A class of deuterated 3-cyanoquinoline compounds, pharmaceutical compositions, preparation methods and uses thereof
A technology of compounds and substituents, applied in the direction of drug combinations, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of short plasma half-life and poor metabolic properties
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Embodiment 1
[0229] Example 1: 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-deuteromethyl-piperazin-1-yl)-propane Oxy]-6-methoxy-quinoline-3-methylcyanide
[0230]
[0231]4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)-3-carbonitrile Quinoline (Intermediate 8) (69mg, 0.13mmol) was dissolved in methanol (2mL), and 37% aqueous formaldehyde (63mg, 0.78mmol) and glacial acetic acid (0.1mL) were successively added thereto, and the reaction solution was stirred at room temperature for 2 hours Then sodium borodeuteride (16 mg, 0.39 mmol) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, extracted with dichloromethane, the organic phase was washed with saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtai...
Embodiment 2
[0234] Example 2: 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-dideuteromethyl-piperazin-1-yl)-propane Oxy]-6-methoxy-quinoline-3-methylcyanide
[0235]
[0236] 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)-3-carbonitrile Quinoline (Intermediate 8) (69mg, 0.13mmol) was dissolved in methanol (2mL), to which was added a solution of 20% deuterioformaldehyde (125mg, 0.78mmol) and glacial acetic acid (0.05mL), the reaction solution After stirring at room temperature for 2 hours, solid sodium borohydride (15 mg, 0.39 mmol) was added thereto, and the reaction solution was stirred overnight at room temperature after the addition. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, extracted with dichloromethane, the organic phase was washed with saturated brine, dried, filtered and concentrated under reduced pressure, and the residue was separated and purified by silica gel...
Embodiment 3
[0239] Example 3: 4-(4-chloro-2-cyclopropyl-5-methoxy-phenylamino)-7-[3-(4-trideuteromethyl-piperazin-1-yl)-propane Oxy]-6-methoxy-quinoline-3-methylcyanide
[0240]
[0241] 4-(4-Chloro-2-cyclopropyl-5-methoxy-phenylamino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)-3-carbonitrile Quinoline (Intermediate 8) (69mg, 0.13mmol) was dissolved in methanol (2mL), and a concentration of 20% dideuterioformaldehyde solution (125mg, 0.78mmol) and glacial acetic acid (0.05mL) were added successively to it, and the reaction After the solution was stirred at room temperature for 2 hours, solid sodium borodeuteride (16 mg, 0.39 mmol) was added thereto, and the reaction solution was stirred overnight at room temperature after the addition. After the reaction, the reaction was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was washed with saturated sodium bicarbonate solution, water and saturated brine, dried, filtered and concentr...
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