Pyrazoloquinolinone derivatives, process for their preparation and therapeutic use
A technology of pyrazolo and quinoline, which is applied in the field of pyrazoloquinolinone derivatives, and can solve problems such as large toxicity
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Embodiment 1
[0877] Example 1: 7-(pyridin-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinoline -4-Kone Hydrochloride (Compound 1)
[0878] Step 1.1. (3E,Z)-7-Bromo-3-[(dimethylamino)methylene]quinoline-2,4(1H,3H)-dione
[0879] To a suspension of 7-bromo-4-hydroxyquinolin-2(1H)-one (12.3 g, 51.2 mmol) in 250 mL of toluene in a three-necked flask was added N,N-dimethylformamide Dimethanol (103 mL, 0.77 mol). The reaction mixture was stirred at 80 °C for 24 hours, then cooled to room temperature and filtered. The resulting solid was washed with toluene and dried in vacuo to yield 13.5 g of (3E,Z)-7-bromo-3-[(dimethylamino)methylene]quinoline-2,4(1H,3H)- Diketone in the form of beige solid (yield: 89%).
[0880] LCMS (Method C): MH + = 295.0, RT = 5.86 minutes
[0881] Step 1.2.7-Bromo-4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde
[0882] To (3E, Z)-7-bromo-3-[(dimethylamino)methylene]quinoline-2,4(1H,3H)-dione (5 g, 16.9 mmol) at 0°C at 50 Phosphorus oxychlori...
Embodiment 2
[0900] Example 2: 7-(2-aminopyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c ] Quinolin-4-one hydrochloride (compound 2)
[0901] Step 2.1.7-(3-Aminopyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5 -Dihydro-4H-pyrazolo[4,3-c]quinolin-4-one
[0902] 7-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyridine under argon Azolo[4,3-c]quinolin-4-one and 7-bromo-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl) -1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (9.7g, 19.4mmol), potassium carbonate (5.3g, 38.4mmol), 3-(4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (4.82g, 21.9mmol), 14ml of anhydrous DMF, 1.8ml of Gas of water and catalyst PdCl 2 (dppf) (0.79 g, 0.96 mmol) was added sequentially to the microwave reactor. The reactor was sealed and the mixture was stirred at 130 °C for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc, poured into saturated NaHCO 3 aq...
Embodiment 3
[0908] Example 3: 7-(pyridin-3-yloxy)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c] Quinolin-4-one hydrochloride (compound 99)
[0909] Step 3.1.7-Bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinoline -4-one and 7-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c] Quinolin-4-one
[0910] To 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [as described in step 1.3.] (1.49 g, 5.64 mmol) in 30 mL of anhydrous To the suspension in DMF were added cesium carbonate (2.0 g, 6.21 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (10 mL, 56.4 mmol) dropwise. The reaction mixture was stirred at room temperature under nitrogen for 16 hours, then poured into water and extracted with a THF / EtOAc mixture (50 / 50). The organic phase was washed with saturated NaCl aqueous solution and washed with Na 2 SO 4 Dry, filter and concentrate to dryness. The resulting residue was purified by flash chromatography on silica gel (D...
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