Millex lcr

Example 103

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In a 125 mL round-bottomed flask, were combined trans-2,2-dimethyl-N-(4-(6-methylpyridin-3-yl)pyrrolidin-3-yl)-3-((3-(trifluoromethyl)pyridin-2-yl)oxy)propanamide (0.102 g, 0.241 mmol), 2-bromoacetonitrile (0.043 g, 0.36 mmol), and potassium carbonate (0.100 g, 0.724 mmol) in DMF (2 mL) to give a white suspension. The reaction mixture was stirred at 50° C. for 2 hours and was then filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR) which was rinsed with methanol. The filtrate was purified by preparative HPLC (Method B) and the product-containing fractions were evaporated to give the title compound as a brown film (45.2 mg, 41%). ¹H NMR (500 MHz, CD₃OD) δ ppm 1.27 (app d, J=10.7 Hz, 6H), 2.48 (s, 3H), 2.70-2.75 (m, 1H), 2.80 (s, 1H), 3.18 (s, 1H), 3.23 (s, 1H), 3.33-3.39 (m, 1H), 3.81 (d, J=6.4 Hz, 2H), 4.40 (d, J=5.4 Hz, 2H), 4.42-4.51 (m, 1H), 7.02-7.11 (m, 1H), 7.22 (s, 1H), 7.66-7.75 (m, 1H), 7.91-7.98 (m, 1H), 8.25-8.30 (m, 1H), 8.30-8.36 (m, 1H); ESI-MS [M+H]⁺ calc'd for C₂₃H₂₆F₃N₅O₂, 462.20. found, 462.5.

Example 81

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Diisopropyl azodicarboxylate (0.244 mL, 1.24 mmol) was added dropwise to a solution of triphenylphosphine (0.320 g, 1.22 mmol), 2-chlorophenol (0.127 g, 0.990 mmol), and 1-(hydroxymethyl)-N-(1-methylpiperidin-4-yl)cyclopropane-1-carboxamide (0.236 g, 1.16 mmol) in toluene (9.90 mL). The solution was heated to 80° C. for 6 hours and then concentrated under reduced pressure. The residue was diluted with DMF and methanol, filtered through a hydrophilic PTFE 0.45 m filter (Millipore® Millex-LCR) and purified by preparative HPLC (Method B) to give the title compound (0.012 g, 4%). ¹H NMR (500 MHz, CD₃OD) δ 0.89 (m, 2H), 1.24 (m, 2H), 1.58 (m, 2H), 1.80 (m, 2H), 2.16 (m, 2H), 2.24 (s, 3H), 2.81 (m, 2H), 3.69 (m, 1H), 4.19 (m, 2H), 6.95 (m, 1H), 7.16 (m, 1H), 7.29 (m, 1H), 7.40 (m, 1H); ESI-MS [M+H]⁺ calc'd for C₁₇H₂₃ClN₂O₂, 323.15. found, 323.30.

Example 204

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To a solution of 3-(4-fluorophenoxy)-2,2-dimethylpropanoic acid (40.0 mg, 0.188 mmol), 1-methylpiperidin-4-amine (23.7 mg, 0.207 mmol), and HATU (89.0 mg, 0.226 mmol) in DMF (628 μL) was added DIPEA (99 μL, 0.56 mmol). The reaction mixture was stirred at room temperature overnight and then filtered through a hydrophilic PTFE 0.45 m filter (Millipore® Millex-LCR) which was rinsed with methanol. The filtrate was purified by preparative HPLC (Method B) give the title compound as a pale-yellow oil (37.5 mg, 64%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (s, 6H), 1.40-1.53 (m, 2H), 1.87-1.99 (m, 2H), 2.08-2.20 (m, 2H), 2.28 (s, 3H), 2.66-2.79 (m, 2H), 3.70-3.88 (m, 1H), 3.89 (s, 2H), 6.02-6.20 (m, 1H), 6.78-6.93 (m, 1H), 6.89-6.90 (m, 1H), 6.98 (d, J=8.2 Hz, 2H); ESI-MS [M+H]⁺ calc'd for C₁₇H₂₅FN₂O₂, 309.19. found, 309.3.

Example 186

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A solution of 3-(2-chlorophenoxy)-2,2-dimethylpropanoic acid (59 mg, 0.26 mmol), 1,3-dimethylpiperidin-4-amine (45.3 mg, 0.335 mmol), HATU (130 mg, 0.335 mmol) and Et₃N (144 μL, 1.03 mmol) in THF (1.29 mL) was stirred at room temperature for 12 hours. The reaction mixture was filtered through a hydrophilic PTFE 0.45 m filter (Millipore® Millex-LCR) which was rinsed with methanol. The filtrate was purified by preparative HPLC (Method A) to give a TFA salt of the title compound as a pale yellow solid (89 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.96 (d, J=6.5 Hz, 3H), 1.35 (app d, J=5.5 Hz, 6H), 1.91-2.05 (m, 1H), 2.06-2.14 (m, 1H), 2.14-2.24 (m, 1H), 2.42-2.52 (m, 1H), 2.70-2.85 (m, 4H), 3.48-3.56 (m, 1H), 3.57-3.65 (m, 1H), 3.75-3.86 (m, 1H), 3.93-4.00 (m, 2H), 6.58 (br d, J=8.8 Hz, 1H), 6.93 (qd, J=8.0, 1.2 Hz, 2H), 7.22 (td, J=7.8, 1.6 Hz, 1H), 7.39 (dd, J=7.8, 1.5 Hz, 1H); ESI-MS [M+H]⁺ calc'd for C₁₈H₂₇ClN₂O₂, 339.18. found, 339.4.

Example 101

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A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol), DIPEA (10.8 mg, 0.083 mmol), and 2,2-difluoroacetic anhydride (7.3 mg, 0.042 mmol) in DCM (278 μL) was stirred at room temperature for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.92-2.02 (m, 2H), 2.09-2.17 (m, 2H), 2.80 (t, J=5.9 Hz, 0.8H), 2.86 (t, J=5.4 Hz, 1.2H), 2.96-3.04 (m, 2H), 3.34-3.43 (m, 2H), 3.77 (td, J=14.3, 4.0 Hz, 2H), 3.90 (t, J=5.8 Hz, 1.2H), 3.93 (t, J=6.1 Hz, 0.8H), 4.46 (tt, J=7.6, 3.7 Hz, 1H), 4.61 (s, 0.8H), 4.63 (s, 1.2H), 5.89-6.21 (m, 1H), 6.42-6.71 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 504.4.

Example 115

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A solution of cyclopropanecarboxylic acid (1.6 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (181 μL) was stirred at room temperature for 10 min followed by the addition of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 0.80-1.01 (m, 4H), 1.13 (d, J=6.6 Hz, 1.4H), 1.27 (d, J=6.3 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.06-2.20 (m, 2H), 2.56-2.60 (m, 0.5H), 2.66-2.70 (m, 0.5H), 3.02 (br s, 2H), 3.13-3.15 (m, 0.5H), 3.16-3.20 (m, 0.5H), 3.34-3.46 (m, 2H), 3.72-3.87 (m, 2H), 4.04 (d, J=18.2 Hz, 1H), 4.41-4.58 (m, 2H), 5.02 (d, J=17.4 Hz, 1.4H), 5.15-5.19 (m, 0.6H), 5.90-6.23 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]⁺ 507.9.

Example 102

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A solution of (S)-2-methoxypropanoic acid (2.9 mg, 0.028 mmol), DIPEA (3.9 mg, 0.028 mmol), and HATU (10.6 mg, 0.028 mmol) in DMF (278 μL) was stirred at room temperature for 10 min then treated with N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.028 mmol). Stirring was continued overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (3 mg) as a clear oil. ¹H NMR (400 MHz, methanol-d₄, mixture of rotamers) δ ppm 1.32 (d, J=6.6 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.91-2.04 (m, 2H), 2.09-2.19 (m, 2H), 2.76 (t, J=6.2 Hz, 0.9H), 2.84 (t, J=5.4 Hz, 1.1H), 2.95-3.05 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.78 (td, J=14.6, 4.3 Hz, 2H), 3.83-3.98 (m, 2H), 4.32-4.41 (m, 1H), 4.42-4.49 (m, 1H), 4.56 (m, 1.1H), 4.68 (m, 0.9H), 5.89-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]⁺ 512.4.