4-(trifluoromethyl)piperidine;hydrochloride

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

Procedure: Mix 3′,5′-dichloro-4′-[(R)-trans-1-(4-methoxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.350 g, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.11 mmol), N-methylmorpholine (0.33 mL, 2.95 mmol), hydroxybenzotriazole (0.247 g, 0.74 mmol) and 4-trifluoromethyl-piperidine hydrochloride (0.226 g, 1.47 mmol) in CH2Cl2 (10 mL). Stir for 12 hours at room temperature. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with saturated aqueous sodium bicarbonate brine. Dry over magnesium sulfate, filter, and concentrate under vacuum. Purify by flash column chromatography to recover 0.350 g (78%) of the title compound: MS (m/z): 611 (M+). Quench with 1N HCl extract with ethyl acetate Wash the extract with saturated aqueous sodium bicarbonate brine Dry over magnesium sulfate filter concentrate under vacuum Purify by flash column chromatography to recover 0.350 g (78%) of the title compound

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

Procedure: Treat a solution of 3′,5′-dichloro-4′-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.25 g, 0.56 mmol), 4-(trifluoromethyl)piperidine hydrochloride (0.13 g, 0.67 mmol), 1-hydroxybenzotriazole (0.23 g, 0.67 mmol), and 4-methylmorpholine (0.18 mL, 1.67 mmol) in dichloromethane (10 mL) with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.13 g, 0.67 mmol) and stir at room temperature for 6 hr. Quench the reaction with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel column chromatography using hexanes:ethyl acetate to afford 0.23 g (72%) of desired product: MS (m/z): 583 (M+). Quench the reaction with 1N hydrochloric acid extract with ethyl acetate Wash the organic layer with brine dry over magnesium sulfate filter Purify the crude material by silica gel column chromatography

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

Procedure: Prepare the title compound in a 51% yield by coupling procedure 1 starting from 3′,5′-dichloro-4′-[(R)-2-oxo-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid and 4-trifluoromethyl-piperidine hydrochloride.

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

Procedure: To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL), triethylamine (0.84 mL, 6.00 mmol) and 4-trifluoromethylpiperidine hydrochloride (284 mg, 1.50 mmol) were added. After stirring for 2 h, the reaction was concentrated and diluted with ethyl acetate and washed with water. After drying (Na2SO4), filtering, and concentrating, the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes to provide 2-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)benzonitrile [95 mg, LC-MS: 319.19 (M+H)+]. The product (52 mg) was dissolved in MeOH (5 mL), conc. HCl (25.0 mg) was added, and the whole was hydrogenated at 50 psi overnight. The reaction was concentrated and purified via preparative HPLC(CH3CN/water/TFA) to provide 210A. LC-MS: 323.21 (M+H)+. the reaction was concentrated diluted with ethyl acetate washed with water After drying (Na2SO4) filtering concentrating the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes

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

Procedure: To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL), triethylamine (0.84 mL, 6.00 mmol) and 4-trifluoromethylpiperidine hydrochloride (284 mg, 1.50 mmol) were added. After stirring for 2 h, the reaction was concentrated and diluted with ethyl acetate and washed with water. After drying (Na2SO4), filtering, and concentrating, the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes to provide 2-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)benzonitrile [95 mg, LC-MS: 319.19 (M+H)+]. The product (52 mg) was dissolved in MeOH (5 mL), conc. HCl (25.0 mg) was added, and the whole was hydrogenated at 50 psi overnight. The reaction was concentrated and purified via preparative HPLC(CH3CN/water/TFA) to provide 210A. LC-MS: 323.21 (M+H)+. the reaction was concentrated diluted with ethyl acetate washed with water After drying (Na2SO4) filtering concentrating the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes

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

Procedure: Dissolve (3R,5S)-Trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 43) (0.307 g, 0.48 mmol) in 5 ml of argon-sparged toluene. Treat with 4-trifluoromethylpiperidine-HCl salt (0.27 g, 1.43 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.02 g, 0.024 mmol) and triethylamine (0.21 ml, 1.48 mmol). Stir under 48 psi carbon monoxide pressure at 80° C. for 4 hr. Add 3 ml of argon-sparged dimethyl formamide and more triethylamine (0.25 ml, 1.76 mmol). Heat at 80° C. for 5 hrs under 50 psi carbon monoxide pressure. LCMS shows consumption of starting material. Cool to ambient temperature and add ethyl acetate (50 ml) and water (10 ml). Extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Dissolve the crude product in 5 ml of dimethoxyethane and treat with 2 M aqueous lithium hydroxide solution (1 ml). Stir for 2 hrs at ambient temperature. Dilute with ethyl acetate (50 ml) and water (10 ml) and extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Chromatography (silica, 97:3 CH2Cl2/2M NH3 in MeOH) yields 0.080 g as a white solid MS (m/z): 543 (M+1). sparged toluene Add 3 ml of argon- consumption of starting material add ethyl acetate (50 ml) and water (10 ml) Extract the aqueous phase with ethyl acetate (50 ml) Wash the organic phases with water (10 ml) and brine (10 ml) Combine the organic phases, dry over sodium sulfate concentrate under reduced pressure Dissolve the crude product in 5 ml of dimethoxyethane treat with 2 M aqueous lithium hydroxide solution (1 ml) Dilute with ethyl acetate (50 ml) and water (10 ml) extract the aqueous phase with ethyl acetate (50 ml) Wash the organic phases with water (10 ml) and brine (10 ml) Combine the organic phases, dry over sodium sulfate concentrate under reduced pressure Chromatography (silica, 97:3 CH2Cl2/2M NH3 in MeOH) yields 0.080 g as a white solid MS (m/z)

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

Procedure: Dissolve (3R,5S)-Trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(2-trifluoromethanesulfonyl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 43) (0.307 g, 0.48 mmol) in 5 ml of argon-sparged toluene. Treat with 4-trifluoromethylpiperidine-HCl salt (0.27 g, 1.43 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.02 g, 0.024 mmol) and triethylamine (0.21 ml, 1.48 mmol). Stir under 48 psi carbon monoxide pressure at 80° C. for 4 hr. Add 3 ml of argon-sparged dimethyl formamide and more triethylamine (0.25 ml, 1.76 mmol). Heat at 80° C. for 5 hrs under 50 psi carbon monoxide pressure. LCMS shows consumption of starting material. Cool to ambient temperature and add ethyl acetate (50 ml) and water (10 ml). Extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Dissolve the crude product in 5 ml of dimethoxyethane and treat with 2 M aqueous lithium hydroxide solution (1 ml). Stir for 2 hrs at ambient temperature. Dilute with ethyl acetate (50 ml) and water (10 ml) and extract the aqueous phase with ethyl acetate (50 ml). Wash the organic phases with water (10 ml) and brine (10 ml). Combine the organic phases, dry over sodium sulfate and concentrate under reduced pressure. Chromatography (silica, 97:3 CH2Cl2/2M NH3 in MeOH) yields 0.080 g as a white solid MS (m/z): 543 (M+1). sparged toluene Add 3 ml of argon- consumption of starting material add ethyl acetate (50 ml) and water (10 ml) Extract the aqueous phase with ethyl acetate (50 ml) Wash the organic phases with water (10 ml) and brine (10 ml) Combine the organic phases, dry over sodium sulfate concentrate under reduced pressure Dissolve the crude product in 5 ml of dimethoxyethane treat with 2 M aqueous lithium hydroxide solution (1 ml) Dilute with ethyl acetate (50 ml) and water (10 ml) extract the aqueous phase with ethyl acetate (50 ml) Wash the organic phases with water (10 ml) and brine (10 ml) Combine the organic phases, dry over sodium sulfate concentrate under reduced pressure Chromatography (silica, 97:3 CH2Cl2/2M NH3 in MeOH) yields 0.080 g as a white solid MS (m/z)

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

Procedure: To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at room temperature was added K2CO3 (590 mg, 4.3 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, Matrix Scientific). The reaction mixture was stirred at 80° C. for 4 h. The resulting mixture was allowed to cool to room temperature and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water (2×), MeOH (1×), and EtOAc (3×), then dried in vacuum. The title compound was obtained as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1). Anal. Calcd for C17H16F3N5OS: C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N, 17.61; F, 14.33. to cool to room temperature The resulting precipitate was collected by filtration washed with water (2×), MeOH (1×), and EtOAc (3×) dried in vacuum

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

Procedure: To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at room temperature was added K2CO3 (590 mg, 4.3 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, Matrix Scientific). The reaction mixture was stirred at 80° C. for 4 h. The resulting mixture was allowed to cool to room temperature and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water (2×), MeOH (1×), and EtOAc (3×), then dried in vacuum. The title compound was obtained as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (N+1). Anal. Calcd for C17H16F3N5OS: C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N, 17.61; F, 14.33. to cool to room temperature The resulting precipitate was collected by filtration washed with water (2×), MeOH (1×), and EtOAc (3×) dried in vacuum

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

Procedure: The product from Step 2 (140 mg, 0.408 mmol), 4-trifluoromethylpiperidine hydrochloride (78 mg, 0.408 mmol) and sodium cyanoborohydride (77 mg, 1.22 mmol) in methanol (15 ml) were stirred at room temperature for 18 hours. The mixture was quenched with water and then with sodium bicarbonate solution (sat). The product was extracted with DCM and the organic phase was dried and concentrated. The crude product was purified by column chromatography on silica gel eluting with 40:1 DCM-2M NH3 in MeOH to give a colourless oil. The product was re-purified by column chromatography on silica gel eluting with 7:1 isohexane-ethyl acetate to give a colourless oil 87 mg (44%). 1H NMR (CDCl3, 400 MHz) δ 6.99 (1H, d, J=8.0 Hz), 6.89 (2H, m), 4.98 (1H, m), 4.02 (1H, m), 2.95–3.02 (4H, m), 2.45–2.62 (6H, m), 2.35 (2H, m), 1.58–2.04 (11H, m), 1.47 (9H, m), 1.19 (2H, m). m/z 481 (M+H+). The mixture was quenched with water The product was extracted with DCM the organic phase was dried concentrated The crude product was purified by column chromatography on silica gel eluting with 40:1 DCM-2M NH3 in MeOH to give a colourless oil The product was re-purified by column chromatography on silica gel eluting with 7:1 isohexane-ethyl acetate

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

Procedure: To a solution of 4-(trifluoromethyl)piperidine HCl (1.7 g, 8.97 mmol) and DIEA (3.13 mL, 17.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.97 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.9 g (71%). 1H NMR (500 MHz, CDCl3) δ 5.25-5.20 (m, 1H), 3.54-3.51 (m, 2H), 3.15 (dt, J=12.5, 2.0 Hz, 2H), 2.87 (s, 3H), 2.57 (s, 3H), 2.30-2.23 (m, 1H), 2.02-1.99 (m, 2H), 1.79 (dq, J=12.4, 4.1 Hz, 2H) 1.43 (d, J=6.2 Hz, 6H). UPLC (M+H)=453.2. The resulting mixture was placed in a pre-heated oil bath cooled washed with water, brine dried (MgSO4) The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes)

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

Procedure: To a solution of 4-(trifluoromethyl)piperidine HCl (1.7 g, 8.97 mmol) and DIEA (3.13 mL, 17.9 mmol) in anhydrous CH3CN (15 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.97 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, diluted with ether, washed with water, brine, and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.9 g (71%). 1H NMR (500 MHz, CDCl3) δ 5.25-5.20 (m, 1H), 3.54-3.51 (m, 2H), 3.15 (dt, J=12.5, 2.0 Hz, 2H), 2.87 (s, 3H), 2.57 (s, 3H), 2.30-2.23 (m, 1H), 2.02-1.99 (m, 2H), 1.79 (dq, J=12.4, 4.1 Hz, 2H) 1.43 (d, J=6.2 Hz, 6H). UPLC (M+H)=453.2. The resulting mixture was placed in a pre-heated oil bath cooled washed with water, brine dried (MgSO4) The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes)