1-methylcyclobutan-1-amine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 1-methylcyclobutanamine (21.00 mg, 0.25 mmol) was added in one portion at room temperature and the reaction mixture was stirred for 16 hours. The solvent was evaporated at 80° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 13.7%) as an off-white solid. MS: (M+H)+=379; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.10 (s, 1H), 8.47-8.38 (m, 2H), 8.24 (s, 1H), 7.70 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=9.2 Hz), 4.15 (s, 3H), 2.54-2.45 (m, 2H), 2.15-2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (s, 3H). The solvent was evaporated at 80° C. under reduced pressure the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.

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

Procedure: To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 1-methylcyclobutanamine (21.00 mg, 0.25 mmol) was added in one portion at room temperature and the reaction mixture was stirred for 16 hours. The solvent was evaporated at 80° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 13.7%) as an off-white solid. MS: (M+H)+=379; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.10 (s, 1H), 8.47-8.38 (m, 2H), 8.24 (s, 1H), 7.70 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=9.2 Hz), 4.15 (s, 3H), 2.54-2.45 (m, 2H), 2.15-2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (s, 3H). The solvent was evaporated at 80° C. under reduced pressure the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.

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

Procedure: 5-(tert-Butyl)-3′,4′-dichloro-3-(((1-methylcyclobutyl)amino)methyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (from Example 19, Step 1) and 1-methylcyclobutylamine.

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

Procedure: 5-(tert-Butyl)-3′,4′-dichloro-3-(((1-methylcyclobutyl)amino)methyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (from Example 19, Step 1) and 1-methylcyclobutylamine.

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

Procedure: To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 383 mg (4.50 mmol) of 1-methylcyclobutanamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h and then at 90° C. for 2 h. Another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 90° C. for a further 6 h and then at 100° C. for 6 h. Subsequently, another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 100 for a further 20 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 27.2 mg (24% of theory) at 90° C. for 2 h the mixture was stirred in the microwave at 90° C. for a further 6 h at 100° C. for 6 h the mixture was stirred in the microwave at 100 for a further 20 h The solvent was removed under reduced pressure the crude product was purified by means of preparative HPLC

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid (41.0 mg, 0.118 mmol), 1-methylcyclobutylamine (22.5 mg, 0.264 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81.1 mg, 0.156 mmol), N,N-diisopropylethylamine (64 uL, 0.37 mmol), 4-dimethylaminopyridine (2.89 mg, 0.0237 mmol), and N,N-dimethylformamide (2.0 mL, 26 mmol) was stirred at 50° C. for 15 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine, filtered through a plug of silica gel, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.3 mg (78%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide. LCMS (ESI): RT (min)=5.083, M+H=414.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.73 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 2.40-2.29 (m, 5H), 2.13-2.04 (m, 1H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H), 0.91-0.80 (m, 4H). washed with water and brine filtered through a plug of silica gel evaporated in vacuo The crude product was purified via reverse phase HPLC

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzoic acid (41.0 mg, 0.118 mmol), 1-methylcyclobutylamine (22.5 mg, 0.264 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (81.1 mg, 0.156 mmol), N,N-diisopropylethylamine (64 uL, 0.37 mmol), 4-dimethylaminopyridine (2.89 mg, 0.0237 mmol), and N,N-dimethylformamide (2.0 mL, 26 mmol) was stirred at 50° C. for 15 hours. The reaction mixture was poured into ethyl acetate and washed with water and brine, filtered through a plug of silica gel, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.3 mg (78%) of 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide. LCMS (ESI): RT (min)=5.083, M+H=414.2, method=E; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.35 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.73 (dd, J=8.5, 1.5 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 2.40-2.29 (m, 5H), 2.13-2.04 (m, 1H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H), 0.91-0.80 (m, 4H). washed with water and brine filtered through a plug of silica gel evaporated in vacuo The crude product was purified via reverse phase HPLC

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

Procedure: To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 1-methylcyclobutanamine (21.00 mg, 0.25 mmol) was added in one portion at room temperature and the reaction mixture was stirred for 16 hours. The solvent was evaporated at 80° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 13.7%) as an off-white solid. MS: (M+H)+=379; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.10 (s, 1H), 8.47-8.38 (m, 2H), 8.24 (s, 1H), 7.70 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=9.2 Hz), 4.15 (s, 3H), 2.54-2.45 (m, 2H), 2.15-2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (s, 3H). The solvent was evaporated at 80° C. under reduced pressure the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of 375 mg (2.31 mmol) of (R)-2-(tetrazolo [1,5-a]pyrid-6-yl)oxirane and 972 mg (11.42 mmol) of (1-methylcyclobutyl)amine [J. Am. Chem. Soc., 83, 2723 (1961)] in 0.9 ml of absolute ethanol was heated at 70° C. for 3 hours with stirring under nitrogen. The reaction mixture was then concentrated to dryness (wt. 547 mg) and the residue purified by preparative Tlc on silica gel (95:5:1 methylene chloride:methanol:conc. ammonium hydroxide) to give 402 mg of product. The reaction mixture was then concentrated to dryness (wt. 547 mg) the residue purified by preparative Tlc on silica gel (95:5:1 methylene chloride:methanol:conc. ammonium hydroxide)

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

Procedure: 5-(tert-Butyl)-3′,4′-dichloro-3-(((1-methylcyclobutyl)amino)methyl)-[1,1′-biphenyl]-2-ol was prepared as a white solid using the procedure described in Example 5 from 5-(tert-butyl)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (from Example 19, Step 1) and 1-methylcyclobutylamine.