2-(2,2-dimethylpyrrolidin-1-yl)ethanamine

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

Procedure: 6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound; the mixture was partitioned between water (1 L) and EtOAc (750 ml) The resulting suspension was removed by filtration the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4 filtered evaporated to dryness Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone

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

Procedure: 3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774 ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28 ml) to give a yellow solution. ®T3P (propylphosphonic anhydride) (1.620 ml, 2.036 mmol) was added and the mixture was stirred at room temperature for 90 mins. The reaction mixture was diluted with EtOAc and washed with 0.5M LiCl in H2O and sat NaHCO3. The organic portion was dried MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc/iso-hexane to afford the title compound as a white solid; washed with 0.5M LiCl in H2O filtered concentrated in vacuo The residue was triturated with EtOAc/iso-hexane

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

Procedure: A solution of 4-fluoro-3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamido)benzoic acid (step 1) (6.31 g, 16.63 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.84 g, 19.96 mmol) and triethylamine (6.96 ml, 49.9 mmol) in DMF (36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3. The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml). The combined organic extracts was dried MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc and dried at 45° C. to afford the title compound; The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3 The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml) filtered concentrated in vacuo The resulting solid was triturated with EtOAc dried at 45° C.

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

Procedure: 6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound; the mixture was partitioned between water (1 L) and EtOAc (750 ml) The resulting suspension was removed by filtration the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4 filtered evaporated to dryness Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone

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

Procedure: 6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound; the mixture was partitioned between water (1 L) and EtOAc (750 ml) The resulting suspension was removed by filtration the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4 filtered evaporated to dryness Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone

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

Procedure: 3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774 ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28 ml) to give a yellow solution. ®T3P (propylphosphonic anhydride) (1.620 ml, 2.036 mmol) was added and the mixture was stirred at room temperature for 90 mins. The reaction mixture was diluted with EtOAc and washed with 0.5M LiCl in H2O and sat NaHCO3. The organic portion was dried MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc/iso-hexane to afford the title compound as a white solid; washed with 0.5M LiCl in H2O filtered concentrated in vacuo The residue was triturated with EtOAc/iso-hexane

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

Procedure: A solution of 4-fluoro-3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamido)benzoic acid (step 1) (6.31 g, 16.63 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.84 g, 19.96 mmol) and triethylamine (6.96 ml, 49.9 mmol) in DMF (36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3. The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml). The combined organic extracts was dried MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc and dried at 45° C. to afford the title compound; The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3 The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml) filtered concentrated in vacuo The resulting solid was triturated with EtOAc dried at 45° C.

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

Procedure: A solution of 4-fluoro-3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamido)benzoic acid (step 1) (6.31 g, 16.63 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.84 g, 19.96 mmol) and triethylamine (6.96 ml, 49.9 mmol) in DMF (36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3. The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml). The combined organic extracts was dried MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc and dried at 45° C. to afford the title compound; The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3 The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml) filtered concentrated in vacuo The resulting solid was triturated with EtOAc dried at 45° C.

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

Procedure: 6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stiring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound; the mixture was partitioned between water (1 L) and EtOAc (750 ml) The resulting suspension was removed by filtration the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4 filtered evaporated to dryness Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone

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

Procedure: 6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound; the mixture was partitioned between water (1 L) and EtOAc (750 ml) The resulting suspension was removed by filtration the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4 filtered evaporated to dryness Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone

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

Procedure: 3-(7-Bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoic acid (prepared by hydrolysis of methyl 3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-fluorobenzoate (Intermediate 1A) using NaOH) (700 mg, 1.851 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (290 mg, 2.036 mmol) and triethylamine (0.774 ml, 5.55 mmol) were dissolved in EtOAc (7.284 ml) and DMF (1.28 ml) to give a yellow solution. ®T3P (propylphosphonic anhydride) (1.620 ml, 2.036 mmol) was added and the mixture was stirred at room temperature for 90 mins. The reaction mixture was diluted with EtOAc and washed with 0.5M LiCl in H2O and sat NaHCO3. The organic portion was dried MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc/iso-hexane to afford the title compound as a white solid; washed with 0.5M LiCl in H2O filtered concentrated in vacuo The residue was triturated with EtOAc/iso-hexane

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

Procedure: A solution of 4-fluoro-3-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamido)benzoic acid (step 1) (6.31 g, 16.63 mmol), 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.84 g, 19.96 mmol) and triethylamine (6.96 ml, 49.9 mmol) in DMF (36.9 ml) and EtOAc (2 ml) was treated dropwise with ®T3P (propylphosphonic anhydride) (50% w/w in EtOAc) (15.88 g, 24.95 mmol). The resulting mixture was stirred at RT for 16 hrs and diluted with 10% MeOH/EtOAc (62.7 ml). The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3. The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml). The combined organic extracts was dried MgSO4, filtered and concentrated in vacuo. The resulting solid was triturated with EtOAc and dried at 45° C. to afford the title compound; The mixture was washed with 0.5 M LiCl, H2O and sat. NaHCO3 The aqueous layer was back-extracted with 10% MeOH EtOAc (62.7 ml) (3×100 ml) filtered concentrated in vacuo The resulting solid was triturated with EtOAc dried at 45° C.