Prep hplc

Example 3

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A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.45 mmol), Pd(dppf)Cl₂ (49.31 mg, 0.07 mmol), Cs₂CO₃ (292.77 mg, 0.90 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (235.31 mg, 0.67 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was concentrated to a residue. The residue was diluted with H₂O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 10 μm) A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN; 55-75% B over 6 minutes) to give the product (81.74 mg, 0.20 mmol) as a solid. ¹H NMR (400 MHz, CDCl3) δ_H=9.59 (d, 1H), 8.53 (d, 1H), 8.40 (s, 1H), 8.03 (dd, 1H), 1.89 (s, 6H). LCMS R_t=1.09 min in 2 min chromatography, MS ESI calcd. for C₁₅H₁₁F₇N₅O [M+H]⁺ 410.1, found 410.0.

Example 40

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To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was added HATU (155 mg, 0.41 mmol), DIPEA (87.81 mg, 0.68 mmol) and morpholine (23.68 mg, 0.27 mmol). The resulting mixture was stirred at 15° C. for 16 hours. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction solution. After separation, the organic layer was washed with brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated to give the crude product that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN); 37-67% B over 10 minutes) to afford Compound 40 (8.33 mg, 0.02 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ=7.76 (d, 2H), 7.60 (d, 1H), 7.51-7.41 (m, 4H), 4.91 (s, 2H), 3.72-3.66 (m, 2H), 3.60-3.54 (m, 4H), 3.47-3.41 (m, 2H). LCMS R_t=1.17 min using Method A, MS ESI calcd. for C₂₀H₁₈F₃N₂O₅ [M+H]⁺ 423.1, found 423.0.

Example 17

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To the mixture of Compound 16 (100. mg, 0.28 mmol), HATU (161.4 mg, 0.42 mmol) and DIEA (73.04 mg, 0.57 mmol) in DMF (2 mL) was added pyrrolidine (24.16 mg, 0.34 mmol) and the mixture was stirred at 15° C. for 16 hours. The mixture was diluted with sat. NH₄Cl (10 mL), extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give the crude product, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN); 40-70% B over 10 minutes) to afford Compound 17 (19.77 mg, 0.05 mmol) as a solid. ¹H NMR (DMSO-d₆+D₂O 400 MHz) δ_H=7.73 (d, 2H), 7.48 (s, 1H), 7.44-7.40 (m, 4H), 4.70 (s, 2H), 3.52 (t, 2H), 3.28 (t, 2H), 1.97-1.87 (m, 2H), 1.83-1.71 (m, 2H). LCMS R_t=1.26 min using Method A, MS ESI calcd. for C₂₀H₁₈F₃N₂O₄ [M+H]⁺ 407.1, found 407.0.

Example 154

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A mixture of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (300 mg, 1.47 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.03 g, 4.40 mmol), Cs₂CO₃ (955.61 mg, 2.93 mmol) and Pd(dppf)Cl₂ (160.96 mg, 0.22 mmol) in 1,4-dioxane (10 mL) and water (0.50 mL) was stirred at 70° C. under N₂. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to give a residue. The residue was diluted in EtOAc (20 mL), washed with water (20 mL×2) and brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=30% to 80%) to give the product (330 mg).

The impure product (100 mg) was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 20-40% B over 6 minutes) to give the product (29.12 mg, 0.11 mmol) as a solid. ¹H NMR (400 MHz DMSO-d₆) δ_H=9.66 (s, 1H), 9.13 (s, 1H), 8.09 (d, 2H), 7.85 (t, 1H), 7.49 (d, 2H), 5.31 (t, 1H), 4.58 (d, 2H). LCMS R_t=1.04 min in 2.0 min chromatography, 0-60AB, purity 100%, MS ESI calcd. for C₁₃H₁₁F₂N₄O [M+H]⁺277.1, found 276.9.

Example 26

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To the mixture of Compound 24 (150 mg, 0.4100 mmol), HATU (232.79 mg, 0.61 mmol) and DIEA (105.37 mg, 0.82 mmol) in DMF (2 mL) was added pyrrolidine (34.86 mg, 0.49 mmol) and the mixture was stirred at 15° C. for 16 hours. The mixture was diluted with sat.NH₄Cl (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give a residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN); 43-73% B over 10 minutes) to afford Compound 26 (72.24 mg, 0.17 mmol) as an oil. ¹H NMR (DMSO-d₆+D₂O 400 MHz) δ_H=7.77 (d, 2H), 7.58 (s, 1H), 7.46-7.33 (m, 4H), 4.07 (t, 2H), 3.30 (t, 2H), 3.17 (t, 2H), 2.73 (t, 2H), 1.82-1.73 (m, 2H), 1.71-1.62 (m, 2H). LCMS R_t=1.20 min ung Method A, MS ESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found 421.0.

Example 96

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A mixture of 3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), Et₃N (0.17 mL, 1.21 mmol) and methanesulfonyl chloride (55.23 mg, 0.48 mmol) in DCM (25 mL) was stirred at 20° C. for 16 hours. The reaction was diluted with sat.NH₄Cl (15 mL), and extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN; 55-75% B over 6 minutes) to give the product (22.24 mg, 48.7 μmol, 20% yield, 100%) as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_H=7.77 (d, 2H), 7.59 (s, 1H), 7.46-7.34 (m, 4H), 4.13-4.07 (m, 1H), 3.98-3.86 (m, 2H), 3.31-3.17 (m, 2H), 2.83 (s, 3H), 2.04-1.78 (m, 4H). LCMS R_t=1.25 min in 2 min chromatography, MS ESI calcd. for C₂₀H₂₀F₃N₂O₅S [M+H]⁺ 457.1, found 457.1.

Example 91

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A mixture of 3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one hydrochloride (100 mg, 0.24 mmol), Et₃N (0.17 mL, 1.21 mmol) and methanesulfonyl chloride (55.23 mg, 0.48 mmol) in CH₂Cl₂ (10 mL) was stirred at 25° C. for 16 hours. The reaction was quenched with sat.NH₄Cl (10 mL), and the mixture was extracted with CH₂Cl₂ (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give the crude product. The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B═CH₃CN; 55-75% B over 6 minutes) to give the product (47.27 mg, 0.10 mmol, 43% yield) as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_H=7.78 (d, 2H), 7.61 (s, 1H), 7.48-7.38 (m, 4H), 4.13-4.07 (m, 1H), 3.97-3.86 (m, 2H), 3.31-3.20 (m, 2H), 2.86 (s, 3H), 2.05-1.79 (m, 4H). LCMS R_t=1.26 min in 2.0 min chromatography, MS ESI calcd. for C₂₀H₂₀F₃N₂O₅S [M+H]⁺ 457.1, found 457.0.