(4,4-difluorocyclohexyl)methanamine;hydrochloride

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 mL process vial was charged with (R)-2-(6-chloro-5-iodo-1-oxoisoquinolin-2(1H)-yl)propyl acetate (18a) (400 mg, 0.0009 mol), (4,4-difluorocyclohexyl)methanamine hydrochloride (150 mg, 0.00081 mol), molybdenum hexacarbonyl (500 mg, 0.002 mol), palladium acetate (15 mg, 0.000067 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 0.003 mol) and 1,4-dioxane (4 mL, 0.04 mol). The vessel was sealed under air and stirred at 110° C. for 1 hour and cooled to room temperature. The mixture was concentrated and purified by flash chromatography to afford the desired product as a yellow oil. (143 mg, 37%). The vessel was sealed under air cooled to room temperature The mixture was concentrated purified by flash chromatography

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 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4,4-difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.25 (m, 2 H) 1.60-1.82 (m, 5 H) 1.95 (d, J=8.1 Hz, 2 H) 2.37 (s, 3 H) 3.15 (t, J=6.3 Hz, 2H) 7.59 (d, J=7.6 Hz, 1 H) 7.67 (s, 1 H) 8.36 (br. s., 1 H) 8.70 (br. s., 1 H) 8.82-8.88 (m, 1H) 13.16 (br. s., 1 H). MS m/z [M+H]+ 452.5.

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 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4,4-difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.25 (m, 2 H) 1.60-1.82 (m, 5 H) 1.95 (d, J=8.1 Hz, 2 H) 2.37 (s, 3 H) 3.15 (t, J=6.3 Hz, 2H) 7.59 (d, J=7.6 Hz, 1 H) 7.67 (s, 1 H) 8.36 (br. s., 1 H) 8.70 (br. s., 1 H) 8.82-8.88 (m, 1H) 13.16 (br. s., 1 H). MS m/z [M+H]+ 452.5.

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 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4,4-difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.25 (m, 2H) 1.60-1.82 (m, 5H) 1.95 (d, J=8.1 Hz, 2H) 2.37 (s, 3H) 3.15 (t, J=6.3 Hz, 2H) 7.59 (d, J=7.6 Hz, 1H) 7.67 (s, 1H) 8.36 (br. s., 1H) 8.70 (br. s., 1H) 8.82-8.88 (m, 1H) 13.16 (br. s., 1H). MS m/z [M+H]+ 452.5.

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

Procedure: Following the same procedure as in Step C of Example 4 using [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (210 mg, 1.12 mmol), methyl (4-fluoro-3-nitrophenyl)carbamate (200 mg, 0.934 mmol) and TEA (0.390 mL, 2.80 mmol) in 10 mL of EtOH. The crude product was purified by silica gel flash chromatography using 5% ether/DCM as eluent. Yield: 200 mg (62%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.34-1.47 (m, 2H), 1.65-1.75 (m, 2H), 1.78-1.85 (m, 1H), 1.90-1.93 (m, 1H), 1.94-1.97 (m, 1H), 2.10-2.21 (m, 2H), 3.23 (dd, J=6.64, 5.66 Hz, 2H), 3.78 (s, 3H), 6.48 (br.s, 1H), 6.83 (d, J=9.18 Hz, 1H), 7.66 (br.s, 1H), 8.05 (br.s, 1H), 8.07 (d, J=2.54 Hz, 1H). The crude product was purified by silica gel flash chromatography

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

Procedure: Following the same procedure as in Step C of Example 4 using [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (210 mg, 1.12 mmol), methyl (4-fluoro-3-nitrophenyl)carbamate (200 mg, 0.934 mmol) and TEA (0.390 mL, 2.80 mmol) in 10 mL of EtOH. The crude product was purified by silica gel flash chromatography using 5% ether/DCM as eluent. Yield: 200 mg (62%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.34-1.47 (m, 2H), 1.65-1.75 (m, 2H), 1.78-1.85 (m, 1H), 1.90-1.93 (m, 1H), 1.94-1.97 (m, 1H), 2.10-2.21 (m, 2H), 3.23 (dd, J=6.64, 5.66 Hz, 2H), 3.78 (s, 3H), 6.48 (br.s, 1H), 6.83 (d, J=9.18 Hz, 1H), 7.66 (br.s, 1H), 8.05 (br.s, 1H), 8.07 (d, J=2.54 Hz, 1H). The crude product was purified by silica gel flash chromatography

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

Procedure: tert-Butyl [(4,4-difluorocyclohexyl)methyl]carbamate (505 mg, 2.03 mmol) was stirred in 5 mL of 1M HCl/AcOH at rt for 2 h. The solvent was evaporated. The residue was washed with ether, filtered and dried. Yield: 330 mg (88%). 1H NMR (400 MHz, METHANOL-D4): δ 1.28-1.40 (m, 2H), 1.71-1.82 (m, 2H), 1.84 (d, J=3.12 Hz, 2H), 1.86-1.89 (m, 1H), 2.03-2.15 (m, 2H), 2.85 (d, J=7.03 Hz, 2H). The solvent was evaporated The residue was washed with ether filtered dried

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 mL process vial was charged with (R)-2-(6-chloro-5-iodo-1-oxoisoquinolin-2(1H)-yl)propyl acetate (18a) (400 mg, 0.0009 mol), (4,4-difluorocyclohexyl)methanamine hydrochloride (150 mg, 0.00081 mol), molybdenum hexacarbonyl (500 mg, 0.002 mol), palladium acetate (15 mg, 0.000067 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (500 mg, 0.003 mol) and 1,4-dioxane (4 mL, 0.04 mol). The vessel was sealed under air and stirred at 110° C. for 1 hour and cooled to room temperature. The mixture was concentrated and purified by flash chromatography to afford the desired product as a yellow oil. (143 mg, 37%). The vessel was sealed under air cooled to room temperature The mixture was concentrated purified by flash chromatography

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

Procedure: N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5 mmol) at 80° C. for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was crystallized from EtOAc. The left over mother liquor was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 1.50 g (78%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.33-1.47 (m, 2H), 1.66-1.77 (m, 2H), 1.77-1.86 (m, 1H), 1.89-1.93 (m, 1H), 1.93-1.97 (m, 1H), 2.10-2.17 (m, 2H), 2.18 (s, 3H), 3.23 (dd, J=6.74, 5.76 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.15 (s, 1H), 7.80 (dd, J=9.18, 2.54 Hz, 1H), 8.09 (d, J=2.54 Hz, 2H). The solvent was evaporated The residue was dissolved in EtOAc washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution dried over anhydrous Na2SO4 The product was crystallized from EtOAc The left over mother liquor was purified by silica gel flash chromatography

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

Procedure: N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5 mmol) at 80° C. for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was crystallized from EtOAc. The left over mother liquor was purified by silica gel flash chromatography using 2:1/hexanes:acetone as eluent. Yield: 1.50 g (78%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.33-1.47 (m, 2H), 1.66-1.77 (m, 2H), 1.77-1.86 (m, 1H), 1.89-1.93 (m, 1H), 1.93-1.97 (m, 1H), 2.10-2.17 (m, 2H), 2.18 (s, 3H), 3.23 (dd, J=6.74, 5.76 Hz, 2H), 6.83 (d, J=9.37 Hz, 1H), 7.15 (s, 1H), 7.80 (dd, J=9.18, 2.54 Hz, 1H), 8.09 (d, J=2.54 Hz, 2H). The solvent was evaporated The residue was dissolved in EtOAc washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution dried over anhydrous Na2SO4 The product was crystallized from EtOAc The left over mother liquor was purified by silica gel flash chromatography

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

Procedure: The title compound was prepared in 13% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (4,4-difluorocyclohexyl)methanamine hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.13 (2H, m), 1.75 (4H, m), 1.96 (2H, m), 2.42 (2H, d, J=6.7 Hz), 2.88 (2H, t, J=6.0 Hz), 4.06 (2H, t, J=6.0 Hz), 7.53 (1H, dd, J=4.9 Hz), 7.73 (1H, s), 7.79 (1H, s), 8.25 (1H, s), 8.55 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H22F2N4O2, 365. Found, 365.

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

Procedure: The title compound was prepared in 13% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and (4,4-difluorocyclohexyl)methanamine hydrogen chloride according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 1.13 (2H, m), 1.75 (4H, m), 1.96 (2H, m), 2.42 (2H, d, J=6.7 Hz), 2.88 (2H, t, J=6.0 Hz), 4.06 (2H, t, J=6.0 Hz), 7.53 (1H, dd, J=4.9 Hz), 7.73 (1H, s), 7.79 (1H, s), 8.25 (1H, s), 8.55 (1H, d, J=4.9 Hz). [M+H] Calc'd for C18H22F2N4O2, 365. Found, 365.