3,3-difluorocyclobutan-1-amine;hydrochloride

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%). The compound was prepared

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

Procedure: Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 46.7 mg, 0.106 mmol), 3,3-difluorocyclobutanamine hydrochloride (PharmaStone, Lexington, Mass.; 45.5 mg, 0.317 mmol), and DIPEA (0.110 mL, 0.634 mmol) in DMSO (0.8 mL), heating at 80° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2434(3,3-difluorocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26.5 mg, 0.069 mmol, 66% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s.), 7.88 (1H, dd, J=7.6, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.0 Hz), 7.51 (1H, d, J=5.5 Hz), 7.37 (1H, t, J=7.8 Hz), 7.06 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 4.39-4.51 (1H, m), 3.45 (2H, td, J=6.7, 2.5 Hz), 3.04-3.15 (2H, m), 2.88 (2H, t, J=6.7 Hz), 2.86-2.92 (2H, m), 2.57 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −82.16 to −81.43 (1F, m), −95.87 to −95.05 (1F, m). m/z (ESI, +ve) 384.2 (M+H)+. Prepared similar to Chromatographic purification (silica gel, 0-100% EtOAc/hexanes

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (0.46 g, 1.221 mmol), 3,3-difluorocyclobutanamine hydrochloride (0.526 g, 3.66 mmol), and potassium fluoride (0.092 g, 1.587 mmol) in DMSO (5 mL) and added DIPEA (1.063 mL, 6.10 mmol) at 23° C. The reaction was stirred at 23° C. for 5 days and diluted with water (20 mL) to furnish a yellow-orange suspension. The resulting solid was filtered, rinsed with water, and dried in vacuo to give the title compound (516.4 mg, 95%) as a yellow-orange solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.87-1.98 (m, 2H), 2.07-2.18 (m, 2H), 2.77-2.91 (m, 2H), 2.96-3.07 (m, 2H), 3.23-3.32 (m, 2H), 3.69-3.78 (m, 2H), 4.35-4.45 (m, 1H), 4.63 (tt, J=7.9, 3.8 Hz, 1H), 7.00-7.07 (m, 1H), 7.24-7.40 (m, 3H), 7.48 (d, J=5.4 Hz, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.82 (s, 1H); ESI-MS m/z [M+H]+ 447.9. to furnish a yellow-orange suspension The resulting solid was filtered rinsed with water dried in vacuo

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

Procedure: A mixture of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (60.0 mg, 0.14 mmol), 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylic acid (48.4 mg, 0.0913 mmol), 3,3-difluorocyclobutanamine hydrochloride (20. mg, 0.14 mmol, Molbridge: Cat. #MB00001399) and N,N-diisopropylethylamine (64 μL, 0.36 mmol) in methylene chloride (2 mL) was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with dichloromethylene (2×2 mL). The combined organic layers were washed with water (1 mL), concentrated and dried under reduced pressure. The residue was dissolved in dichloromethylene (1 mL) and trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 1.5 hours, and concentrated under reduced pressure. The residue was dissolved in methanol (2.5 mL). Ethylenediamine (0.21 mL, 3.2 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=490.1. 1H NMR (300 MHz, DMSO-d6): δ 12.50 (br, 1H), 9.01 (s, 1H), 8.93 (d, J=7.8 Hz, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.89 (d, J=2.7 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.70 (dd, J=3.4, 2.5 Hz, 1H), 7.15 (dd, J=3.5, 1.5 Hz, 1H), 7.04 (dd, J=8.6, 2.8 Hz, 1H), 4.63 (d, J=9.0 Hz, 2H), 4.36 (d, J=8.9 Hz, 2H), 4.23 (m, 1H), 3.73 (s, 2H), 2.80 (m, 4H). extracted with dichloromethylene (2×2 mL) The combined organic layers were washed with water (1 mL) concentrated dried under reduced pressure The residue was dissolved in dichloromethylene (1 mL) The mixture was stirred at room temperature for 1.5 hours concentrated under reduced pressure The residue was dissolved in methanol (2.5 mL) The reaction mixture was stirred at room temperature for 2 hours purified by RP-HPLC (pH=10)

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%). The compound was prepared

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%). The compound was prepared

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%). The compound was prepared

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

Procedure: The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%). The compound was prepared

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

Procedure: 3-(Chloromethyl)benzoyl chloride (13.93 mmol, 2.63 g) was stirred in dichloromethane (50 ml) at 0° C. Triethylamine (41.8 mmol, 5.81 ml, 4.23 g) and 3,3-difluorocyclobutanamine hydrochloride (13.93 mmol, 2 g) were combined in dichloromethane and added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (3.33 g). MS (ESI) m/z 260.3 [M+H]+ added dropwise The reaction mixture was washed with water dried over sodium sulfate concentrated under vacuum

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

Procedure: 0.60 g 3,3-Difluoro-cyclobutylamine hydrochloride were suspended using 40 ml CH2Cl2 and 2.9 ml of triethylamine added at ambient temperature while receiving a clear solution. Thereafter, 1.0 ml of methanesulfonylchloride were added dropwise at ambient temperature and the mixture left at that temperature for 16 h. The volatiles were removed in vacuo, the residue was redissolved using 200 ml of EE and 100 ml of a saturated aqueous Na2CO3-solution and the layers separated. The organic layer was washed twice using 20 ml of a saturated aqueous NaHSO4-solution each time and washed twice using 30 ml of a saturated aqueous Na2CO3-solution each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 700 mg of a colorless resin. added at ambient temperature The volatiles were removed in vacuo the residue was redissolved the layers separated The organic layer was washed twice washed twice The organic layer was dried over MgSO4 the solvent removed in vacuo

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

Procedure: To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (1.09 g, 3 mmol) and 3,3-difluorocyclobutyl amine hydrochloride (1 g, 7 mmol) in DMF (10 ml), added PyBOP (1.56 g, 3 mmol) then triethyl amine (1.8 ml, 12 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C19H20BF2N3O5S): 451.12. MS found (ESI negative): (M−H)−=450.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H), 9.15 (s, 1H), 8.48 (d, J=6.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4 Hz, 1H), 6.40 (d, J=2 Hz, 1H), 6.35 (dd, J=8.4 Hz, 1H), 5.92 (s, 2H), 4.85 (s, 2H), 4.05 (m, 1H), 3.75 (s, 2H), 2.89 (m, 2H), 2.59 (m, 2H). washed with 1N HCl, water and brine Dried over anhydrous sodium sulfate Concentrated the residue was dissolved in DMSO purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column)

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

Procedure: Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 46.7 mg, 0.106 mmol), 3,3-difluorocyclobutanamine hydrochloride (PharmaStone, Lexington, Mass.; 45.5 mg, 0.317 mmol), and DIPEA (0.110 mL, 0.634 mmol) in DMSO (0.8 mL), heating at 80° C. for 1.5 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2434(3,3-difluorocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26.5 mg, 0.069 mmol, 66% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s.), 7.88 (1H, dd, J=7.6, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.0 Hz), 7.51 (1H, d, J=5.5 Hz), 7.37 (1H, t, J=7.8 Hz), 7.06 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 4.39-4.51 (1H, m), 3.45 (2H, td, J=6.7, 2.5 Hz), 3.04-3.15 (2H, m), 2.88 (2H, t, J=6.7 Hz), 2.86-2.92 (2H, m), 2.57 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −82.16 to −81.43 (1F, m), −95.87 to −95.05 (1F, m). m/z (ESI, +ve) 384.2 (M+H)+. Prepared similar to Chromatographic purification (silica gel, 0-100% EtOAc/hexanes