N-methyloxan-4-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and N-methyltetrahydro-2H-pyran-4-amine (Peakdale and Cat. No. 2006971). LCMS (M+H)+: m/z=571.3. This compound was prepared

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

Procedure: N-Methyltetrahydro-2H-pyran-4-amine (0.4 g, 3.4 mmol), [2,1,3]-benzothiadiazole-5-carboxylic acid (0.23 g, 1.4 mmol), DMAP (0.2 g: 1.6 mmol), HOBT (0.2 g, 1.5 mmol), triethylamine (1.0 ml) and EDCI (1 g, 6.4 mmol) were dissolved in DMF (30 ml). The mixture was stirred at room temperature for 18 h and then concentrated under vacuum. Chloroform (100 ml) was added and the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (100 ml) and the combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with chloroform/THF (90:10), to give the product as an oil which crystallized on standing. Mp=106-108° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 8.06 (d, J=9.0 Hz, 1H); 8.01 (s, 1H); 7.60 (d, J=9.0 Hz, 1H); 4.92-4.75 and 4.15-3.10 (m, 5H); 3.10-2.80 (m, 3H) and 2.05-1.50 ppm (s, 4H). concentrated under vacuum Chloroform (100 ml) was added the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml) The aqueous was extracted with chloroform (100 ml) the combined organics were dried (MgSO4) concentrated under vacuum the crude product was purified on a silica gel column eluting with chloroform/THF (90:10)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude N-methyltetrahydro-2H-pyran-4-amine (104 mg, 0.9 mmol) was dissolved in NMP (0.8 mL). To the solution, Cs2CO3 (366 mg, 1.13 mmol) and 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as in Method 22) (80 mg, 0.34 mmol) were added at room temperature. The reaction mixture was heated to 95° C. After 90 minutes, the reaction mixture was cooled to room temperature, filtered and purified by reverse phase preparative HPLC yielding 24 mg (23%) of pure 6-chloro-N-methyl-2-morpholino-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine. LC/MS (m/z): 313.2 (MH+), Rt 2.61 minutes. the reaction mixture was cooled to room temperature filtered purified by reverse phase preparative HPLC

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

Procedure: A solution of 338 mg (1.0 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 172 mg (1.5 mmol) N-methyl-tetrahydro-2H-pyran-4-amine and 509 μl (3.0 mmol) DIPEA in NMP (1 ml) was heated in the microwave at 180° C. for 2 h. Subsequently the RM was diluted with a 2M aq. NaOH sol, water and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 13:7) provided 77 mg (0.18 mmol, 18%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl-tetrahydro-pyran-4-yl-amino)-pyridine-3-carboxylic acid amide (example 258). [M+H]+ 418.2 the layers were separated The organic layer was washed with water and brine dried over MgSO4 concentrated in vacuo Purification of the residue by CC (hexane/EtOAc 13:7)

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

Procedure: A solution of 338 mg (1.0 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 172 mg (1.5 mmol) N-methyl-tetrahydro-2H-pyran-4-amine and 509 μl (3.0 mmol) DIPEA in NMP (1 ml) was heated in the microwave at 180° C. for 2 h. Subsequently the RM was diluted with a 2M aq. NaOH sol, water and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 13:7) provided 77 mg (0.18 mmol, 18%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl-tetrahydro-pyran-4-yl-amino)-pyridine-3-carboxylic acid amide (example 258). [M+H]+ 418.2 the layers were separated The organic layer was washed with water and brine dried over MgSO4 concentrated in vacuo Purification of the residue by CC (hexane/EtOAc 13:7)

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

Procedure: N-Methyltetrahydro-2H-pyran-4-amine (0.4 g, 3.4 mmol), [2,1,3]-benzothiadiazole-5-carboxylic acid (0.23 g, 1.4 mmol), DMAP (0.2 g: 1.6 mmol), HOBT (0.2 g, 1.5 mmol), triethylamine (1.0 ml) and EDCI (1 g, 6.4 mmol) were dissolved in DMF (30 ml). The mixture was stirred at room temperature for 18 h and then concentrated under vacuum. Chloroform (100 ml) was added and the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (100 ml) and the combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with chloroform/THF (90:10), to give the product as an oil which crystallized on standing. Mp=106-108° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 8.06 (d, J=9.0 Hz, 1H); 8.01 (s, 1H); 7.60 (d, J=9.0 Hz, 1H); 4.92-4.75 and 4.15-3.10 (m, 5H); 3.10-2.80 (m, 3H) and 2.05-1.50 ppm (s, 4H). concentrated under vacuum Chloroform (100 ml) was added the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml) The aqueous was extracted with chloroform (100 ml) the combined organics were dried (MgSO4) concentrated under vacuum the crude product was purified on a silica gel column eluting with chloroform/THF (90:10)