2-methyl-2-piperazin-1-ylpropan-1-ol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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: A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-1-ylpropan-1-ol (48 mg, 0.31 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (133 μL, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%). LCMS (method H): RT 2.02 min [M+H]+ 455.3 was washed with MeOH the product eluted with 2M NH3/MeOH/DCM The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%)

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

実験手順: To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2 H, s), 2.90 (5 H, t, J=4.78 Hz), 2.38-2.13 (4 H, m), 1.03 (6 H, s) was washed with MeOH/DCM the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%)

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

実験手順: A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)acetic acid (80 mg, 0.25 mmol), 2-methyl-2-piperazin-1-ylpropan-1-ol (48 mg, 0.31 mmol), HATU (116 mg, 0.31 mmol) and DIPEA (133 μL, 0.76 mmol) in DMF (3 mL) was stirred at r.t. for 65 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH/DCM. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (65 mg, 56%)._LCMS (method H): RT 2.02 min [M+H]+ 455.3 was washed with MeOH the product eluted with 2M NH3/MeOH/DCM The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%)

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

実験手順: To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2H, s), 2.90 (5H, t, J=4.78 Hz), 2.38-2.13 (4H, m), 1.03 (6H, s) was washed with MeOH/DCM the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%)

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

実験手順: A mixture of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid benzyl ester (3.0 g, 10.3 mmol) in methanol (70 mL) and palladium on charcoal (0.5 g, 10%) was hydrogenated at room temperature at 40 p.s.i. overnight. The mixture was filtered through Celite and the filtrate evaporated under reduced pressure to give the title compound (1.55 g, 98%) as a white solid. was hydrogenated at room temperature at 40 p.s.i overnight The mixture was filtered through Celite the filtrate evaporated under reduced pressure

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-methyl-2-piperazin-1-ylpropan-1-ol (71 mg, 0.45 mmol) and NEt3 (105 μL, 0.75 mmol) in DCM (10 mL) at 0° C. was added 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (97 mg, 0.15 mmol) and the resulting mixture warmed to RT after 10 min then stirred for 16 h. The reaction mixture was washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM then C18, gradient 10-40% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then freeze-dried from MeCN/H2O to afford 138 (20 mg, 26%) as a white solid. LCMS: RT 2.86 min [M+H]+ 516.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.37 Hz), 7.88 (1H, s), 7.69 (1H, s), 7.64 (1H, dd, J=8.60, 2.40 Hz), 7.19 (1H, d, J=8.61 Hz), 5.86-5.84 (1H, m), 4.62-4.57 (2H, m), 4.54-4.50 (2H, m), 3.28-3.11 (6H, m), 2.69 (4H, brd s), 1.60 (6H, d, J=6.63 Hz), 1.03 (6H, brd s) The reaction mixture was washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM was washed with MeOH the product eluted with 2M NH3/MeOH then freeze-dried from MeCN/H2O

反応条件: temp:0.00; pressure:0.00; stir: