Quinazoline derivatives
A derivative, quinazoline technology, applied in the field of novel quinazoline derivatives or their pharmaceutically acceptable salts, can solve the problems of reducing unwanted side effects, achieve high bioavailability, and reduce side effects
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Examples
Embodiment 1
[1674] N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-N-methylacetamide
[1675]
[1676] HATU (197 mg), diisopropylethylamine (90 μl), acetic acid (22 μl) and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-( A mixture of methylamino)ethoxy]quinazolin-4-amine (150mg) in DCM (20ml) was stirred for 2 hours. The solution was washed with water, then brine and concentrated in vacuo. The residue was purified by chromatography using DCM-5% methanol as eluent to afford the title compound (114 mg, 69%) as a white solid; NMR
[1677] spectrum (DMSO-d6) 1.95(s, 3H), 3.00(s, 3H), 3.89(t, 2H), 4.48(m, 2H), 5.29(s, 2H), 7.18(d, 1H), 7.24(d , 1H), 7.35(m, 2H), 7.59(m, 2H), 7.72(dd, 1H), 7.85(dt, 1H), 7.96(d, 1H), 8.46(s, 1H), 8.58(m, 1H), 9.70(bs, 1H); mass spectrometry MH + 478.5.
[1678] N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazoline-4- The amines were prepared as follows:
[1679] DMF (0.2ml) was added to a ...
Embodiment 2
[1685] In a method similar to the method described in Example 1, a suitable quinazoline is reacted with a suitable acid to obtain the compounds shown in Table 1:
[1686] Table I
[1687]
[1688] serial number
and
note
Q 1
R 3
R 4
R 5a
R 6
Z
[1]
2-pyridyl
Cl
H
H
methyl
Methoxy
[2]
2-pyridyl
Cl
H
H
methyl
Dimethylamino
[3]
2-pyridyl
Cl
(R)-Methyl
H
methyl
Methoxy
[4]
2-pyridyl
Cl
H
(R)-Methyl
H
H
[5]
2-pyridyl
Cl
H
(R)-Methyl
H
Oh
[6]
2-pyridyl
Cl
H
H
H
H
[7]
2-pyridyl
Cl
(R)-Methyl
H
methyl
H
[1689] [1] N-{2-[(4-{3-chloro-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy]ethyl}-2-methyl Oxy-N-methylacetamide. By combining methoxyacetic acid and...
Embodiment 3
[1711] 2-Hydroxy-N-methyl-N-{2-[(4-{3-methyl-4-(pyridin-2-ylmethoxy)anilino}quinazolin-5-yl)oxy] Ethyl}acetamide
[1712]
[1713] 2-Hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (100mg) , picolyl chloride hydrochloride (60 mg) and potassium carbonate (120 mg) were stirred in DMF (5 ml), and 18-crown-6 (10 mg) was added thereto. The reaction was stirred at room temperature for 2 days. DMF was removed under vacuum, water (5ml) was added and the suspension was extracted with DCM (2x5ml). The DCM fraction was purified by chromatography using 2.5-5% 10:1 DCM / methanol containing 0.5% ammonia (0.880) as eluent. Appropriate fractions were evaporated and the residue was precipitated with DCM / ether to give the title product (28 mg, 23%) as a light yellow solid;
[1714] NMR spectrum (DMSO-d6, 100°C) 2.29(s, 3H), 3.00(s, 3H), 3.90(t, 2H), 4.16(s, 2H), 4.50(t, 2H), 5.20(s, 2H), 7.01(d, 1H), 7.16(d, 1H), 7.34(d, 2H), 7.51(m, 2H), 7.55(d...
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