1-methylazetidin-3-amine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylazetidin-3-amine

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylazetidin-3-amine

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.135 mmol), 1-methylazetidin-3-amine (87 mg, 0.405 mmol), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-((1-methyl-3-azetidinyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (MeOH-d4) δ: 7.80-7.85 (m, 1H), 7.63-7.68 (m, 1H), 7.36-7.42 (m, 1H), 6.93 (s, 1H), 3.59-3.65 (m, 2H), 3.22-3.26 (m, 2H), 3.11-3.14 (m, 1H), 2.97-3.04 (m, 2H), 2.59 (s, 3H), 2.01 (s, 3H). m/z (ESI, +ve) 363.2 (M+H)+. Prepared similarly to Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Prepared similarly to that described in Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.135 mmol), 1-methylazetidin-3-amine (87 mg, 0.405 mmol), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-((1-methyl-3-azetidinyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (MeOH-d4) δ: 7.80-7.85 (m, 1H), 7.63-7.68 (m, 1H), 7.36-7.42 (m, 1H), 6.93 (s, 1H), 3.59-3.65 (m, 2H), 3.22-3.26 (m, 2H), 3.11-3.14 (m, 1H), 2.97-3.04 (m, 2H), 2.59 (s, 3H), 2.01 (s, 3H). m/z (ESI, +ve) 363.2 (M+H)+. Prepared similarly to Purification by high-throughput parallel purification (Rilas Technologies, Woburn, Mass.)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylene chloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL, 0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL, 0.0003767 mol). The solution was stirred for 1 h at room temperature and concentrated in vacuo. The acid chloride was re-dissolved in methylene chloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of 1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine (0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol). The reaction was stirred at room temperature for 3 h. Brine and methylene chloride were added and the aqueous layer was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 453 (90.1 mg) as a beige solid. MS(ESI+) 533.2. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H), 5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m, 4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6, 6H) concentrated in vacuo The reaction was stirred at room temperature for 3 h the aqueous layer was extracted 3× with methylene chloride dried with MgSO4 concentrated The crude was purified by reverse-phase HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylene chloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL, 0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL, 0.0003767 mol). The solution was stirred for 1 h at room temperature and concentrated in vacuo. The acid chloride was re-dissolved in methylene chloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of 1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine (0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol). The reaction was stirred at room temperature for 3 h. Brine and methylene chloride were added and the aqueous layer was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 453 (90.1 mg) as a beige solid. MS(ESI+) 533.2. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H), 5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m, 4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6, 6H) concentrated in vacuo The reaction was stirred at room temperature for 3 h the aqueous layer was extracted 3× with methylene chloride dried with MgSO4 concentrated The crude was purified by reverse-phase HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylazetidin-3-amine

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1-methylazetidin-3-amine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propionic acid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylene chloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL, 0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL, 0.0003767 mol). The solution was stirred for 1 h at room temperature and concentrated in vacuo. The acid chloride was re-dissolved in methylene chloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of 1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine (0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol). The reaction was stirred at room temperature for 3 h. Brine and methylene chloride were added and the aqueous layer was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 453 (90.1 mg) as a beige solid. MS (ESI+) 533.2. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H), 5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m, 4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6, 6H) concentrated in vacuo The reaction was stirred at room temperature for 3 h the aqueous layer was extracted 3× with methylene chloride dried with MgSO4 concentrated The crude was purified by reverse-phase HPLC

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (100 mg, 0.29 mmol) in dichloromethane (6.7 mL) was added N-hydroxybenzotriazole (59.7 mg, 0.44 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (169.7 mg, 0.88 mmol), followed by 4-methylmorpholine (89.5 mg, 0.88 mmol) and the resultant mixture was stirred at room temperature for 40 min. Then 1-methylazetidin-3-amine (30.5 mg, 0.35 mmol) was added to the flask and the reaction mixture was stirred for an additional 60 min, LC-MS showed the reaction was complete. The reaction was quenched with water, separated, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 129 mg of methyl 3,3-dimethyl-2-(3-(1-methylazetidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was washed with ether to afford 103 mg desired product as a white powder, yield: 85.8%. The reaction was quenched with water separated the aqueous layer was extracted with dichloromethane (twice) The combined organic layers were washed with 2% sodium hydroxide aqueous solution (twice) and brine (3 times) dried over anhydrous magnesium sulfate Removal of the solvent in vacuo