2,4-dichloro-1-(isocyanatomethyl)benzene

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: To a solution of 4-(2-cyclohexylethyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (0.47 g, 2.0 mmol, prepared as described in Example 13) in ethanol (10 mL), triethylamine (0.28 ml, 2.0 mmol) and 2,4-dichlorobenzyl isocyanate (0.41 g, 2.0 mmol) were added dropwise. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was re-evaporated with acetone and then dissolved in acetone (15 mL) and left for crystallization. The solid was isolated by filtration, washed with acetone and dried. This afforded 0.60 g (69%) of the title compound as a solid. concentrated under reduced pressure The residue was re-evaporated with acetone dissolved in acetone (15 mL) left for crystallization The solid was isolated by filtration washed with acetone dried

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

Procedure: To a mixture of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.55 mmol), ethanol (10 mL) and triethylamine (1.10 mL, 7.89 mmol), 2,4-dichlorobenzyl isocyanate (0.52 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was distributed between water (20 mL) and ethyl acetate (75 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in diethylether (50 mL) and the crude product was filtered off. Recrystallization from acetone (25 mL) gave 0.30 g (37%) of the title urea as a colourless solid. was added concentrated under reduced pressure The organic phase was washed with water (10 mL) and brine (10 mL) dried (MgSO4) concentrated under reduced pressure The residue was triturated in diethylether (50 mL) the crude product was filtered off Recrystallization from acetone (25 mL)

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

Procedure: To a mixture of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.55 mmol), ethanol (10 mL) and triethylamine (1.10 mL, 7.89 mmol), 2,4-dichlorobenzyl isocyanate (0.52 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was distributed between water (20 mL) and ethyl acetate (75 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in diethylether (50 mL) and the crude product was filtered off. Recrystallization from acetone (25 mL) gave 0.30 g (37%) of the title urea as a colourless solid. was added concentrated under reduced pressure The organic phase was washed with water (10 mL) and brine (10 mL) dried (MgSO4) concentrated under reduced pressure The residue was triturated in diethylether (50 mL) the crude product was filtered off Recrystallization from acetone (25 mL)

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

Procedure: 8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 mL, 1:4) was treated with 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to provide the title compound. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O.HCl+0.25EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84. the mixture was filtered the filter cake was dried under reduced pressure

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

Procedure: 8-Bromo-5-isoquinolinamine (120 mg, 0.52 mmol) in THF:toluene (5 mL, 1:4) was treated with 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake was dried under reduced pressure to provide the title compound. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O.HCl+0.25EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84. the mixture was filtered the filter cake was dried under reduced pressure

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

Procedure: 5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H, J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl). a precipitate formed which was collected by filtration washed with toluene air-dried Remaining impurities were removed CH3OH and then filtering the mixture

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

Procedure: 5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H, J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl). a precipitate formed which was collected by filtration washed with toluene air-dried Remaining impurities were removed CH3OH and then filtering the mixture

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

Procedure: The product from Example 73A (120 mg, 0.52 mmol) in THF:toluene (1:4, 5 mL) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (108 mg, 0.52 mmol) in THF (0.5 mL). After stirring for 16 hours at room temperature, the mixture was filtered and the filter cake dried under reduced pressure to provide the title compound as a white solid (178 mg, 78%). The hydrochloride salt was obtained by dissolving the product in hot THF and adding HCl in diethyl ether (2M). The yellow precipitate was collected by filtration and dried under reduced pressure. MS (ESI+) m/z 426 (M+H)+; MS (ESI−) m/z 424 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.42 (d, 5.8, 2H), 7.22 (t, J 5.8, 1H), 7.65 (m, 1H), 7.91 (d, J 8.5, 1H), 8.02 (d, J 6.1, 1H), 8.22 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 9.01 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C17H12BrCl2N3O HCl 0.25EtOH: C, 44.41; H, 3.14; N, 8.88. Found: C, 44.80; H, 2.76; N, 8.84. the mixture was filtered the filter cake dried under reduced pressure

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

Procedure: The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.226 g, 73%). MS (ESI+) m/z 404 (M+H)+; MS (ESI−) m/z 402 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.96 (s, 3H), 4.44 (d, J 6.0, 2H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H), 7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s, 1H), 9.35 (s, 1H); Anal. Calcd for C19H15Cl2N3O3: C, 56.45; H, 3.74; N, 10.39. Found: C, 56.08; H, 3.67; N, 10.03. the reaction mixture was concentrated under reduced pressure the residue was triturated with diethyl ether

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

Procedure: 1-Methyl-1H-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80° C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 9.22 (s, 1H), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (m, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37CI)+. to cool to ambient temperature filtered to air-dry