N-(4-aminocyclohexyl)methanesulfonamide

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

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

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

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

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

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

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

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide was dissolved in n-butanol and N-(4-aminocyclohexyl)methanesulfonamide (27.0 mg, 0.140 mmol) was added at rt followed by TEA (52.2 μl, 0.375 mmol). The reaction was heated to 60° C. for 12 h. Purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and washed with NaHCO3, dried over MgSO4 and solvent removed to give the title compound as a yellow solid (0.010 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=5.1 Hz, 1H), 7.38-7.55 (m, 1H), 7.11-7.31 (m, 2H), 6.93-7.10 (m, 3H), 6.72-6.88 (m, 1H), 6.42-6.48 (m, 1H), 6.28-6.35 (m, 1H), 5.79-5.88 (m, 1H), 3.52-3.63 (m, 1H), 3.29-3.45 (m, 6H), 3.05-3.16 (m, 1H), 2.91 (s, 3H), 1.77-2.02 (m, 6H), 1.19-1.42 (m, 4H). MS (ESI): 690 [M+H]+. Purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column) washed with NaHCO3 dried over MgSO4 and solvent removed

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-{5-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (50 mg, 0.093 mmol) and N-(4-aminocyclohexyl)-methanesulfonamide (19.62 mg, 0.102 mmol) were dissolved in n-butanol (1 mL) and TEA (0.052 mL, 0.371 mmol) was added. The reaction was stirred in a closed vessel at 90° C. for 18 h. The reaction mixture was cooled to rt and solvent was removed. The residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and solvent removed to give the title compound as a white solid (0.006 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 8.09 (d, J=5.0 Hz, 1H), 7.67-7.78 (m, 1H), 7.41 (d, J=3.5 Hz, 1H), 7.28 (q, J=8.7 Hz, 2H), 7.00 (dt, J=2.6, 1.3 Hz, 1H), 6.10-6.28 (m, 1H), 3.56-3.70 (m, 1H), 3.41-3.52 (m, 1H), 3.09 (td, J=4.2, 1.7 Hz, 1H), 2.92 (s, 3H), 1.83-1.98 (m, 4H), 1.21-1.50 (m, 13H). MS (ESI): 695 [M+H]+. The reaction mixture was cooled to rt solvent was removed The residue was purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column) solvent removed

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

Procedure: 1,1-Dimethylethyl {4-[(methylsulfonyl)amino]cyclohexyl}carbamate (0.922 g, 3.15 mmol) was dissolved in DCM (50 mL). TFA was added (2.429 mL, 31.5 mmol) and the reaction allowed to stir at rt for 1 h. Evaporated off the volatiles and added DCM (50 mL) followed by evaporation of volatiles. The DCM addition/evaporation was repeated several times to give a maroon semi-solid. The residual semi-solid was treated with diethyl ether (10 mL) after which the suspension was sonicated and triturated, then filtered. Solids were triturated with more diethyl ether (10 mL). The product was suction dried to give title compound of Step B as a light pink solid (0.938 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (br. s., 2H), 7.07 (d, J=7.2 Hz, 1H), 3.33 (s, 2H), 3.01-3.14 (m, 1H), 2.78-3.01 (m, 2H), 1.80-2.02 (m, 4H), 1.17-1.47 (m, 4H). Evaporated off the volatiles added DCM (50 mL) followed by evaporation of volatiles The DCM addition/evaporation to give a maroon semi-solid was sonicated triturated filtered Solids were triturated with more diethyl ether (10 mL) The product was suction dried