(sulfamoylamino)methane

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

Procedure: The compound was prepared in a similar manner to Example 408 from 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and N-methylsulfamide. LCMS (Method D): RT=4.48 min, m/z: 524.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.46-7.38 (m, 4H), 7.27 (t, J=7.7 Hz, 4H), 7.22-7.08 (m, 3H), 6.95 (d, J=12.7 Hz, 1H), 4.46 (s, 1H), 4.21 (d, J=6.2 Hz, 2H), 3.24 (d, J=7.4 Hz, 2H), 3.00 (t, J=6.6 Hz, 2H), 2.92-2.79 (m, 1H), 2.53 (d, J=4.9 Hz, 2H), 2.11-1.99 (m, 1H), 1.25 (d, J=7.1 Hz, 1H), 0.93-0.83 (m, 2H), 0.67 (m, 2H).

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

Procedure: Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with methyl sulfamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-2-yl)-3-chlorobenzoic acid, the title compound was obtained following trituration with hexanes as a colorless solid (0.11 g, 66%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H) 7.98-7.97 (m, 1H), 7.88-7.85 (m, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.64-7.60 (m, 1H), 3.22 (s, 1H), 2.50 (d, J=4.4 Hz, 3H), 2.23 (s, 2H), 1.95-1.85 (m, 8H), 1.72 (s, 2H), 1.63-1.59 (m, 2H); MS (ES−) m/z 381.2, 383.2 (M−1).

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

Procedure: Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with methyl sulfamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-4-((2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following trituration with diethyl ether (10 mL) as a colorless powder (0.073 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.73-7.66 (m, 2H), 7.34 (d, J=12.2 Hz, 1H), 4.54 (s, 2H), 2.53 (d, J=4.6 Hz, 3H), 2.15-2.07 (m, 4H), 1.97-1.78 (m, 6H), 1.70-1.60 (m, 4H); MS (ES−) m/z 454.1, 456.1 (M−1).

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

Procedure: A solution of tert-butyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (0.50 g, 1.30 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5.0 mL). The resulting mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was treated with methanol (20 mL) and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 mL), treated with carbonyl diimidazole (0.42 g, 2.60 mmol), and refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and added (methylsulfamoyl)amine (0.43 g, 3.90 mmol) and 1,8-diazabicycloundec-7-ene (0.58 mL, 3.90 mmol). The reaction mixture was refluxed under nitrogen for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.12 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.46 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 1H), 3.92 (s, 2H), 2.52-2.48 (m, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.55 (m, 12H), 0.98-0.90 (m, 2H), 0.77-0.70 (m, 2H); MS (ES+) m/z 420.2 (M+1). concentrated in vacuo The residue was treated with methanol (20 mL) concentrated in vacuo The residue was dissolved in anhydrous tetrahydrofuran (20 mL) refluxed under nitrogen for 30 min The reaction mixture was refluxed under nitrogen for 30 minutes The reaction mixture was cooled to ambient temperature washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel column chromatography (2:1 hexanes

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

Procedure: Following the procedure as described in Example 158 step 5 and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.08 g, 29%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.77-8.64 (m, 1H), 7.62-7.51 (m, 1H), 6.65-6.52 (m, 1H), 5.30-5.18 (m, 1H), 3.95-3.85 (m, 2H), 2.83-2.72 (m, 3H), 2.28-1.66 (m, 8H), 1.57-1.42 (m, 2H), 1.01-0.90 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 421.1 (M+1).

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

Procedure: Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.13 g, 25%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.76-8.65 (m, 1H), 7.57-7.50 (m, 1H), 6.62-6.52 (m, 1H), 5.31-5.22 (m, 1H), 3.86-3.78 (m, 2H), 2.79-2.74 (m, 3H), 2.11-1.99 (m, 1H), 1.95-1.65 (m, 6H), 1.41-1.03 (m, 5H), 0.98-0.89 (m, 2H), 0.69-0.61 (m, 2H); MS (ES−) m/z 383.3 (M−1).

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

Procedure: Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.13 g, 47%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.77-8.62 (m, 1H), 7.66-7.56 (m, 1H), 6.65-6.51 (m, 1H), 5.30-5.18 (m, 1H), 3.76 (s, 2H), 2.82-2.71 (m, 3H), 2.09-1.73 (m, 7H), 1.69-1.59 (m, 2H), 1.17 (s, 3H), 1.01-0.90 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 435.1 (M+1).

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

Procedure: A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), methyl(sulfamoyl)amine (23 mg, 0.21 mmol), 1-ethyl-(3-dimethylamino-propyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3) to give target product (35.4 mg, 56%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.78 min, m/z: 456.7 [M+H]+; 1H-NMR (500 MHz, MeOH-d4,): δ 7.77 (d, J=6.0 Hz, 1H), 7.42 (d, J=10.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.52 (dd, J=9.0, 2.5 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.71 (s, 3H), 1.80 (t, J=6.5 Hz, 2H), 1.32 (s, 6H). extracted with EtOAc (50×3 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3)

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

Procedure: A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), methyl(sulfamoyl)amine (23 mg, 0.21 mmol), 1-ethyl-(3-dimethylamino-propyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in DCM (20 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3) to give target product (35.4 mg, 56%) as a pale yellow solid. LCMS (ESI) Method A: RT=5.78 min, m/z: 456.7 [M+H]; 1H-NMR (500 MHz, MeOH-d4,): δ 7.77 (d, J=6.0 Hz, 1H), 7.42 (d, J=10.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.52 (dd, J=9.0, 2.5 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.14 (s, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.71 (s, 3H), 1.80 (t, J=6.5 Hz, 2H), 1.32 (s, 6H). extracted with EtOAc (50×3 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by reverse phase Combiflash (18%-25% MeCN in 0.5% NH4HCO3)