[(1R)-1-(4-fluorophenyl)ethyl]urea

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 mL microwave vial was charged with cesium carbonate (71.7 mg, 0.220 mmol), (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (40 mg, 0.085 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (23.3 mg, 0.128 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (3.21 mg, 5.97 μmol) and BrettPhos-G3-Pd (5.41 mg, 5.97 μmol). Dioxane (1 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added and the contents heated to 65° C. for 4 h with shaking. The reaction mixture was filtered, washing through with DCM (2 mL) and concentrated. The resulting residue was re-dissolved in TFA (1 mL) and stirred at room temperature for 30 minutes. Triethylsilane (0.014 ml, 0.085 mmol) was added drop wise and the reaction mixture was stirred for an additional 5 minutes. The volatiles were removed in vacuo, the resulting residue was re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered HPLC to afford (R)-methyl (6-(3-(1-(4-fluorophenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (5.4 mg, 0.011 mmol, 13.1% yield) as a white solid. MS ESI calc'd. For C17H18FN6O3 [M+H]+ 373. found 373. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.39 (s, 1H); 9.26 (s, 1H); 8.94 (s, 1H); 7.76 (s, 1H); 7.43 (s, 1H); 7.35 (dd, J=8.4, 5.5 Hz, 2H); 7.13 (t, J=8.8 Hz, 2H); 4.84 (t, J=7.2 Hz, 1H); 3.68 (s, 3H); 1.37 (d, J=7.0 Hz, 3H). the vial was flushed with argon capped The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added the contents heated to 65° C. for 4 h with shaking The reaction mixture was filtered washing through with DCM (2 mL) concentrated The resulting residue was re-dissolved in TFA (1 mL) stirred at room temperature for 30 minutes the reaction mixture was stirred for an additional 5 minutes The volatiles were removed in vacuo the resulting residue was re-dissolved in DMSO (1.5 mL) submitted for purification by mass-triggered HPLC

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 mL microwave vial was charged with cesium carbonate (71.7 mg, 0.220 mmol), (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (40 mg, 0.085 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (23.3 mg, 0.128 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (3.21 mg, 5.97 μmol) and BrettPhos-G3-Pd (5.41 mg, 5.97 μmol). Dioxane (1 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added and the contents heated to 65° C. for 4 h with shaking. The reaction mixture was filtered, washing through with DCM (2 mL) and concentrated. The resulting residue was re-dissolved in TFA (1 mL) and stirred at room temperature for 30 minutes. Triethylsilane (0.014 ml, 0.085 mmol) was added drop wise and the reaction mixture was stirred for an additional 5 minutes. The volatiles were removed in vacuo, the resulting residue was re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered HPLC to afford (R)-methyl (6-(3-(1-(4-fluorophenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (5.4 mg, 0.011 mmol, 13.1% yield) as a white solid. MS ESI calc'd. For C17H18FN6O3 [M+H]+ 373. found 373. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.39 (s, 1H); 9.26 (s, 1H); 8.94 (s, 1H); 7.76 (s, 1H); 7.43 (s, 1H); 7.35 (dd, J=8.4, 5.5 Hz, 2H); 7.13 (t, J=8.8 Hz, 2H); 4.84 (t, J=7.2 Hz, 1H); 3.68 (s, 3H); 1.37 (d, J=7.0 Hz, 3H). the vial was flushed with argon capped The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added the contents heated to 65° C. for 4 h with shaking The reaction mixture was filtered washing through with DCM (2 mL) concentrated The resulting residue was re-dissolved in TFA (1 mL) stirred at room temperature for 30 minutes the reaction mixture was stirred for an additional 5 minutes The volatiles were removed in vacuo the resulting residue was re-dissolved in DMSO (1.5 mL) submitted for purification by mass-triggered HPLC

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (332 mg, 0.781 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 20C; 193 mg, 1.059 mmol), BrettPhos pre-catalyst (48.0 mg, 0.060 mmol), and cesium carbonate (759 mg, 2.330 mmol) were taken up in 1,4-dioxane (6 mL) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction was stirred at 100° C. for 3 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(1-(4-fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C35H31FN6O [M+1]+ 571. found 571. The vial was evacuated back-filled with N2 (×3) Room temperature the reaction mixture was filtered through Celite eluting with MeOH the filtrate was concentrated in vacuo Purification of the residue by flash chromatography (0-100% EtOAc-DCM)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (332 mg, 0.781 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 20C; 193 mg, 1.059 mmol), BrettPhos pre-catalyst (48.0 mg, 0.060 mmol), and cesium carbonate (759 mg, 2.330 mmol) were taken up in 1,4-dioxane (6 mL) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction was stirred at 100° C. for 3 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(1-(4-fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C35H31FN6O [M+1]+ 571. found 571. The vial was evacuated back-filled with N2 (×3) Room temperature the reaction mixture was filtered through Celite eluting with MeOH the filtrate was concentrated in vacuo Purification of the residue by flash chromatography (0-100% EtOAc-DCM)

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

Procedure: (R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183. Upon cooling to room temperature a precipitate formed which was collected by filtration washed with water The solid was partitioned between water and EtOAc the aqueous phase extracted once more with EtOAc The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: tert-Butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (77 mg, 0.259 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 15B; 60 mg, 0.329 mmol), bippyphos (15.6 mg, 0.031 mmol), Pd2(dba)3 (9.6 mg, 10.48 μmol), and tripotassium phosphate (82 mg, 0.388 mmol) were taken up in DME (1.3 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 18 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL) and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. For C17H18FN5O2 [M+1]+ 344. found 344. 1H NMR (500 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 7.76 (br s, 1H), 7.46 (s, 1H), 7.39-7.33 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.89-4.82 (m, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.41-1.34 (m, 6H). The vial was evacuated back-filled with N2 (×3) Room temperature the reaction mixture was filtered through Celite eluting with MeOH the filtrate was concentrated in vacuo The residue was dissolved in TFA (2 mL) the solution stirred at room temperature for 3 h The solvent was removed in vacuo, saturated NaHCO3 was added the products extracted into EtOAc (×2) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification of the residue by flash chromatography (0-100% EtOAc-DCM)

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

Procedure: tert-Butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (77 mg, 0.259 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 15B; 60 mg, 0.329 mmol), bippyphos (15.6 mg, 0.031 mmol), Pd2(dba)3 (9.6 mg, 10.48 μmol), and tripotassium phosphate (82 mg, 0.388 mmol) were taken up in DME (1.3 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 18 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL) and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. For C17H18FN5O2 [M+1]+ 344. found 344. 1H NMR (500 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 7.76 (br s, 1H), 7.46 (s, 1H), 7.39-7.33 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.89-4.82 (m, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.41-1.34 (m, 6H). The vial was evacuated back-filled with N2 (×3) Room temperature the reaction mixture was filtered through Celite eluting with MeOH the filtrate was concentrated in vacuo The residue was dissolved in TFA (2 mL) the solution stirred at room temperature for 3 h The solvent was removed in vacuo, saturated NaHCO3 was added the products extracted into EtOAc (×2) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification of the residue by flash chromatography (0-100% EtOAc-DCM)

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

Procedure: (R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea), without further purification. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183. Upon cooling to room temperature a precipitate formed which was collected by filtration washed with water The solid was partitioned between water and EtOAc the aqueous phase extracted once more with EtOAc The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: In a manner similar to that described in Scheme 6 and Example 30, 6-chloro-3-(2,2-difluoro-1-methylcyclopropyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine was reacted with (R)-1-(1-(4-fluorophenyl)ethyl)urea (Xantphos, Pd(OAc)2, Cs2CO3, dioxane, 80° C., overnight) and then deprotected with TFA to provide (R)-1-(3-(2,2-difluoro-1-methylcyclopropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea 2,2,2-trifluoroacetate. MS ESI calc'd. for C19H18F3N5O[M+1]+ 390, found 390.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 5 mL microwave vial was charged with cesium carbonate (71.7 mg, 0.220 mmol), (6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (40 mg, 0.085 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (23.3 mg, 0.128 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (3.21 mg, 5.97 μmol) and BrettPhos-G3-Pd (5.41 mg, 5.97 μmol). Dioxane (1 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added and the contents heated to 65° C. for 4 h with shaking. The reaction mixture was filtered, washing through with DCM (2 mL) and concentrated. The resulting residue was re-dissolved in TFA (1 mL) and stirred at room temperature for 30 minutes. Triethylsilane (0.014 ml, 0.085 mmol) was added drop wise and the reaction mixture was stirred for an additional 5 minutes. The volatiles were removed in vacuo, the resulting residue was re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered HPLC to afford (R)-methyl (6-(3-(1-(4-fluorophenyl)ethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate. TFA (5.4 mg, 0.011 mmol, 13.1% yield) as a white solid. MS ESI calc'd. For C17H18FN6O3 [M+H]+ 373. found 373. 1H NMR (ppm, 600 MHz, DMSO-d6): δ 10.39 (s, 1H); 9.26 (s, 1H); 8.94 (s, 1H); 7.76 (s, 1H); 7.43 (s, 1H); 7.35 (dd, J=8.4, 5.5 Hz, 2H); 7.13 (t, J=8.8 Hz, 2H); 4.84 (t, J=7.2 Hz, 1H); 3.68 (s, 3H); 1.37 (d, J=7.0 Hz, 3H). the vial was flushed with argon capped The reaction mixture was diluted with DCM (2 ml), MP-TMT (119 mg, 0.119 mmol) added the contents heated to 65° C. for 4 h with shaking The reaction mixture was filtered washing through with DCM (2 mL) concentrated The resulting residue was re-dissolved in TFA (1 mL) stirred at room temperature for 30 minutes the reaction mixture was stirred for an additional 5 minutes The volatiles were removed in vacuo the resulting residue was re-dissolved in DMSO (1.5 mL) submitted for purification by mass-triggered HPLC

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Chloro-N-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (332 mg, 0.781 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 20C; 193 mg, 1.059 mmol), BrettPhos pre-catalyst (48.0 mg, 0.060 mmol), and cesium carbonate (759 mg, 2.330 mmol) were taken up in 1,4-dioxane (6 mL) in a 20 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction was stirred at 100° C. for 3 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(1-(4-fluorophenyl)ethyl)-3-(3-(methylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C35H31FN6O [M+1]+ 571. found 571. The vial was evacuated back-filled with N2 (×3) Room temperature the reaction mixture was filtered through Celite eluting with MeOH the filtrate was concentrated in vacuo Purification of the residue by flash chromatography (0-100% EtOAc-DCM)

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

Procedure: (R)-1-(4-Fluorophenyl)ethanamine (5.15 g, 37.0 mmol) was taken up in HCl (2N, 40 mL) and potassium cyanate (15.01 g, 185 mmol) was added. The mixture was stirred at 80° C. for 3 h. Upon cooling to room temperature, a precipitate formed which was collected by filtration and washed with water. The solid was partitioned between water and EtOAc, and the aqueous phase extracted once more with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give (R)-1-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. for C9H11FN2O [M+1]+ 183. found 183. Upon cooling to room temperature a precipitate formed which was collected by filtration washed with water The solid was partitioned between water and EtOAc the aqueous phase extracted once more with EtOAc The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo