tert-butyl (2S)-2-(2-methylpropyl)piperazine-1-carboxylate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (2-aminopyridin-3-yl)(6-chloro-3-(trifluoromethyl)pyridin-2-yl)methanone (2.12 g, 7.028 mmol), potassium carbonate (1.166 g, 8.434 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (1.874 g, 7.731 mmol) and dimethylformamide (4 mL). The reaction mixture was heated under microwave irradiation at 90° C. for 50 minutes. The reaction mixture was cooled down to room temperature and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and partitioned between dichloromethane and a saturated solution of sodium carbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (2.203 g, 77% yield). The reaction mixture was cooled down to room temperature partitioned between a saturated solution of sodium bicarbonate and ethyl acetate The organic extract was washed with brine dried over magnesium sulfate filtered concentrated in vacuo trifluoroacetic acid (8 ml) was added The reaction mixture was concentrated to dryness partitioned between dichloromethane The organic extract was dried over magnesium sulfate filtered concentrated in vacuo The residue was purified on silica gel by flash column chromatography

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpiperazine (384 mg, 1.6 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil: 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2)

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpiperazine (384 mg, 1.6 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil: 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,6-diiodopyrazine (1 g, 3.013 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (949.3 mg, 3.917 mmol) and K2CO3 (624.7 mg, 4.520 mmol) in DMF (5 mL) was heated to 90° C. and stirred for 17 hrs. It was then allowed to cool and diluted with ethyl acetate and water, further washed organic layer with water and brine, dried (MgSO4) and concentrated to give an orange oil. It was then columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-tert-butyl 4-(6-iodopyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate as a yellow oil 1.05 g, 78%). ES+ 447. 1HNMR (CDCl3) 0.98 (6H, d), 1.23-1.45 (2H, m), 1.55-1.63 (1H, m), 2.91-3.00 (1H, m), 3.03-3.21 (2H, m), 3.98-4.20 (3H, m), 4.25 (1H, brs), 7.95 (1H, s), 8.06 (1H, s). to cool dried (MgSO4) concentrated to give an orange oil

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,6-diiodopyrazine (1 g, 3.013 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (949.3 mg, 3.917 mmol) and K2CO3 (624.7 mg, 4.520 mmol) in DMF (5 mL) was heated to 90° C. and stirred for 17 hrs. It was then allowed to cool and diluted with ethyl acetate and water, further washed organic layer with water and brine, dried (MgSO4) and concentrated to give an orange oil. It was then columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-tert-butyl 4-(6-iodopyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate as a yellow oil 1.05 g, 78%). ES+ 447. 1HNMR (CDCl3) 0.98 (6H, d), 1.23-1.45 (2H, m), 1.55-1.63 (1H, m), 2.91-3.00 (1H, m), 3.03-3.21 (2H, m), 3.98-4.20 (3H, m), 4.25 (1H, brs), 7.95 (1H, s), 8.06 (1H, s). to cool dried (MgSO4) concentrated to give an orange oil

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

Procedure: 2,4-dibromo-5-methyl-thiazole (1.189 g, 3.563 mmol), (S)—N-Boc-2-isobutylpiperazine (863.5 mg, 3.563 mmol) and potassium carbonate (1.477 g, 10.69 mmol) in DMF (15 mL) were heated at 95° C. for 18 h. Cooled to rt, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity); 1H NMR DMSO-d6 δ 0.90 (t, 6H), 1.36-1.31 (br m, 2H), 1.42 (s, 9H), 1.46-1.42 (masked signal, 1H), 2.18 (s, 3H), 3.02-2.91 (m, 2H), 3.14 (dd, 1H), 3.60 (d, 1H), 3.78-3.68 (m, 1H), 3.86 (d, 1H), 4.19 (br s, 1H); ES+ 420.11. washed with water, brine dried (MgSO4) filtered concentrated in vacuo Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-bromothiazol-2-yl)-1-trityl-pyrazolo[5,4-b]pyridine (234 mg, 0.4470 mmol), sodium tert-butoxide (60.14 mg, 0.6258 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (130.0 mg, 0.5364 mmol), Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) in toluene (3 mL) were heated in microwave for 2 h at 100° C. Added more Pd2 dba3 (4.093 mg, 0.004470 mmol) and RUPHOS (8.343 mg, 0.01788 mmol) and heated at 100° C. for a further 1 h in microwave. Cooled to room temperature, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (12 g SiO2, 0 to 15% EtOAc/petrol) to leave product as a luminous green sticky oil (149 mg, 49%); 1H NMR DMSO-d6 δ 1.01 (dd, 6H), 1.53 (s, 9H), 1.69-1.57 (m, 2H), 1.81-1.76 (m, 1H), 2.80 (td, 1H), 2.94 (dd, 1H), 3.28 (t, 1H), 3.81 (d, 1H), 3.90 (d, 1H), 4.09 (br s, 1H), 4.37 (br s, 1H), 7.15 (dd, 1H), 7.28 (s, 16H), 8.29 (dd, 1H), 8.70 (dd, 1H); ES+ 685.47. Cooled to room temperature washed with water, brine dried (MgSO4) filtered concentrated in vacuo Crude product purified by flash chromatography (12 g SiO2, 0 to 15% EtOAc/petrol)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,6-diiodopyrazine (1 g, 3.013 mmol), tert-butyl (2S)-2-isobutylpiperazine-1-carboxylate (949.3 mg, 3.917 mmol) and K2CO3 (624.7 mg, 4.520 mmol) in DMF (5 mL) was heated to 90° C. and stirred for 17 hrs. It was then allowed to cool and diluted with ethyl acetate and water, further washed organic layer with water and brine, dried (MgSO4) and concentrated to give an orange oil. It was then columned on silica gel eluting with 1:1 EtOAc/hexanes to give (S)-tert-butyl 4-(6-iodopyrazin-2-yl)-2-isobutylpiperazine-1-carboxylate as a yellow oil 1.05 g, 78%). ES+ 447. 1HNMR (CDCl3) 0.98 (6H, d), 1.23-1.45 (2H, m), 1.55-1.63 (1H, m), 2.91-3.00 (1H, m), 3.03-3.21 (2H, m), 3.98-4.20 (3H, m), 4.25 (1H, brs), 7.95 (1H, s), 8.06 (1H, s). to cool dried (MgSO4) concentrated to give an orange oil

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (2-aminopyridin-3-yl)(6-chloro-3-(trifluoromethyl)pyridin-2-yl)methanone (2.12 g, 7.028 mmol), potassium carbonate (1.166 g, 8.434 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (1.874 g, 7.731 mmol) and dimethylformamide (4 mL). The reaction mixture was heated under microwave irradiation at 90° C. for 50 minutes. The reaction mixture was cooled down to room temperature and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and partitioned between dichloromethane and a saturated solution of sodium carbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (2.203 g, 77% yield). The reaction mixture was cooled down to room temperature partitioned between a saturated solution of sodium bicarbonate and ethyl acetate The organic extract was washed with brine dried over magnesium sulfate filtered concentrated in vacuo trifluoroacetic acid (8 ml) was added The reaction mixture was concentrated to dryness partitioned between dichloromethane The organic extract was dried over magnesium sulfate filtered concentrated in vacuo The residue was purified on silica gel by flash column chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (2-aminopyridin-3-yl)(6-chloro-3-(trifluoromethyl)pyridin-2-yl)methanone (2.12 g, 7.028 mmol), potassium carbonate (1.166 g, 8.434 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (1.874 g, 7.731 mmol) and dimethylformamide (4 mL). The reaction mixture was heated under microwave irradiation at 90° C. for 50 minutes. The reaction mixture was cooled down to room temperature and partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and partitioned between dichloromethane and a saturated solution of sodium carbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a pale yellow oil (2.203 g, 77% yield). The reaction mixture was cooled down to room temperature partitioned between a saturated solution of sodium bicarbonate and ethyl acetate The organic extract was washed with brine dried over magnesium sulfate filtered concentrated in vacuo trifluoroacetic acid (8 ml) was added The reaction mixture was concentrated to dryness partitioned between dichloromethane The organic extract was dried over magnesium sulfate filtered concentrated in vacuo The residue was purified on silica gel by flash column chromatography

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpiperazine (384 mg, 1.6 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil: 1H NMR and MS consistent. formed was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-ethoxy-3-(6-fluoro-2-pyridyl)-1-trityl-pyrazolo[3,4-d]pyrimidine (139 mg, 0.27 mmol), (S)-tert-butyl 2-isobutylpiperazine-1-carboxylate (201.5 mg, 0.83 mmol) and DIPEA (214.9 mg, 289.6 μL, 1.66 mmol) were dissolved in DMSO (3.5 mL) and the reaction mixture was heated at 150° C. for 5 hours under microwave conditions. After this time, the reaction mixture was allowed to cool and DCM and water were added. The organic layer was separated dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM). The fractions were isolated and concentrated in vacuo. The residue was taken up in DCM (10 mL) and triethylsilane (128.8 mg, 176.9 μL, 1.11 mmol) and TFA (631.9 mg, 427.0 μL, 5.54 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated and freeze-dried to give the di-TFA salt of the title compound as a solid (1.9 mg, 1% Yield). H1 NMR (400 MHz, DMSO) δ 14.13 (brs, 1H), 8.98-8.60 (m, 2H), 8.58 (s, 1H), 7.83-7.67 (m, 1H), 7.31 (brs, 1H), 4.66-4.48 (m, 3H), 3.80-3.00 (m, 5H), 3.00-2.88 (m, 1H), 1.86-1.72 (m, 1H), 1.54-1.31 (m, 5H), 0.91 (d, J=6.5 Hz, 3H) and 0.85 (d, J=6.5 Hz, 3H) ppm; MS (ES+) 382.0. to cool The organic layer was separated dried (Na2SO4) filtered concentrated in vacuo The crude mixture was purified by column chromatography (ISCO Companion™, 40 g column, eluting with MeOH/DCM) The fractions were isolated concentrated in vacuo After this time the reaction mixture was concentrated in vacuo The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated freeze-dried