indoleaMine-2,3-dioxygenase inhibitor INCB024360

IDO5L is a potent indoleamine 2,3-dioxygenase (IDO) inhibitor with an IC50 of 67 nM.

4-Amino-N-hydroxy- 1, 2, 5 -oxadiazole-3 -carboximidoyl chloride (3; 1.63 g, 10.020 mmol) and 3-chloro-4-fluoroaniline (1.60 g, 11.0 mmol) were added in ethanol (40 mL). Then, NaHCO3 (2.10 g, 25.0 mmol) in water (20 mL) was added. The reaction was stirred and heated at 60°C for 1 h. The reaction mixture was concentrated by a rotary evaporator and dissolved in ethyl acetate (100 mL), after being washed by brine (50 mL) twice and dried over Na2SO4. After solvent evaporation, the residue was recrystallized in ethyl25 acetate/hexanes to afford IDO5L (2.38 g, 88percent) as a brown solid. Rf (ethyl acetate/hexanes: 1/1 (v/v)): 0.45.‘H-NMR (400 MHz, DMSO-d6): ö 11.41 (s, br, 1 H), 8.91(s, br, 1 H), 7.21 (dd, J = 9.2 and 9.2 Hz, 1 H), 6.98 (dd, J = 6.4 and 2.8 Hz, 1 H), 6.72—6.76 (m, 1 H), and 6.27 (s, 2 H).30 ‘3C-NMR (100 MHz, DMSO-d6): ö 155.3, 152.2 (d, J’CF = 239.3 Hz), 140.4, 139.3, 137.9 (d, J3CF = 2.9 Hz), 122.0, 120.8 (d, J3CF = 6.8 Hz), 118.7 (d, J2CF = 18.5 Hz), and 116.2 (d, J2CF = 21.7 Hz).HRMS calculated for C9H8C1FN5O2 [M + H]: mlz = 272.0345, found 272.0340.General procedure: A 150 mL round-bottomed flask with a magnetic stir bar wascharged with compound 8a (5.0 g, 15.8 mmol), ethyl acetate(100 mL) and N, N0-carbonyldiimidazole (5.12 g, 31.6 mmol, 2 equiv).The resulting mixture was stirred at ambient temperature for 2 h.On completing of the reaction monitored by TLC, the mixture waswashed with 1 N hydrochloric acid (60 mL), water (70 mL), brineand evaporated in vacuo. The crude product was recrystallized inethanol to give the desired product (4.80 g, 89%) as a white needlelikecrystal.General procedure: A 150 mL round-bottomed flask with a magnetic stir bar wascharged with compound 8a (5.0 g, 15.8 mmol), ethyl acetate(100 mL) and N, N0-carbonyldiimidazole (5.12 g, 31.6 mmol, 2 equiv).The resulting mixture was stirred at ambient temperature for 2 h.On completing of the reaction monitored by TLC, the mixture waswashed with 1 N hydrochloric acid (60 mL), water (70 mL), brineand evaporated in vacuo. The crude product was recrystallized inethanol to give the desired product (4.80 g, 89%) as a white needlelikecrystal.General procedure: A 150 mL round-bottomed flask with a magnetic stir bar wascharged with compound 8a (5.0 g, 15.8 mmol), ethyl acetate(100 mL) and N, N0-carbonyldiimidazole (5.12 g, 31.6 mmol, 2 equiv).The resulting mixture was stirred at ambient temperature for 2 h.On completing of the reaction monitored by TLC, the mixture waswashed with 1 N hydrochloric acid (60 mL), water (70 mL), brineand evaporated in vacuo. The crude product was recrystallized inethanol to give the desired product (4.80 g, 89%) as a white needlelikecrystal.General procedure: A 150 mL round-bottomed flask with a magnetic stir bar wascharged with compound 8a (5.0 g, 15.8 mmol), ethyl acetate(100 mL) and N, N0-carbonyldiimidazole (5.12 g, 31.6 mmol, 2 equiv).The resulting mixture was stirred at ambient temperature for 2 h.On completing of the reaction monitored by TLC, the mixture waswashed with 1 N hydrochloric acid (60 mL), water (70 mL), brineand evaporated in vacuo. The crude product was recrystallized inethanol to give the desired product (4.80 g, 89%) as a white needlelikecrystal.