5-methyl-2,5-diazaspiro[3.4]octane;dihydrochloride

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 133 mg, 0.88 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-amine (Intermediate 155, 280 mg, 0.74 mmol) and DIPEA (0.153 mL, 0.88 mmol) in DMA (3 mL) and the mixture was heated at 100° C. for 1 h. The mixture was then part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (300 mg) as an orange dry film; 1H NMR: 1.71 (2H, dt), 2.05 (2H, dd), 2.40 (3H, s), 2.67 (2H, t), 3.75 (2H, d), 3.95 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.09 (1H, td), 7.28 (1H, d), 7.35-7.41 (1H, m), 8.25 (1H, s), 8.36 (1H, d), 8.47 (1H, s), 8.50 (1H, d), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES+ MH+ 487.30. The mixture was then part-purified by ion exchange chromatography eluting with 7M methanolic ammonia concentrated in vacuo Further purification by FCC eluting with 1-8% CH3OH in CH2Cl2

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 300 mg, 0.76 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol), DIPEA (0.158 mL, 0.92 mmol) and DMA (4 mL) was heated at 100° C. for 1 h. The mixture was then absorbed onto an SCX column, and the column was washed with CH3OH. The column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% CH3OH in CH2Cl2 gave the title compound (209 mg, 55%) as an orange solid; 1H NMR: 1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H, d), 3.88 (3H, s), 3.96 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H, t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34 (2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES+ MH+ 500.6. The mixture was then absorbed onto an SCX column the column was washed with CH3OH The column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions containing the desired product concentrated in vacuo Purification by FCC eluting with 1.5% CH3OH in CH2Cl2

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 300 mg, 0.78 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 118 mg, 0.94 mmol) and DIPEA (0.162 mL, 0.94 mmol) were heated at 100° C. in DMA (4 mL) for 1.75 h. The mixture was then absorbed onto an SCX column, then the column was washed with CH3OH and then eluted with 1:1 7M methanolic ammonia in CH2Cl2. Fractions that contained the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (321 mg, 84%) as an orange foam; 1H NMR: 1.62-1.74 (2H, m), 1.74-1.85 (2H, m), 1.91-2.00 (2H, m), 2.00-2.06 (2H, m), 2.38 (3H, s), 2.65 (2H, t), 3.03 (2H, t), 3.71 (2H, d), 3.95 (3H, s), 4.04-4.15 (4H, m), 6.27 (1H, s), 7.01 (1H, d), 8.01 (1H, s), 8.09 (1H, s), 8.33 (1H, d), 8.54 (1H, s); m/z: ES′ MH+ 491.6. The mixture was then absorbed onto an SCX column the column was washed with CH3OH eluted with 1:1 7M methanolic ammonia in CH2Cl2 concentrated in vacuo Purification by FCC eluting with 2.5% 7N methanolic ammonia in CH2Cl2

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-methyl-2,5-diazaspiro[3.4]octane dihydrochloride salt (Intermediate 47, 400 mg) in CH3OH/water was absorbed onto an SCX column. The column was washed with CH3OH and eluted with methanolic ammonia. The fractions containing product were combined and concentrated (caution: product is volatile). A mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol), 5-methyl-2,5-diazaspiro[3.4]octane (91 mg, 0.72 mmol) and DIPEA (0.365 mL, 2.11 mmol) in DMA (3 mL) was heated at 140° C. for 0.5 h in a microwave. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the product were combined and concentrated to provide a solid. This solid was suspended in CH3OH, filtered, washed with diethyl ether and dried to give the title compound (267 mg, 85%) as a red solid; 1H NMR: 1.63-1.78 (2H, m), 2-2.12 (2H, m), 2.41 (3H, s), 2.69 (2H, t), 3.77 (2H, d), 3.90 (3H, s), 4.13 (2H, d), 6.30 (1H, s), 7.14 (1H, td), 7.34 (1H, t), 8.12 (1H, s), 8.41-8.46 (2H, m), 8.74 (1H, s), 8.86 (1H, d), 8.96 (1H, s); m/z: ES+ MH+ 521.46. was absorbed onto an SCX column The column was washed with CH3OH eluted with methanolic ammonia The fractions containing product concentrated (caution: product is volatile) absorbed onto an SCX column The column was washed with CH3OH eluted with 1:1 methanolic ammonia in CH2Cl2 Fractions containing the product concentrated to provide a solid filtered washed with diethyl ether dried