8-azabicyclo[3.2.1]octane;hydrochloride

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-(trifluoromethyl)benzonitrile (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. to cool to ambient temperature partitioned between diethyl ether and saturated NaHCO3 solution The separated aqueous phase was extracted with diethyl ether the combined organic layers were washed with water, brine dried (Na2SO4) filtered the filtrate was concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-3-(trifluoromethyl)benzonitrile (1.35 g, 7.14 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (1.26 g, 8.57 mmol), and N,N-diisopropylethylamine (1.79 g, 13.8 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 24 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The separated aqueous phase was extracted with diethyl ether and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. to cool to ambient temperature partitioned between diethyl ether and saturated NaHCO3 solution The separated aqueous phase was extracted with diethyl ether the combined organic layers were washed with water, brine dried (Na2SO4) filtered the filtrate was concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-fluorobenzonitrile (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. to cool to ambient temperature partitioned between diethyl ether and saturated NaHCO3 solution The aqueous phase was separated extracted with diethyl ether washed with water, brine dried (Na2SO4) filtered the filtrate was concentrated under reduced pressure

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

Procedure: The title compound was prepared using the procedure described in Example 325A except using 3,4,5-trifluorobenzonitrile and azepane instead of 3,4-difluorobenzonitrile and 8-aza-bicyclo[3.2.1]octane hydrochloride. 1H NMR (DMSO-d6) δ 7.62 (d, 2H), 3.39 (m, 4H), 1.73 (m, 4H), 1.61 (m, 4H); MS (ESI) m/z 237 (M+H)+.

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

Procedure: The title compound was prepared using the procedure described in Example 325A except using 3,4,5-trifluorobenzonitrile and azepane instead of 3,4-difluorobenzonitrile and 8-aza-bicyclo[3.2.1]octane hydrochloride. 1H NMR (DMSO-d6) δ 7.62 (d, 2H), 3.39 (m, 4H), 1.73 (m, 4H), 1.61 (m, 4H); MS (ESI) m/z 237 (M+H)+.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Difluorobenzonitrile (1.75 g; 25.1 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (2.1 g; 13.8 mmol), and diisopropylethylamine (3.2 g; 25.1 mmol), were combined in DMSO (30 mL) and heated at 120° C. overnight. The mixture was allowed to cool to ambient temperature, poured into brine (75 mL), and extracted with diethyl ether (2×50 mL). The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel (ethyl acetate as eluent) to provide the title compound. 1H NMR (DMSO-d6) δ 7.69 (dd, 1H), 7.42 (dd, 1H), 7.15 (t, 1H), 4.41 (s, 2H), 1.98 (m, 2H), 1.62-1.86 (m, 5H), 1.41 (m, 3H); MS (ESI) m/z 231, (M+H)+. to cool to ambient temperature extracted with diethyl ether (2×50 mL) dried over MgSO4 filtered the filtrate was concentrated under reduced pressure The residue was filtered through a pad of silica gel (ethyl acetate as eluent)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,4-Difluorobenzonitrile (1.75 g; 25.1 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (2.1 g; 13.8 mmol), and diisopropylethylamine (3.2 g; 25.1 mmol), were combined in DMSO (30 mL) and heated at 120° C. overnight. The mixture was allowed to cool to ambient temperature, poured into brine (75 mL), and extracted with diethyl ether (2×50 mL). The organics were combined, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was filtered through a pad of silica gel (ethyl acetate as eluent) to provide the title compound. 1H NMR (DMSO-d6) δ 7.69 (dd, 1H), 7.42 (dd, 1H), 7.15 (t, 1H), 4.41 (s, 2H), 1.98 (m, 2H), 1.62-1.86 (m, 5H), 1.41 (m, 3H); MS (ESI) m/z 231, (M+H)+. to cool to ambient temperature extracted with diethyl ether (2×50 mL) dried over MgSO4 filtered the filtrate was concentrated under reduced pressure The residue was filtered through a pad of silica gel (ethyl acetate as eluent)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.107 mmol, 1 equiv) in DMF (0.54 mL) was added 8-azabicyclo[3.2.1]octane hydrochloride (31 mg, 0.214 mmol, 2 equiv) and DIPEA (0.075 mL, 0.428 mmol, 4 equiv). The resulting solution was stirred at 85° C. for 18 h. Complete conversion to pyrimidyl amine was observed. To this solution was then added phenyl boronic acid (30 mg, 0.250 mmol, 2.5 equiv), potassium phosphate, tribasic (0.25 mL of a 2 M aqueous solution, 0.500 mmol, 4.7 equiv), and PdCl2(dppf).CH2Cl2 adduct (8 mg, 0.010 mmol, 0.09 equiv). The mixture was heated at 85° C. for 2 h. Upon completion of the Suzuki reaction, the reaction temperature was lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (24 mg, 1.00 mmol, 9 equiv) added and heating was continued for 2 h. Upon completion of hydrolysis, reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×200 mm, 5-μμm particles Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B, to provide (S)-2-(2-([1,1′-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (8.9 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.44-7.38 (m, 1H), 7.00 (s, 1H), 5.45 (br. s., 1H), 5.15 (br. s., 1H), 4.37 (br. s., 1H), 2.86 (br. s., 1H), 2.46 (s, 3H), 2.29 (br. s., 1H), 1.92 (d, J=13.7 Hz, 3H), 1.78 (d, J=12.8 Hz, 2H), 1.69 (d, J=14.0 Hz, 3H), 1.14 (s, 9H). LCMS (ESI, M+1): 525.4. The mixture was heated at 85° C. for 2 h Upon completion of the Suzuki reaction was lowered to 60° C heating was continued for 2 h Upon completion of hydrolysis, reaction was removed from heat filtered through a syringe filter The crude reaction mixture was purified via preparative LC/MS with the following conditions Gradient: 40-80% B over 20 minutes

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.107 mmol, 1 equiv) in DMF (0.54 mL) was added 8-azabicyclo[3.2.1]octane hydrochloride (31 mg, 0.214 mmol, 2 equiv) and DIPEA (0.075 mL, 0.428 mmol, 4 equiv). The resulting solution was stirred at 85° C. for 18 h. Complete conversion to pyrimidyl amine was observed. To this solution was then added phenyl boronic acid (30 mg, 0.250 mmol, 2.5 equiv), potassium phosphate, tribasic (0.25 mL of a 2 M aqueous solution, 0.500 mmol, 4.7 equiv), and PdCl2(dppf).CH2Cl2 adduct (8 mg, 0.010 mmol, 0.09 equiv). The mixture was heated at 85° C. for 2 h. Upon completion of the Suzuki reaction, the reaction temperature was lowered to 60° C. Methanol (1 mL), water (0.3 mL), and LiOH.H2O (24 mg, 1.00 mmol, 9 equiv) added and heating was continued for 2 h. Upon completion of hydrolysis, reaction was removed from heat and filtered through a syringe filter. The crude reaction mixture was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×200 mm, 5-μμm particles Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B, to provide (S)-2-(2-([1,1′-biphenyl]-3-yl)-7-((1R,5 S)-8-azabicyclo[3.2.1]octan-8-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (8.9 mg, 17% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.44-7.38 (m, 1H), 7.00 (s, 1H), 5.45 (br. s., 1H), 5.15 (br. s., 1H), 4.37 (br. s., 1H), 2.86 (br. s., 1H), 2.46 (s, 3H), 2.29 (br. s., 1H), 1.92 (d, J=13.7 Hz, 3H), 1.78 (d, J=12.8 Hz, 2H), 1.69 (d, J=14.0 Hz, 3H), 1.14 (s, 9H). LCMS (ESI, M+1): 525.4. The mixture was heated at 85° C. for 2 h Upon completion of the Suzuki reaction was lowered to 60° C heating was continued for 2 h Upon completion of hydrolysis, reaction was removed from heat filtered through a syringe filter The crude reaction mixture was purified via preparative LC/MS with the following conditions Gradient: 40-80% B over 20 minutes

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

Procedure: Tropane (1.0 mL, 7.44 mmol) was dissolved in toluene (10 mL), chloroethyl carbonate (2.2 mL, 23 mmol) was added slowly, and the mixture stirred at 80° C. for 24 hours. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was dried and concentrated by anhydrous magnesium sulfate. The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL), and heated with stirring at 100° C. for 2 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid. the mixture extracted with ethyl acetate The organic phase was dried concentrated by anhydrous magnesium sulfate The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL) heated with stirring at 100° C. for 2 hours The solvent was distilled off under reduced pressure, toluene was added to the residue the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid

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

Procedure: Tropane (1.0 mL, 7.44 mmol) was dissolved in toluene (10 mL), chloroethyl carbonate (2.2 mL, 23 mmol) was added slowly, and the mixture stirred at 80° C. for 24 hours. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was dried and concentrated by anhydrous magnesium sulfate. The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL), and heated with stirring at 100° C. for 2 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid. the mixture extracted with ethyl acetate The organic phase was dried concentrated by anhydrous magnesium sulfate The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL) heated with stirring at 100° C. for 2 hours The solvent was distilled off under reduced pressure, toluene was added to the residue the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid

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

Procedure: Tropane (11.0 mL, 7.44 mmol) was dissolved in toluene (10 mL), chloroethyl carbonate (2.2 mL, 23 mmol) was added slowly, and the mixture stirred at 80° C. for 24 hours. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was dried and concentrated by anhydrous magnesium sulfate. The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL), and heated with stirring at 100° C. for 2 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid. the mixture extracted with ethyl acetate The organic phase was dried concentrated by anhydrous magnesium sulfate The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL) heated with stirring at 100° C. for 2 hours The solvent was distilled off under reduced pressure, toluene was added to the residue the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid