Synergistic modulation of FLT3 kinase using aminoquinoline and aminoquinazoline kinase modulators

[0771] (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester (Compound No. 1)

[0772]

[0773] Add 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol) prepared in Example 3a, 4- Cumyl phenyl ester (20 mg, 0.12 mmol) and dichloroethane (1 mL). After the mixture was stirred at 60°C for 16 hours, the contents were subjected to aqueous workup and purification by TLC to obtain the desired product in 65% yield.

[0774] 1 H NMR (300MHz, CDCl 3 )δ8.67(s, 1H), 7.33-7.25(m, 3H), 7.18(d, J=7.6Hz, 2H), 7.09(s, 1H), 6.64(s, 1H), 5.08(m, 1H ), 4; 02(s, 3H), 3.99(s, 3H), 3.95-3.89(m, 2H), 3.55-3.48(m, 2H), 2.88(sept, J=6.1Hz, 1H), 2.22- 2.14(m, 2H), 2.04-1.91(m, 2H), 1.23(d, J=6.1Hz, 6H);

[0775] LC / MS (ESI): theoretical mass 450.2, found 451.6 (M+H) + .

[0777] (4-Isopropyl-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-pyrrolidin-3-yl ester (Compound No. 2)

[0778]

[0779] a. (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester

[0780]

[0781] To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added portionwise 4-nitrochloroformic acid with stirring under brief ice bath cooling over ~30 seconds phenyl phenyl ester (4.09 g, 20.3 mmol). After stirring at room temperature for 1 h, the homogeneous solution was diluted with DCM (100 mL), washed with 0.6M HCl (1×250 mL), 0.025M HCl (1×400 mL), water (1×100 mL) and 1M NaHCO 3 (1 x 100 mL) wash. The organic layer was dried (Na 2 8O 4 ), concentrated to afford the title compound as a pale pink solid (5.80 g, 95%).

[0782] 1 H NMR (300MHz, CDCl 3 )δ8.28(m, 2H), 7.42-7.32(m, 4H), 7.23(m, 2H), 6.93(brs, 1H), 2.90(h, J=6.9Hz, 1H), 1.24(d, J =6.9Hz, 6H).

[0783] LC / MS (ESI): theoretical mass 300.1, found 601.3 (2...

[0790] (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester (compound No. 3)

[0791]

[0792] a.1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol

[0793]

[0794] A solution of 4-hydroxypiperidine (40.4 mg, 0.400 mmol) in isopropanol (1 mL) was treated with 4-chloro-6,7-dimethoxy-quinazoline (89.9 mg, 0.401 mmol). After stirring overnight at 100 °C, the reaction was cooled to room temperature and dissolved in DCM (10 mL) and H 2 O (10mL). Na 2 SO 4 Dry and concentrate in vacuo to afford the title compound as a solid (60 mg, 52%).

[0795] b. (4-Isopropoxy-phenyl)-carbamic acid 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl ester

[0796]

[0797] Add 1-(6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-ol (29 mg, 0.1 mmol) prepared substantially according to Example 3a, chloroformic acid p-nitrogen to the bottle phenyl phenyl ester (24 mg, 0.12 mmol), triethylamine (20 mg, 0.2 mmol) and dichloroethane (1 mL). After the mixture ...