Triazolopyridazine compound and application thereof
A compound and triazolo technology, applied in the field of triazolopyridazine compounds, can solve problems such as single structure
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Embodiment 1
[0130] Method A
[0131] 3-(7-(tert-butyl)-6-((6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methoxy)- [1,2,4]Triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole
[0132]
[0133] 3-(7-(tert-butyl)-6-(((6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)methoxy)-[1,2 ,4]Triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole (100 mg, 0.25 mmol, intermediate 38) was dissolved in methanol (1.5 mL), cyano was added Sodium borohydride (46 mg, 0.75 mmol), the mixture was stirred at room temperature for 10 minutes, then 37% aqueous formaldehyde solution (1 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. An appropriate amount of 1 M aqueous sodium hydroxide solution was added to the reaction solution to quench the reaction, Dichloromethane (20 mL) was extracted three times, the organic phases were combined, washed three times with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound...
Embodiment 6
[0135] Method B
[0136] 3-(7-(tert-butyl)-6-((6-(1-ethylpyrrolidin-3-yl)pyridin-2-yl)methoxy)-[1,2,4]triazole [4,3-b]pyridazin-3-yl)-5-methylisoxazole
[0137]
[0138] 3-(7-(tert-butyl)-6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole (100 mg , 0.34 mmol), (6-(1-ethylpyrrolidin-3-yl)pyridin-2-yl)methanol (60 mg, 0.34 mmol) and cesium carbonate (225 mg, 0.7 mmol) were sequentially added to acetonitrile (5 mL) , the mixture was reacted at 50 °C overnight. The reaction solution was added to water (20 mL), extracted three times with dichloromethane (20 mL), dried and concentrated, and purified by preparative thin layer chromatography (dichloromethane / methanol=10 / 1) to obtain the title compound (5 mg, yield 4%) as a white solid ). 1 HNMR (400MHz, DMSO-d6) δ 8.15 (s, 1 H), 7.86 (t, J=7.58 Hz, 1 H), 7.55 (d, J=7.83 Hz, 1 H), 7.40 (d, J=7.34 Hz, 1 H), 6.97 (s, 1 H), 5.61 (s, 2 H), 3.68 - 3.78 (m, 1 H), 3.59 (br. s., 2 H), 3.15 - 3.24 (m, 2 H), 3.06 (d, J=...
Embodiment 23
[0140] Method E
[0141] 3-(7-(tert-butyl)-6-(((2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methoxy)- [1,2,4]Triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole hydrochloride
[0142]
[0143] 3-(7-(tert-butyl)-6-((2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methoxy)-[1,2, 4] Triazolo[4,3-b]pyridazin-3-yl)-5-methylisoxazole (60 mg, 0.15 mmol) was dissolved in a mixed solvent of dichloromethane and methanol (1 mL / 1 mL), divided into Sodium cyanoborohydride (30 mg, 0.45 mmol) and 37% formaldehyde solution (40 mg, 0.45 mmol) were added in batches, and the mixture was stirred at room temperature for half an hour. The reaction solution was quenched by adding 1M aqueous sodium hydroxide solution, extracted three times with an appropriate amount of dichloromethane, the organic phases were combined, 4M hydrogen chloride ethyl acetate solution (0.2 mL) was added, the precipitated solid was collected by filtration, and dried to obtain the title compound (24 mg) , yield 32%). ...
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