A class used as gpr17 and cyslt 1 Compounds of dual antagonists, their preparation methods and uses
A compound, C1-C4 technology, applied in the field of compounds used as dual antagonists of GPR17 and CysLT1
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preparation Embodiment 1
[0114] Preparation Example 1 (compound number CHY90)
[0115]
[0116]Add 3,5-dichloroaniline (5g, 30.8mmol) into a single-necked round-bottom flask, add water (20mL), add concentrated hydrochloric acid (20mL) dropwise under ice-water bath conditions, after the dropwise addition, add ice water dropwise Cooled sodium nitrite (2.34g, 33.91mmol) aqueous solution 11mL, after dripping, stirred for 20 minutes under ice-water bath condition; Add ethyl 2-methylacetoacetate (6.6g, 45.78 mmol), add ethanol (25mL), dropwise add potassium hydroxide (15.5g, 0.28mol) aqueous solution 30mL under ice-water bath, dropwise, add dropwise in the first bottle after stirring for 15 minutes under ice-water bath condition, 40 Stir at ℃ for 15 minutes, cool to room temperature, extract with ether (20mL×3 times), combine the organic phases, wash with saturated brine (20mL), anhydrous MgSO 4 After drying, the solvent was removed under reduced pressure and purified by silica gel column chromatography...
preparation Embodiment 2
[0129] Preparation example two (compound number CHY98)
[0130]
[0131] Compound 38 (100mg, 0.37mmol) was added to 5mL of methanol, and it became cloudy. Sodium borohydride (28mg, 0.73mmol) was added in an ice-water bath and reacted at room temperature for 8 hours. If the reaction was not complete by TLC, an additional 50mg of sodium borohydride was added. , overnight at room temperature, TLC detected that the reaction was complete, and the methanol was spun off under reduced pressure, diluted with water (10 mL), filtered, and dried to obtain compound 37 (100 mg, 100%, white solid). 1 H NMR (300MHz, DMSO-d 6 ):δ8.40(d,J=9.0Hz,1H),8.03-7.31(m,10H),5.26(s,1H),4.56(s,2H).
[0132] Compound M8 (20mg, 0.050mmol) was dissolved in anhydrous DMF (1mL), compound 37 (16mg, 0.058mmol), DCC (16mg, 0.078mmol), DMAP (4mg, 0.033mmol) were added respectively, and reacted overnight at room temperature. Add ethyl acetate (5mL) to dilute, wash with water (5mL×2 times), wash with saturated ...
preparation Embodiment 3
[0136] Preparation Example Three (Compound No. CHY96)
[0137]
[0138] Add 4-pentyn-1-ol (100mg, 1.19mmol) and pyridine (141mg, 1.57mmol) to anhydrous dichloromethane (2mL) successively, add p-toluenesulfonyl chloride (248mg, 1.30mmol) dropwise under ice-water bath dichloromethane (2mL) solution, reacted at room temperature for 2 hours, washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, anhydrous MgSO 4 After drying, concentration and purification by silica gel column chromatography (PE / EtOAc=10:1), compound M11 (73 mg, 23.8%, colorless oil) was obtained. 1 H NMR (300MHz, CDCl3): δ7.81-7.78(m, 2H), 7.36-7.33(m, 2H), 4.15(t, J=6Hz, 2H), 2.45(s, 3H), 2.25(td, J=6.9,2.7 Hz,2H),1.90-1.81(m,2H),1.58(s,2H).
[0139] Dissolve compound M11 (13mg, 0.055mmol) in 0.5mL DMF, add compound M8 (20mg, 0.050mmol) and sodium bicarbonate (12mg, 0.15mmol), react overnight at room temperature, no reaction detected by TLC, add cesium carbonate (24mg , 0.074mm...
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