(1S)-1-cyclopropylethanamine

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

Procedure: A solution of (S)-1-cyclopropylethanamine (32 mg, 0.373 mmol), 3 mL of dichloromethane, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (77 mg, 0.169 mmol), 4-dimethylaminopyridine (21 mg, 0.169 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.371 mmol) was stirred 18 h, then concentrated to an off-white solid. The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution; dried over Na2SO4, filtered and concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification. MS: (M+Na)+=547. concentrated to an off-white solid The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution dried over Na2SO4 filtered concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification

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

Procedure: A solution of (S)-1-cyclopropylethanamine (32 mg, 0.373 mmol), 3 mL of dichloromethane, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (77 mg, 0.169 mmol), 4-dimethylaminopyridine (21 mg, 0.169 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.371 mmol) was stirred 18 h, then concentrated to an off-white solid. The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution; dried over Na2SO4, filtered and concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification. MS: (M+Na)+=547. concentrated to an off-white solid The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution dried over Na2SO4 filtered concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropylethanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 1 H) 0.28-0.36 (m, 1 H) 0.36-0.44 (m, 1 H) 0.44-0.53 (m, 1 H) 0.92-1.08 (m, 1 H) 1.25 (d, J=6.82 Hz, 3 H) 2.43 (s, 3 H) 3.39-3.60 (m, 1 H) 7.66 (dd, J=8.08, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=6.57 Hz, 1 H) 8.17 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.59 (d, J=8.08 Hz, 1 H) 8.79-9.05 (m, 1 H) 13.19 (br. s., 1 H). MS m/z [M+H]+ 388.2.

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

Procedure: A mixture of 5-chloropyrazine-2-carboxylic acid (0.5 g, 3 mmol), (1S)-1-cyclopropylethanamine (0.30 g, 3.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.7 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.5 mmol) in methylene chloride (5 mL) was stirred at room temperature overnight (22 h.). The mixture was concentrated under reduced pressure. The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.54 g). LCMS (M+H)+: m/z=226.1. The mixture was concentrated under reduced pressure The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%)

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

Procedure: A mixture of 5-chloropyrazine-2-carboxylic acid (0.5 g, 3 mmol), (1S)-1-cyclopropylethanamine (0.30 g, 3.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.7 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.5 mmol) in methylene chloride (5 mL) was stirred at room temperature overnight (22 h.). The mixture was concentrated under reduced pressure. The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.54 g). LCMS (M+H)+: m/z=226.1. The mixture was concentrated under reduced pressure The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%)

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

Procedure: A mixture of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid (20.0 mg, 0.0365 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.044 mmol) in dichloromethylene (1.0 mL) was added to a mixture of (1S)-1-cyclopropylethanamine (4.7 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol) in methylene chloride (0.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was treated with methylene chloride (1.3 mL) and trifluoroacetic acid (0.6 mL), and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.3 mL). Ethylenediamine (0.086 mL, 1.3 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) (the conditions are already mention before the examples) to afford the desired product. LCMS (M+H)+: m/z=485.2. extracted with dichloromethylene (2×2 mL) The combined organic layers were washed with water (1 mL) concentrated dried under reduced pressure The residue was treated with methylene chloride (1.3 mL) and trifluoroacetic acid (0.6 mL) stirred at room temperature for 1.5 hours The mixture was concentrated under reduced pressure The residue was dissolved in methanol (1.3 mL) The reaction mixture was stirred at room temperature for 2 hours purified by RP-HPLC (pH=10) (the conditions

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

Procedure: (1S)-1-Cyclopropylethanamine (0.50 mL, 5.4 mmol, Alfa Aesar: Cat. #H27499) was added to a mixture of 5-bromopyridine-2-carboxylic acid (1.0 g, 5.0 mmol, Alfa Aesar: Cat. #B25675) in methylene chloride (30.0 mL), followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.4 g, 5.4 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous Na2CO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS (M+H)+: m/z=269.0/271.0. extracted with dichloromethylene (3×20 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%)

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

Procedure: (1S)-1-Cyclopropylethanamine (0.50 mL, 5.4 mmol, Alfa Aesar: Cat. #H27499) was added to a mixture of 5-bromopyridine-2-carboxylic acid (1.0 g, 5.0 mmol, Alfa Aesar: Cat. #B25675) in methylene chloride (30.0 mL), followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.4 g, 5.4 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous Na2CO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS (M+H)+: m/z=269.0/271.0. extracted with dichloromethylene (3×20 mL) The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-15%)

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 1H) 0.28-0.36 (m, 1H) 0.36-0.44 (m, 1H) 0.44-0.53 (m, 1H) 0.92-1.08 (m, 1H) 1.25 (d, J=6.82 Hz, 3H) 2.43 (s, 3H) 3.39-3.60 (m, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.73 (s, 1H) 7.78 (d, J=6.57 Hz, 1H) 8.17 (br. s., 1H) 8.43 (d, J=6.57 Hz, 2H) 8.59 (d, J=8.08 Hz, 1H) 8.79-9.05 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 388.2.

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-cyclopropylethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.26 (m, 1H) 0.28-0.36 (m, 1H) 0.36-0.44 (m, 1H) 0.44-0.53 (m, 1H) 0.92-1.08 (m, 1H) 1.25 (d, J=6.82 Hz, 3H) 2.43 (s, 3H) 3.39-3.60 (m, 1H) 7.66 (dd, J=8.08, 1.52 Hz, 1H) 7.73 (s, 1H) 7.78 (d, J=6.57 Hz, 1H) 8.17 (br. s., 1H) 8.43 (d, J=6.57 Hz, 2H) 8.59 (d, J=8.08 Hz, 1H) 8.79-9.05 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 388.2.

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

Procedure: A solution of (S)-1-cyclopropylethanamine (32 mg, 0.373 mmol), 3 mL of dichloromethane, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (77 mg, 0.169 mmol), 4-dimethylaminopyridine (21 mg, 0.169 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (71 mg, 0.371 mmol) was stirred 18 h, then concentrated to an off-white solid. The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution; dried over Na2SO4, filtered and concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification. MS: (M+Na)+=547. concentrated to an off-white solid The solid was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution The organic layer was sequentially washed with 10 mL of water, 10 mL of a 10% NaOH solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution dried over Na2SO4 filtered concentrated to 70 mg (80%) of crude 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-cyclopropyl-ethyl)-amide, which was used without further purification

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

Procedure: A mixture of 5-chloropyrazine-2-carboxylic acid (0.5 g, 3 mmol), (1S)-1-cyclopropylethanamine (0.30 g, 3.5 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.8 g, 4.7 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.5 mmol) in methylene chloride (5 mL) was stirred at room temperature overnight (22 h.). The mixture was concentrated under reduced pressure. The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%) to afford the desired product (0.54 g). LCMS (M+H)+: m/z=226.1. The mixture was concentrated under reduced pressure The residue was was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-5%)