Reaction Steps
To a solution of N-hydroxyacetamidine (315 mg, 4.25 mmol) in of THF (10 mL) at 0° C. was added sodium hydride (60% in oil, 340 mg, 8.5 mmol) in small portions and the resulting mixture was stirred for 20 min. 5-Isopropyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester was then added and the mixture was heated in a pressure vessel at 80° C. for 18 h. The reaction mixture was cooled down and the precipitate was filtered and. The filtrate was diluted with ethyl acetate and washed with saturated ammonium chloride, brine (50 mL), dried (MgSO4), filtered and concentrated to afford 5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (520 mg, 95%). B. To a solution of oxadiazole from previous step (300 mg, 1.08 mmol) in toluene (7 mL) were added phosphorus oxychloride (122 μL, 1.29 mmol) and diisopropylethylamine (150 μL, 0.86 mmol) and the reaction mixture was heated to reflux for 3 days. The reaction mixture was cooled down and poured over ice-cooled saturated sodium bicarbonate solution. The separated aqueous layer was extracted with ethyl acetate (2×25 mL) and the combined organic layers were washed with brine (50 mL), dried (MgSO4.), filtered and evaporated to afford crude 4-chloro-5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine which was directly used in next step (280 mg, 94%). C. Diisopropylethylamine (0.1 mL, 0.5 mmol) was added to a solution of 4-chloro-5-isopropyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.18 mmol, see Example 25) and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ylamine (30 mg, 0.18 mmol) in DMF (1.0 mL). The mixture was stirred at RT for 16 h., quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated. The residue was purified by preparative HPLC to afford the title compound (34 mg, 43%). LCMS : m/z 393 (M+H)+. Monohydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 11.99 (1H, s), 8.12 (1H, s.), 7.89 (1H, s), 7.50 (1H, s), 6.55 (1H, br. s.), 4.16 (1H, m), 2.43 (3H, s), 144 (6H, d, J=7.3 Hz). The intermediate, 4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-ylamine was prepared as follows: D. A 100 mL oven-dried round-bottom flask was evacuated and backfilled with Argon. The flask was charged with 4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (763 mg, 2.61 mmol), THF (17.4 mL) and the mixture was cooled to −78° C. A solution of sec-butyllithium (1.10 M in THF, 5.21 mL, 5.74 mmol) was added dropwise and after 30 minutes, 1-sulfonylazido-4-methylbenzene (1.29 g, 6.52 mmol) in THF (7.4 mL) was added rapidly. After 25 min, a solution of saturated ammonium chloride was added and the mixture was allowed to reach RT. The mixture was extracted with ethyl acetate (3×50 mL), combined organic layers were washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo. The crude material was stirred in hexanes to remove the excess of 1-azido-4-methylbenzene and the filtrate was purified by flash chromatography eluting a mixture of 2.5% ethyl acetate in hexanes to give 5-azido-4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (746 mg, 86%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, d, J=10.3 Hz), 7.56 (1H, d, J=3.3 Hz), 6.71 (1H, d, J=3.6 Hz) 1.84 (3H, m), 1.05 (9H, s), 1.03 (9H, s). LCMS: m/z 334 (M+H+), E. The procedure described for desilylation in Example 7 was applied to afford 5-azido-4-fluoro-1H-pyrrolo[2,3-b]pyridine. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (1H, s), 8.14 (1H, d, J=10.1 Hz), 7.57 (1H, t, J=2.5 Hz), 6.53 (1H, dd, J=1.8, 3.3 Hz). LCMS; m/z 178 (M+H). F. The procedure for conversion of azide group to amine group described in example 18 was applied to 5-azido-4-fluoro-1H-pyrrolo[2,3-b]pyridine using 45 p.s.i. of hydrogen to afford 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ylamine (91% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (1H, s), 7.84 (1H, d, J=10.9 Hz), 7.30 (1H, t, J=3.0 Hz), 6.28 (1H, dd, J=1.9, 3.6 Hz). LCMS; m/z 152 (M+H+). HRMS calculated for C7H6FN3: 151.0545, found: 151.0549
