3-oxa-8-azabicyclo[3.2.1]octane;hydrochloride

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (0.91 g, 2.5 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.37 g, 2.5 mmol) in ethanol (13 mL) was treated with triethylamine (1 mL) and heated in a microwave reactor for 20 minutes at 130° C. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+ The reaction mixture was purified by automated flash chromatography (methanol/chloroform)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH2Cl2 (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol) and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room temperature over night. The reaction mixture was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white solid (3.0 g, 96% yield). MS (ESI) m/z 312.1. The reaction mixture was washed with water and brine dried over MgSO4 The solvent was removed in vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (34 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the titled compound (30 mg, 0.038 mmol, 34% yield) consistent by LCMS and NMR, with sufficient purity by HPLC. The reaction was purified by preparative reverse phase HPLC on a C18 column concentrated

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.18 g, 0.49 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (approximately 100 mg, 0.67 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (750 μL, 5.7 mmol) and was then heated in the microwave reactor for 10 minutes at 130° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol. MS (ES+): 400.3 (M+H)+ The reaction mixture was concentrated to dryness under reduced pressure the residue was purified by reverse-phase high performance liquid chromatography a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.18 g, 0.49 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (approximately 100 mg, 0.67 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (750 μL, 5.7 mmol) and was then heated in the microwave reactor for 10 minutes at 130° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol. MS (ES+): 400.3 (M+H)+ The reaction mixture was concentrated to dryness under reduced pressure the residue was purified by reverse-phase high performance liquid chromatography a gradient elution of 20% acetonitrile/80% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 150-mL sealed tube containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.72 g, 2.0 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.33 g, 2.2 mmol) in ethanol (20 mL) was added triethylamine (1.0 mL, 2.2 mmol). The mixture was heated with a heat gun until all solid material was dissolved, then mixture was allowed to cool, at which time a precipitate was formed. The solid was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide 8-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a pale yellow solid (0.59 g, 68%). MS (ES+): 435.0 (M+H)+ To a 150-mL sealed tube containing The mixture was heated with a heat gun until all solid material was dissolved to cool, at which time a precipitate was formed The solid was collected by Buchner filtration washed with methanol dried under house vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride for 100 minutes in Step 1 to give the title compound (14.2 mg, 24% over two steps). LC-MS (Method G): m/z=408.1 [M+H]+; 3.32 min. 1H-NMR (400 MHz, DMSO): δ 13.40 (s, 1H), 8.19 (d, J=4.3, 1H), 7.90 (d, J=5.7, 1H), 7.28 (s, 1H), 7.24-7.13 (m, 2H), 5.54-5.45 (m, 1H), 4.51 (s, 2H), 3.86-3.73 (m, 2H), 3.70 (d, J=10.6, 2H), 3.59-3.46 (m, 4H), 2.13-2.01 (m, 2H), 2.01-1.93 (m, J=6.9, 2H), 1.93-1.84 (m, 2H), 1.76-1.60 (m, 2H). Prepared for 100 minutes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (80 g), triethylamine (113 mL) and DMF (2000 mL) were added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (127 g) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (42.3 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution at 0° C. The obtained solid was collected by filtration, and washed with saturated aqueous sodium bicarbonate solution, water, ethanol and methyl tert-butyl ether to give the title compound (104 g). The obtained solid was collected by filtration washed with saturated aqueous sodium bicarbonate solution, water, ethanol and methyl tert-butyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Cyclopropyl-8-(1,3-oxazol-5-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (135 mg) was dissolved in DMF (4 mL), and HATU (229 mg), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (113 mg) and triethylamine (91 μL) were added thereto. The reaction mixture was stirred at room temperature for 1 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (43 mg). the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) the obtained solid was recrystallized from ethyl acetate/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (300 mg) in DMF (6 mL) were added HATU (443 mg) and triethylamine (0.311 mL), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (160 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (315 mg). the mixture was stirred at room temperature for 30 min the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (300 mg) in DMF (6 mL) were added HATU (443 mg) and triethylamine (0.311 mL), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (160 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (315 mg). the mixture was stirred at room temperature for 30 min the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.1064 g, 0.7112 mmol) in ethanol (2 mL) was added to 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.1 g, 0.3556 mmol). triethylamine (0.250 mL, 1.778 mmol) was added and the mixture was stirred overnight at room temperature. DCM (2 mL) was added to form a complete solution and the mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in DCM (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with DCM (2×2 mL). The combined organic layers were evaporated to give a brown oil. Mass: 162 mg. This was purified by silica chromatography (10 g cartridge; eluent petrol/ethyl acetate 0 to 15%; all output collected) and the second eluting peak isolated to give 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a white solid (111 mg). LCMS: RT=4.95 min. M+1=358. to form a complete solution the mixture was stirred overnight at room temperature The solvent was evaporated The residue was dissolved in DCM (2 mL) The layers were separated the aqueous was extracted with DCM (2×2 mL) The combined organic layers were evaporated to give a brown oil This was purified by silica chromatography (10 g cartridge all output collected) and the second eluting peak isolated