Reaction Steps
To a 5 mL sealed tube was added (3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.33 mmol, 1 equivalent, Example 23, free base), azetidine (93.7 mg, 1.64 mmol, 5 equivalents) and dimethylformamide (2 mL). The reaction vessel was sealed and heated in a 100° C. oil bath. After two days, the vessel was cooled and contents transferred to a separatory funnel with ethyl acetate dilution. The organic phase was extracted with saturated aqueous ammonium chloride solution and deionized water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide racemic (3-(4-(1H-pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-4-chloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol. MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.15 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.02 (dd, J=8.2, 2.1 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.65-7.62 (m, 2H), 7.57 (dd, J=8.9, 2.2 Hz, 1H), 7.24-7.18 (m, 2H), 6.51-6.49 (m, 1H), 6.47 (s, 1H), 4.38 (s, 2H), 4.25-4.20 (m, 4H), 3.53 (s, 3H), 2.30-2.21 (m, 2H). Racemic (3-(4-(1H-pyrazol-1-yl)benzyl)-2-(azetidin-1-yl)-4-chloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol was purified on a chiralcel OD column (20 um, Diacel) with ethanol/heptanes to provide two enantiomers. The first eluting enantiomer was Example 68B: MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.12 (dd, J=2.5, 0.4 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.2, 2.1 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.70 (m, 2H), 7.69-7.66 (m, 1H), 7.64-7.58 (m, 2H), 7.56 (dd, J=8.8, 2.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 6.48 (dd, J=2.4, 1.9 Hz, 1H), 6.35 (d, J=0.8 Hz, 1H), 4.32 (s, 2H), 4.20-4.14 (m, 4H), 3.48 (s, 3H), 2.25-2.15 (m, 2H), and the second eluting enantiomer was Example 68C: MS (ESI): mass calcd. for C33H27ClF3N7O, 629.19; m/z found, 630.2 [M+H]+. 1H NMR (600 MHz, MeOH-d4) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.15-8.11 (m, 1H), 8.05 (d, J=2.0 Hz, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.76-7.70 (m, 2H), 7.68 (d, J=1.5 Hz, 1H), 7.64-7.59 (m, 2H), 7.56 (dd, J=8.9, 2.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 6.48 (dd, J=2.4, 1.9 Hz, 1H), 6.35 (s, 1H), 4.32 (s, 2H), 4.17 (t, J=7.6 Hz, 4H), 3.48 (s, 3H), 2.24-2.17 (m, 2H).
