M + H)+.
Step 2. (2-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-
4-yl]amino}-1,3-oxazol-5-yl)acetic acid (130 mg, 0.29 mmol) in
DMA (0.82 mL) was reacted with 3-fluoroaniline (32 µL, 0.35
mmol) in the presence of 2-hydroxypyridine N-oxide (39 mg, 0.35
mmol), EDCI (68 mg, 0.35 mmol), and DIEA (62 µL, 0.35 mmol)
for 3 h at 50 °C. The DMA was evaporated and the residue purified
by preparative LC-MS to give 24 as a yellow solid (108 mg,
69%): 1H NMR (DMSO-d6, TFA) δ 2.28 (m, 2H), 3.16 (m, 2H),
3.35 (t, 2H), 3.55 (d, 2H), 3.68 (t, 2H), 3.94 (s, 2H), 3.97 (s, 3H),
4.03 (m, 2H), 4.31 (m, 2H), 6.98 (m, 1H), 7.33 (s, 1H), 7.36 (m,
2H), 7.46 (s, 1H), 7.63 (m, 1H), 7.77 (s, 1H), 8.9 (s, 1H); MS
ESI+ m/z 537 (M + H)+. Anal. (C27H29FN6O5‚H2O) C, H, N.
N-(4-Fluorophenyl)-2-{[6-methoxy-7-(3-morpholin-4-ylpro-
poxy)quinazolin-4-yl]amino}-1,3-thiazole-5-carboxamide (26).
Step 1. Ester 25 (1.6 g, 3.4 mmol) in suspension in EtOH (32 mL)
was reacted with NaOH (6 N, 6 mL) at 75 °C for 1 h. The cooled
solution was acidified with HCl (6 N) to pH 4. The solid was
filtered, washed with EtOH and then Et2O, and dried to give 2-{-
[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-
1,3-thiazole-5-carboxylic acid as a yellow solid (1.65 g, 86%): 1H
NMR (DMSO-d6, TFA) δ 2.28 (m, 2H), 3.12 (t, 2H), 3.32 (t, 2H),
3.51 (d, 2H), 3.66 (t, 2H), 3.97 (s, 3H), 3.99 (d, 2H), 4.31 (t, 2H),
7.37 (s, 1H), 8.06 (s, 1H), 8.32 (s, 1H), 9.24 (s, 1H); MS ESI+ m/z
446 (M + H)+.
0.5 h and concentrated. The residue was washed with CH2Cl2:
MeOH (1:1, 25 mL). Alumina was added to the organic phase,
which was evaporated. Purification of the compound was carried
out by chromatography over alumina eluting successively with CH2-
Cl2 and CH2Cl2:MeOH (95:5) to give 26 (58 mg, 64%): 1H NMR
(DMSO-d6, TFA) δ 2.31 (m, 2H), 3.16 (t, 2H), 3.36 (t, 2H), 3.56
(d, 2H), 3.69 (t, 2H), 4.01 (s, 3H), 4.03 (d, 2H), 4.32 (t, 2H), 7.2
(t, 1H), 7.38 (s, 1H), 7.73 (m, 1H), 8.05 (s, 1H), 8.57 (s, 1H), 9.28
(s, 1H); MS ESI+ m/z 539 (M + H)+. Anal. (C26H27FN6O4S‚
0.7H2O) C, H, N, S.
N-(3-Fluorophenyl)-2-(2-{[6-methoxy-7-(3-morpholin-4-yl-
propoxy)quinazolin-4-yl]amino}-1,3-thiazol-4-yl)acetamide (28).
Step 1. Ester 27 (2 g, 4.1 mmol) was saponified as described for
the preparation of 26, step 1, to give (2-{[6-methoxy-7-(3-
morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1,3-thiazol-4-yl)-
acetic acid as a yellow solid (1.99 g, 99%): 1H NMR (DMSO-d6,
TFA) δ 2.31 (m, 2H), 3.16 (t, 2H), 3.35 (t, 2H), 3.56 (d, 2H), 3.71
(t, 2H), 3.79 (s, 2H), 4.0 (s, 3H), 4.03 (m, 2H), 4.31 (m, 2H), 7.25
(s, 1H), 7.34 (s, 1H), 8.01 (s, 1H), 9.13 (s, 1H); MS ESI+ m/z 460
(M + H)+.
Step 2. (2-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-
4-yl]amino}-1,3-thiazol-4-yl)acetic acid (147 mg, 0.3 mmol) was
condensed with 3-fluoroaniline (40 mg, 0.36 mmol) as described
for the preparation of 26, step 2, to give 28 (100 mg, 60%): 1H
NMR (DMSO-d6, TFA) δ 2.3 (m, 2H), 3.16 (t, 2H), 3.36 (t, 2H),
3.56 (d, 2H), 3.69 (t, 2H), 3.91 (s, 2H), 3.99 (s, 3H), 4.04 (m, 2H),
4.31 (m, 2H), 6.9 (m, 1H), 7.29 (s, 1H), 7.33 (s, 1H), 7.37 (m,
2H), 7.64 (m, 1H), 8.01 (s, 1H), 9.13 (s, 1H); MS ESI+ m/z 553.3
(M + H)+. Anal. (C27H29FN6O4S) C, H, N.
N-(3-Fluorophenyl)-2-(2-{[6-methoxy-7-(3-morpholin-4-yl-
propoxy)quinazolin-4-yl]amino}-1,3-thiazol-5-yl)acetamide (30).
Step 1. Ester 29 (4.38 g, 8 mmol) was saponified as described for
the preparation of 26, step 1, to give (2-{[6-methoxy-7-(3-
morpholin-4-ylpropoxy)quinazolin-4-yl]amino}-1,3-thiazol-5-yl)-
acetic acid (3.7 g, 100%): 1H NMR (DMSO-d6, TFA) δ 2.29 (m,
2H), 3.16 (t, 2H), 3.35 (t, 2H), 3.55 (d, 2H), 3.69 (t, 2H), 3.92 (s,
2H), 3.99 (s, 3H), 4.03 (m, 2H), 4.3 (m, 2H), 7.31 (s, 1H), 7.6 (s,
1H), 7.9 (s, 1H), 9.09 (s, 1H); MS ESI+ m/z 460 (M + H)+.
Step 2. (2-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-
4-yl]amino}-1,3-thiazol-5-yl)acetic acid (77 mg, 0.17 mmol) was
condensed with 3-fluoroaniline (23 mg, 0.21 mmol) as described
for the preparation of 26, step 2, to give 30 (35 mg, 40%): 1H
NMR (DMSO-d6, TFA) δ 2.3 (m, 2H), 3.16 (t, 2H), 3.36 (t, 2H),
3.56 (d, 2H), 3.69 (t, 2H), 3.99 (s, 3H), 4.01 (s, 2H), 4.04 (m, 2H),
4.31 (m, 2H), 6.91 (m, 1H), 7.31 (s, 1H), 7.34 (m, 2H), 7.62 (m,
1H), 7.65 (s, 1H), 7.91 (s, 1H), 9.1 (s, 1H); MS ESI+ m/z 553.2
(M + H)+. Anal. (C27H29FN6O4S‚4.1H2O) C, H, N,S.
N′-(2-Cyano-5-hydroxy-4-methoxyphenyl)-N,N-dimethyl-
imidoformamide (33). 8 (15.45 g, 50 mmol) in TFA (200 mL)
was irradiated in a microwave oven at 75 °C for 45 min. The solvent
was evaporated, and the residue was dissolved in CH2Cl2, washed
with Na2CO3, and dried over MgSO4. This was evaporated to give
33 as a pale yellow solid (10.26 g, 94%): 1H NMR (DMSO-d6,
TFA) δ 3.24 (s, 3H), 3.34 (s, 3H), 3.87 (s, 3H), 7.02 (s, 1H), 7.49
(s, 1H), 8.56 (s, 1H); MS ESI+ m/z 220.5 (M + H)+.
N′-[5-(3-Chloropropoxy)-2-cyano-4-methoxyphenyl]-N,N-di-
methylimidoformamide (34). 33 (439 mg, 2 mmol) in CH3CN (5
mL) was reacted with 1-bromo-3-chloropropane (0.22 mL, 2.2
mmol) and Cs2CO3 (1.95 g, 5.98 mmol) at 85 °C for 0.5 h. The
reaction mixture was evaporated, taken up in CH2Cl2:H2O, extracted
with CH2Cl2, dried over MgSO4, and evaporated to give 34 as a
pale yellow solid (450 mg, 76%): 1H NMR (DMSO-d6, TFA) δ
2.26 (t, 2H), 3.26 (s, 3H), 3.37 (s, 3H), 3.81 (t, 2H), 3.87 (s, 3H),
4.23 (t, 2H), 7.34 (s, 1H), 7.53 (s, 1H), 8.56 (s, 1H); MS ESI+ m/z
296.56 (M + H)+. Anal. (C14H18ClN3O2) C,H,Cl,N.
Step 2. 2-{[6-Methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-
4-yl]amino}-1,3-thiazole-5-carboxylic acid (95 mg, 0.17 mmol) in
DMF (1 mL) was reacted with 4-fluoroaniline (23 mg, 0.2 mmol)
in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetram-
ethyluronium hexafluorophosphate (91 mg, 0.24 mmol) and DIEA
(110 mg, 0.85 mmol) at 50 °C for 15 h. The reaction mixture was
then treated with a solution of NaHCO3 (1 mL) with stirring for
N′-[5-(2-Chloroethoxy)-2-cyano-4-methoxyphenyl]-N,N-di-
methylimidoformamide (35). A mixture of 33 (12 g, 36 mmol),
Cs2CO3 (52 g, 164 mmol), and 1-bromo-2-chloroethane (5 mL, 60
mmol) in CH3CN (160 mL) was refluxed for 2 h. The reaction
mixture was cooled, the solvent evaporated, and the residue was
suspended in H2O (300 mL). This was extracted with CH2Cl2 (2 ×