N',N'-dibutylpropane-1,3-diamine

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: 15 g. of o-nitrobromobenzene and 13 g. of 3-dibutylaminopropylamine are agitated with 15 g. of anhydrous sodium acetate for 7 hours at 135° C. The reaction mixture is taken up in 70 ml. of 6N hydrochloric acid and 80 ml. of water, the unreacted o-nitrobromobenzene is subjected to steam distillation, the distillation residue is rendered alkaline with potassium hydroxide solution, and extracted with ether. After distilling the residue of the ether extract, 12 g. of 2-(3-dibutylaminopropylamino)-nitrobenzene is obtained, b.p. 140°-160° C. at 0.1 mm Hg. of water, the unreacted o-nitrobromobenzene is subjected to steam distillation extracted with ether After distilling the residue of the ether extract

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

Procedure: The same procedure as a series of reactions of Example 1 was carried out, except that methyl 4-formylbenzoate was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and N,N-dibutyl-1,3-propanediamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain methyl 4-({[3-(dibutylamino)propyl]amino}methyl)benzoate (compound 11-a). The same procedure as a series of reactions of Example 4→Example 5→Example 6→Example 9→Example 10 was carried out, except that the compound 11-a was used in place of the compound 3 in the process of Example 4, to obtain the title compound having the following physical properties.

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

Procedure: The same procedure as a series of reactions of Example 1 was carried out, except that methyl 4-formylbenzoate was used in place of 1-({[2-(trimethylsilyl)ethyloxy]methyl}-1H-imidazole-2-carboaldehyde and N,N-dibutyl-1,3-propanediamine was used in place of {[4-(methyloxy)phenyl]methyl}amine, to obtain methyl 4-({[3-(dibutylamino)propyl]amino}methyl)benzoate (compound 11-a). The same procedure as a series of reactions of Example 4→Example 5→Example 6→Example 9→Example 10 was carried out, except that the compound 11-a was used in place of the compound 3 in the process of Example 4, to obtain the title compound having the following physical properties.

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: 3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N,4-dimethylbenzamide (0.03 g, 0.062 mmol) was dissolved in THF (5 mL) and (3-aminopropyl)dibutylamine (0.058 g, 0.31 mmol) was added. The reaction was stirred under argon for 24 h. The solvents were pumped off in vacuo, and the residue was flash chromatographed on silica gel (15 g) eluted with CH2Cl2 to 6:0.5:0.05, CH2Cl2:ethanol:NH4OH to give the title compound as a white amorphous solid. mp 112-115° C. LC-MS m/z 594.6 (M+H)+, 1.59 min (ret time). chromatographed on silica gel (15 g) eluted with CH2Cl2 to 6:0.5:0.05, CH2Cl2

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

Procedure: To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (30 mg, 0.06 mmol) in DCM (5 mL) was added N,N-dibutyl-1,3-propanediamine (0.06 mL, 0.26 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (30 mg, 83%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 1.00 (m, 10H), 1.30 (m, 4H), 1.50 (m, 9H), 2.31 (s, 3H), 2.38 (m, 4H), 2.48 (m, 2H), 3.08 (m, 2H), 4.11 (s, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.86 (d, 1H). The result mixture was concentrated

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

Procedure: To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (24 mg, 96%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 0.98 (t, 6H), 1.30 (m, 10H), 1.46 (m, 4H), 1.52 (m, 2H), 2.30 (s, 3H), 2.41 (m, 6H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H). The result mixture was concentrated

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

Procedure: To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (24 mg, 96%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 0.98 (t, 6H), 1.30 (m, 10H), 1.46 (m, 4H), 1.52 (m, 2H), 2.30 (s, 3H), 2.41 (m, 6H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H). The result mixture was concentrated

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

Procedure: To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (16 mg, 66%). LC-MS m/z 674 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.30 (m, 4H), 1.40 (m, 4H), 1.50 (m, 2H), 2.34 (s, 3H), 2.43 (m, 6H), 3.10 (m, 2H), 4.13 (s, 2H), 7.15(m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H). The result mixture was concentrated