1-methylcyclopropan-1-amine

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

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

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

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

Procedure: A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), 1-methylcyclopropanamine (150 mg, 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether (2 mL) then decanted and dried to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (125 mg, crude). LCMS: (M+H)+=285/287. The reaction mixture was evaporated to dryness product extracted with ethyl acetate (3×50 mL) organics combined dried with sodium sulfate filtered concentrated The residue was triturated with petroleum ether (2 mL) then decanted dried

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

Procedure: A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 1-methylcyclopropanamine (0.04 g, 0.56 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours, and then HATU (0.114 g, 0.3 mmol) was added. The final reaction mixture was stirred for another 15 hours. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then 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: 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.035 g, 43%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 8.46-8.44 (m, 2H), 8.04 (s, 1H), 7.38 (d, 1H, J=8.7 Hz), 4.20 (s, 3H), 1.50 (s, 3H), 0.90-0.82 (m, 4H). The final reaction mixture was stirred for another 15 hours The solvent was removed under reduced pressure at 70° C The residue was triturated with water purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% 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: A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 1-methylcyclopropanamine (0.04 g, 0.56 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours, and then HATU (0.114 g, 0.3 mmol) was added. The final reaction mixture was stirred for another 15 hours. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then 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: 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.035 g, 43%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 8.46-8.44 (m, 2H), 8.04 (s, 1H), 7.38 (d, 1H, J=8.7 Hz), 4.20 (s, 3H), 1.50 (s, 3H), 0.90-0.82 (m, 4H). The final reaction mixture was stirred for another 15 hours The solvent was removed under reduced pressure at 70° C The residue was triturated with water purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% 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: A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 1-methylcyclopropanamine (21 mg, 0.29 mmol), HATU (110 mmol, 0.29 mmol) and DIPEA (46 mg, 0.36 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 54.9%) as a white solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 9.09 (s, 1H), 8.54 (s, 1H), 8.48-8.42 (m, 2H), 7.71 (dd, 1H, J=9.9, 2.1 Hz), 7.25-7.24 (m, 1H), 4.16 (s, 3H), 1.49 (s, 3H), 0.81 (brs, 2H), 0.80 (brs, 2H). The solvent was evaporated at 70° C. under reduced pressure the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted dried

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

Procedure: A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 1-methylcyclopropanamine (21 mg, 0.29 mmol), HATU (110 mmol, 0.29 mmol) and DIPEA (46 mg, 0.36 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 54.9%) as a white solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 9.09 (s, 1H), 8.54 (s, 1H), 8.48-8.42 (m, 2H), 7.71 (dd, 1H, J=9.9, 2.1 Hz), 7.25-7.24 (m, 1H), 4.16 (s, 3H), 1.49 (s, 3H), 0.81 (brs, 2H), 0.80 (brs, 2H). The solvent was evaporated at 70° C. under reduced pressure the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted dried

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

Procedure: Bis-(2-oxoethyl)carbamicacidbenzylester (0.90 g, 3.81 mmol) and 1-methyl-cyclopropylamine (0.41 g, 3.81 mmol) were dissolved in dichloroethane (20 mL), and sodium triacetoxyborohydride (3.23 g, 15.24 mmol) was added thereto. The mixture was stirred for 4 days at room temperature. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 20 minutes, and then extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, n-hexane/ethyl acetate=5/1 to ethyl acetate), to obtain the title compound (509 mg, 49%) as an oily matter. the mixture was stirred for 20 minutes extracted with methylene chloride The extract was washed with saturated brine dried over anhydrous sodium sulfate the solvent was concentrated under reduced pressure The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 25S, n-hexane/ethyl acetate=5/1 to ethyl acetate)

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

Procedure: A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), 1-methylcyclopropanamine (150 mg, 2.2 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined dried with sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether (2 mL) then decanted and dried to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (125 mg, crude). LCMS: (M+H)+=285/287. The reaction mixture was evaporated to dryness product extracted with ethyl acetate (3×50 mL) organics combined dried with sodium sulfate filtered concentrated The residue was triturated with petroleum ether (2 mL) then decanted dried

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

Procedure: A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 1-methylcyclopropanamine (0.04 g, 0.56 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours, and then HATU (0.114 g, 0.3 mmol) was added. The final reaction mixture was stirred for another 15 hours. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then 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: 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.035 g, 43%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 8.46-8.44 (m, 2H), 8.04 (s, 1H), 7.38 (d, 1H, J=8.7 Hz), 4.20 (s, 3H), 1.50 (s, 3H), 0.90-0.82 (m, 4H). The final reaction mixture was stirred for another 15 hours The solvent was removed under reduced pressure at 70° C The residue was triturated with water purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% 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: A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 1-methylcyclopropanamine (21 mg, 0.29 mmol), HATU (110 mmol, 0.29 mmol) and DIPEA (46 mg, 0.36 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted and dried to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45 mg, 54.9%) as a white solid. MS: (M+H)+=365; 1H NMR (300 MHz, DMSO): δ 9.09 (s, 1H), 8.54 (s, 1H), 8.48-8.42 (m, 2H), 7.71 (dd, 1H, J=9.9, 2.1 Hz), 7.25-7.24 (m, 1H), 4.16 (s, 3H), 1.49 (s, 3H), 0.81 (brs, 2H), 0.80 (brs, 2H). The solvent was evaporated at 70° C. under reduced pressure the residue was triturated with dichloromethane (10 mL), methanol (10 mL) then decanted dried