methyl 4-chlorosulfonylbutanoate

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

Procedure: To a solution of 5-cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine (90 mg, 0.216 mmol) and triethylamine (0.061 mL, 0.432 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (65 mg, 0.324 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 3 h. After this time, the reaction mixture was diluted with CH2Cl2 (4 mL), and the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min) to afford Compound 11H as a white solid (46 mg, 0.079 mmol, 36.7% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (s, 2 H), 7.06 (s, 1 H), 7.01-7.05 (m, 1 H), 6.60 (d, J=8.3 Hz, 1 H), 5.82 (ddd, J=3.2, 1.9, 1.7 Hz, 1 H), 4.65-4.78 (m, 2 H), 3.85-3.92 (m, 2 H), 3.60 (s, 3 H), 3.46 (t, J=5.8 Hz, 2 H), 3.08 (d, J=15.7 Hz, 1 H), 2.98 (dd, J=8.4, 6.7 Hz, 2 H), 2.65-2.78 (m, 3 H), 2.50 (d, J=1.7 Hz, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.76-1.87 (m, 2 H), 1.67-1.75 (m, 1 H), 1.56-1.65 (m, 1 H), 1.30 (s, 3 H), 1.15-1.28 (m, 2 H), 0.76-0.83 (m, 2 H), 0.45-0.51 (m, 2 H). LC/MS (m/z)=581 (M+H)+. Upon completion of addition the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL) The organic layer was separated dried (Na2SO4) filtered concentrated to yield a residue The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (150 μL) is treated with sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) and stirred at room temperature for 5 min Methyl 4-(chlorosulfonyl)butanoate (106 mg, 0.53 mmol) is added, and the mixture is stirred at 50° C. over night. The mixture is diluted with water and N,N-dimethylformamide and purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.95 min (Z018_S04). is added purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA) 0.95 min (Z018_S04)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (150 μL) is treated with sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) and stirred at room temperature for 5 min Methyl 4-(chlorosulfonyl)butanoate (106 mg, 0.53 mmol) is added, and the mixture is stirred at 50° C. over night. The mixture is diluted with water and N,N-dimethylformamide and purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.95 min (Z018_S04). is added purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA) 0.95 min (Z018_S04)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (150 mg, 0.344 mmol) and triethylamine (0.120 mL, 0.861 mmol) in CH2Cl2 (3 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (104 mg, 0.517 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (4 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 55% EtOAc) to afford methyl 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (84 mg, 0.14 mmol, 41% yield) as a white solid. LCMS (m/z)=600 (M+H)+. at rt for 2 h The reaction mixture was quenched with sat. aq. NaHCO3 (4 mL) extracted with CH2Cl2 (3×5 mL) The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 55% EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (95 mg, 0.223 mmol) and triethylamine (0.078 ml, 0.558 mmol) in CH2Cl2 (2 ml) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (67.2 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 50% EtOAc) to afford methyl 4-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (68 mg, 0.107 mmol, 48% yield) as an off white solid. 1H NMR (500 MHz, chloroform-d) δ 7.64 (d, J=1.9 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.0, 3.6 Hz, 1H), 4.03 (q, J=2.8 Hz, 2H), 3.90-3.82 (m, 2H), 3.69 (s, 3H), 3.65 (ddd, J=13.5, 7.2, 4.1 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.12-3.06 (m, 2H), 2.90 (spt, J=6.9 Hz, 1H), 2.67 (s, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.23-2.12 (m, 4H), 2.06 (dtd, J=13.8, 7.1, 4.0 Hz, 2H), 1.29 (d, J=6.9 Hz, 6H). LCMS (m/z)=590 (M+H)+. at rt overnight The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) extracted with CH2Cl2 (3×3 mL) The combined organic layers were dried (Na2SO4) filtered concentrated The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 50% EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (60 mg, 0.138 mmol) and triethylamine (0.039 mL, 0.275 mmol) in CH2Cl2 (1.5 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (41.5 mg, 0.207 mmol). Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 min. At the conclusion of this period, the reaction mixture was allowed to warm to rt, where it stirred for 1 hr. After this time, the reaction mixture was quenched with saturated aq NaHCO3 (3 mL) and then extracted with CH2Cl2 (3×2 mL). The combined organic layers were washed with brine (2 mL), dried (Na2SO4), filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 5B (56 mg, 0.093 mmol, 68% yield). 1H NMR (500 MHz, chloroform-d) ppm 8.21 (2H, br. s.), 7.62-7.66 (2H, m), 7.37-7.42 (1H, m), 6.06-6.10 (1H, m), 5.43-5.51 (1H, m), 4.18-4.29 (2H, m), 4.00-4.06 (2H, m), 3.67-3.82 (4H, m), 3.60 (2H, t, J=5.6 Hz), 3.07-3.14 (2H, m), 2.65-2.72 (2H, m), 2.54 (2H, t, J=7.0 Hz), 2.43 (2H, t, J=7.6 Hz), 2.12-2.26 (4H, m), 1.92-2.05 (2H, m), 1.50-1.65 (3H, m), 0.96 (3H, t, J=7.3 Hz). LC/MS (m/z)=600 (M+H)+. Upon completion of addition to warm to rt where it stirred for 1 hr After this time, the reaction mixture was quenched with saturated aq NaHCO3 (3 mL) extracted with CH2Cl2 (3×2 mL) The combined organic layers were washed with brine (2 mL) dried (Na2SO4) filtered concentrated to yield the crude product The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc)

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

Procedure: To a solution of 5-cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine (90 mg, 0.216 mmol) and triethylamine (0.061 mL, 0.432 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (65 mg, 0.324 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 3 h. After this time, the reaction mixture was diluted with CH2Cl2 (4 mL), and the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min) to afford Compound 11H as a white solid (46 mg, 0.079 mmol, 36.7% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (s, 2 H), 7.06 (s, 1 H), 7.01-7.05 (m, 1 H), 6.60 (d, J=8.3 Hz, 1 H), 5.82 (ddd, J=3.2, 1.9, 1.7 Hz, 1 H), 4.65-4.78 (m, 2 H), 3.85-3.92 (m, 2 H), 3.60 (s, 3 H), 3.46 (t, J=5.8 Hz, 2 H), 3.08 (d, J=15.7 Hz, 1 H), 2.98 (dd, J=8.4, 6.7 Hz, 2 H), 2.65-2.78 (m, 3 H), 2.50 (d, J=1.7 Hz, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.76-1.87 (m, 2 H), 1.67-1.75 (m, 1 H), 1.56-1.65 (m, 1 H), 1.30 (s, 3 H), 1.15-1.28 (m, 2 H), 0.76-0.83 (m, 2 H), 0.45-0.51 (m, 2 H). LC/MS (m/z)=581 (M+H)+. Upon completion of addition the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL) The organic layer was separated dried (Na2SO4) filtered concentrated to yield a residue The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (150 μL) is treated with sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) and stirred at room temperature for 5 min Methyl 4-(chlorosulfonyl)butanoate (106 mg, 0.53 mmol) is added, and the mixture is stirred at 50° C. over night. The mixture is diluted with water and N,N-dimethylformamide and purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.95 min (Z018_S04). is added purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA) 0.95 min (Z018_S04)