N-[(4-methoxyphenyl)methyl]cyclopropanamine

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 25 mL flask was added a mixture of 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (2.0 g, 6.87 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.34 g, 7.56 mmol) in anhydrous THF (20 mL). The reaction solution was cooled to −78° C. and treated drop wise with 1.0 M lithium bis(trimethylsilyl)amide in THF solution (20.61 mL, 20.61 mmol, 3 eq, 1M solution in THF). The reaction was stirred at −78° C. for 1 hour, then allowed to come to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride. The product was extracted with ethyl acetate; the organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column) to give the pure product 7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-amine (2.1 g) To a 25 mL flask was added to come to room temperature stirred for 3 hours The reaction was quenched with saturated ammonium chloride The product was extracted with ethyl acetate the organic layer was dried with sodium sulfate concentrated in vacuo The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 25 mL flask was added a mixture of 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (2.0 g, 6.87 mmol), N-(4-methoxybenzyl)cyclopropanamine (1.34 g, 7.56 mmol) in anhydrous THF (20 mL). The reaction solution was cooled to −78° C. and treated drop wise with 1.0 M lithium bis(trimethylsilyl)amide in THF solution (20.61 mL, 20.61 mmol, 3 eq, 1M solution in THF). The reaction was stirred at −78° C. for 1 hour, then allowed to come to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride. The product was extracted with ethyl acetate; the organic layer was dried with sodium sulfate and concentrated in vacuo. The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column) to give the pure product 7-bromo-N-cyclopropyl-N-(4-methoxybenzyl)-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-amine (2.1 g) To a 25 mL flask was added to come to room temperature stirred for 3 hours The reaction was quenched with saturated ammonium chloride The product was extracted with ethyl acetate the organic layer was dried with sodium sulfate concentrated in vacuo The crude product mixture was purified via ISCO (0-100% of ethyl acetate/heptane in 10 minutes, 24 g silica column)

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m). cap the solvent was degassed by bubbling argon through it for 10 minutes the suspension was pump/purged three times with argon cooled to room temperature The solids were removed via filtration through CELITE® washing with THF The filtrate was then diluted with water and EtOAc The layers were separated the aqueous phase extracted EtOAc (3×10 mL) washed with water and brine dried over anhydrous sodium sulfate Filtration and concentration afforded a tan solid, which was triturated in DCM cooled to 0° C The resulting precipitate was filtered washed with cold DCM The filtrate was dissolved in a small amount of DCM purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm) concentrated under reduced pressure The material isolated from chromatography the suspension was cooled in an ice bath filtered After 30 minutes the solid was isolated via filtration washed with water and EtOAc dried overnight in vacuo

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

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

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m). cap the solvent was degassed by bubbling argon through it for 10 minutes the suspension was pump/purged three times with argon cooled to room temperature The solids were removed via filtration through CELITE® washing with THF The filtrate was then diluted with water and EtOAc The layers were separated the aqueous phase extracted EtOAc (3×10 mL) washed with water and brine dried over anhydrous sodium sulfate Filtration and concentration afforded a tan solid, which was triturated in DCM cooled to 0° C The resulting precipitate was filtered washed with cold DCM The filtrate was dissolved in a small amount of DCM purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm) concentrated under reduced pressure The material isolated from chromatography the suspension was cooled in an ice bath filtered After 30 minutes the solid was isolated via filtration washed with water and EtOAc dried overnight in vacuo

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m). cap the solvent was degassed by bubbling argon through it for 10 minutes the suspension was pump/purged three times with argon cooled to room temperature The solids were removed via filtration through CELITE® washing with THF The filtrate was then diluted with water and EtOAc The layers were separated the aqueous phase extracted EtOAc (3×10 mL) washed with water and brine dried over anhydrous sodium sulfate Filtration and concentration afforded a tan solid, which was triturated in DCM cooled to 0° C The resulting precipitate was filtered washed with cold DCM The filtrate was dissolved in a small amount of DCM purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm) concentrated under reduced pressure The material isolated from chromatography the suspension was cooled in an ice bath filtered After 30 minutes the solid was isolated via filtration washed with water and EtOAc dried overnight in vacuo

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A ˜1:1 mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide) and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (850 mg, 2.61 mmol, 5A), N-(4-methoxybenzyl)cyclopropanamine (508 mg, 2.87 mmol) and N,N-diisopropylethylamine (0.683 mL, 3.91 mmol) were heated in DMF (10 mL) at 80° C. After 1 hr, the reaction mixture was concentrated to dryness under reduced pressure, suspended in methanol (20 mL), and the solid was isolated via Buchner filtration. The solid was combined with 4.8 g of trans-cyclohexane)-1,4-diamine and heated at 160° C. After 2.5 hrs, the reaction was cooled to room temperature, suspended in water (20 mL), and the isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform). The desired fractions were concentrated, and the solid suspended in water (25 mL), and filtered to isolate 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (834 mg, 1.531 mmol, 58.8% yield) as an off-white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.69 minutes. [M+H]=545.35. the reaction mixture was concentrated to dryness under reduced pressure the solid was isolated via Buchner filtration After 2.5 hrs the reaction was cooled to room temperature the isolated solid was purified with silica gel chromatography (10% methanol to 20% methanol/chloroform) The desired fractions were concentrated filtered

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(4-methoxybenzyl)cyclopropanamine (381 mg, 2.148 mmol) was added to ˜1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (467 mg, 1.432 mmol, example 13A) and DIEA (0.500 mL, 2.86 mmol) in DMF (10 mL). The reaction mixture was heated at 80° C. for 1.5 hrs. Water (20 mL) was added, and the solid was collected via Buchner filtration and dried under reduced pressure overnight to afford 6-Chloro-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid (519 mg, 78%). The crude material was taken into the next step without further purification. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=2.22 minutes. [M+H]=467.21. the solid was collected via Buchner filtration dried under reduced pressure overnight

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A ˜1:1 mixture 6,8-dichloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-chloropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (3 g, 8.6 mmol), N-(4-methoxybenzyl)cyclopropanamine (8.16 g, 23.82 mmol) and N,N-diisopropylethylamine (3.08 g, 23.82 mmol) was suspended in DMF (100 mL) and heated at 80° C. for 1.5 hrs. The reaction mixture was concentrated and dried under reduced pressure for 16 hrs. The residue was suspended in methanol (75 mL) and an off-white solid was collected via Buchner filtration (2×25 mL methanol rinse) to isolate 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (10.2 g, 21.1 mmol, 89%) as a tan solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=2.21 minutes. [M+H]=483.06. The reaction mixture was concentrated dried under reduced pressure for 16 hrs an off-white solid was collected via Buchner filtration (2×25 mL methanol rinse)