Fak inhibitor
A CF3, CF2H technology, applied in pharmaceutical compositions containing such compounds, in the field of prevention and/or treatment of proliferative diseases (such as cancer), can solve problems such as reducing
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Embodiment 1
[0441] Example 1: 2-(2-(2-(2-((4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl) Phenyl)acetamide(1)
[0442]
[0443] (a) tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I1)
[0444] 4-(4'-nitrophenyl)piperazine hydrochloride (5.00 g, 20.5 mmol) was dissolved in DCM (100 mL) and washed with triethylamine (7.15 mL, 51.3 mmol) followed by Boc anhydride (4.93 g, 22.6 mmol) and then stirred at room temperature for 20 hours. Water (100 mL) and DCM (70 mL) were added to the mixture and the layers were separated. The aqueous layer was extracted with DCM (100 mL), the combined organics were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo to yield a yellow-orange solid. The product was purified by silica gel chromatography (Biotage Isolera, 120 g Si cartridge column, 0-100% EtOAc in petroleum ether, 40-60 °C) to give the title compound (I1) (4.895 g, 78% yield ), as a yellow solid; 1 H NMR (400MHz, d 6 -DMSO) δ...
Embodiment 2
[0467] Example 2: 3-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl ) benzamide (2)
[0468]
[0469] (a) 1-methyl-4-(4-nitrophenyl) piperazine (I11)
[0470] To 4-(4'-nitrophenyl)piperazine hydrochloride (1.00 g, 4.10 mmol) was added formic acid (1.55 mL, 41.0 mmol) and 37% aqueous formaldehyde (3.06 mL, 41.0 mmol) in a microwave vessel , and heated the reaction at 120 °C for 3 minutes. To the cooled reaction mixture were added EtOAc (100 mL) and 2M aqueous NaOH (70 mL). The layers were separated and the organic layer was washed with brine (50 mL). The layers were separated and the aqueous brine layer was extracted with EtOAc (50 mL), the organic layers were combined and dried (Na 2 SO 4 ), filtered and concentrated in vacuo to yield a crude product which was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-60% methanol in EtOAc containing 1% ammonia solution) to obtain Yield the title compound (I11)...
Embodiment 3
[0493] Example 3: 2-(2-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl ) ethyl) phenyl) acetamide (3)
[0494]
[0495] 2-(2-(2-(2-((4-(Piperazin-1-yl)phenyl)amino)-5-(trifluoro A suspension of methyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (1) (0.015g, 0.031mmol) was added with 37% aqueous formaldehyde (0.005mL, 0.062mmol) followed by triacetoxy Sodium borohydride (0.033 g, 0.155 mmol). The reaction was stirred at room temperature for 1.5 h, the volatiles were removed in vacuo and washed with EtOAc (15 mL) and saturated NaHCO 3 The residue was diluted with aqueous solution (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2x10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO 4 ), filtered and concentrated in vacuo to yield the title compound (3) (14.5 mg, 97% yield) as a pale yellow solid; 1 H NMR (400MHz, d 6 -DMSO)δ9.97(s,1H),8.60(s,1H),7.57(d,J=9.0Hz,2H),7.4...
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