Selective FAK inhibitors
A technology selected from, CF3, applied in the field of selective FAK inhibitors, can solve problems such as reduction
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Embodiment 1
[0377] Example 1: 2-(2-(2-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl) ethyl) phenyl) acetamide (1)
[0378]
[0379] (a) tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (I1)
[0380] 5-Fluoro-2-nitroanisole (3.00 g, 17.5 mmol), tert-butyl piperazine-1-carboxylate (4.57 g , 24.5mmol) and potassium carbonate (3.63g, 26.3mmol) was heated for 1.5 hours. The reaction mixture was cooled and diluted with water (100 mL). The resulting precipitate was filtered and dried to give a bright yellow solid. This solid was suspended in a 5:1 petroleum ether / diethyl ether (50 mL) solution, sonicated for 2 minutes, filtered and dried to give the title compound (I1) as a bright yellow solid (3.95 g, 66%); 1 H NMR (300 MHz,d 6 -DMSO) δ1.42(s,9H), 3.46(brs,8H), 3.90(s,3H), 6.52(s,1H), 6.57(d,1H,J=9.5Hz) and 7.89(d,1H , J=9.3Hz). LCMS method B: rt7.45min; m / z338.2[M+H] + .
[0381] (b) tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine...
Embodiment 2
[0415] Example 2: 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4 -yl) ethyl) phenyl) acetamide (2)
[0416]
[0417] (a) tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I16)
[0418] Lithium diisopropylamide (2M in heptane / THF / ethylbenzene; 15.1 mL, 30.1 mmol) was added dropwise to 4-oxopiperidine-1- tert-butyl carboxylate solution (3.00 g, 15.1 mmol), and the mixture was stirred for 30 minutes. A solution of N-phenyl-bis(trifluoromethanesulfonimide) (6.46 g, 18.1 mmol) in THF (60 mL) was then added dropwise to the reaction over 30 minutes, and the mixture was stirred at -78°C for 30 minutes. minute. The resulting mixture was then warmed to room temperature and stirred for 24 hours. The solvent was partially removed (approximately 80 mL) and washed with saturated NaHCO 3 solution (50 mL) to quench the reaction mixture. DCM (50 mL) was added to the solution and the layers were separated. The ...
Embodiment 3
[0435] Example 3: 2-(2-(2-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl ) pyrimidin-4-yl) ethyl) phenyl) acetamide (3)
[0436]
[0437] Formaldehyde solution (37% aq.; 32 μL, 0.39 mmol) was added to 2-(2-(2-(2-((2-methoxy-4-(piperidine-4 -yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (40 mg, 78 μmol) in a stirred solution. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added under nitrogen, and the resulting mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with ethyl acetate and absorbed on silica gel. Chromatographic separation (SiO 2 , 0-20% MeOH / DCM) afforded the title compound (3) as a solid (25 mg, 61%); 1 H NMR (400MHz, CD 2 Cl 2 )δ8.53(s,1H),8.34(d,J=8.3Hz,1H),7.94(s,1H),7.29–7.15(m,4H),6.92(dd,J=8.3,1.4Hz,1H ),6.82(d,J=1.7Hz,1H),6.12(bs,1H),5.84(bs,1H),3.91(s,3H),3.68(s,2H),3.60(d,J=10.6Hz ,2H), 3.24–3.03(m,4H), 2.80(s,3H), 2.79(m,2H), 2.71(m,1H), 2.42–2.20(m,...
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