6-Amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester

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

Procedure: 0.341 g (2.64 mmol) of N,N-diisopropylethylamine and 0.265 g (1.32 mmol) of 4-nitrophenyl chloroformate are added to a solution of 0.226 g (1.32 mmol) of ethyl 5-hydroxymethylisoxazole-3-carboxylate in 10 mL of dichloroethane. Stirring is continued at room temperature for hours and 0.280 g (1.32 mmol) of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.6., dissolved in 4 mL of dichloroethane, is then added. Stirring is continued at room temperature for 4 hours. Water is added to the reaction medium, the aqueous phase is separated out and extracted several times with dichloromethane, and the combined organic phases are washed with aqueous sodium hydroxide solution (1N) and then with saturated aqueous ammonium chloride solution. The resulting phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. is continued at room temperature for hours

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

Procedure: The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 0.638 g (2.68 mmol) of tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.5., in 11 mL of ethanol, 0.276 g (1.34 mmol) of Lindlar catalyst (PdCaCO3) is added. After purification on a column of silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.330 g of pure product is obtained in the form of a white powder. obtained in step 11.5 After purification on a column of silica gel eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: 0.341 g (2.64 mmol) of N,N-diisopropylethylamine and 0.265 g (1.32 mmol) of 4-nitrophenyl chloroformate are added to a solution of 0.226 g (1.32 mmol) of ethyl 5-hydroxymethylisoxazole-3-carboxylate in 10 mL of dichloroethane. Stirring is continued at room temperature for hours and 0.280 g (1.32 mmol) of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.6., dissolved in 4 mL of dichloroethane, is then added. Stirring is continued at room temperature for 4 hours. Water is added to the reaction medium, the aqueous phase is separated out and extracted several times with dichloromethane, and the combined organic phases are washed with aqueous sodium hydroxide solution (1N) and then with saturated aqueous ammonium chloride solution. The resulting phase is dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. is continued at room temperature for hours

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

Procedure: The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 0.638 g (2.68 mmol) of tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.5., in 11 mL of ethanol, 0.276 g (1.34 mmol) of Lindlar catalyst (PdCaCO3) is added. After purification on a column of silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.330 g of pure product is obtained in the form of a white powder. obtained in step 11.5 After purification on a column of silica gel eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: The process is performed according to the procedure described in Example 6 (step 6.4.). Starting with 0.638 g (2.68 mmol) of tert-butyl 6-azido-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.5., in 11 mL of ethanol, 0.276 g (1.34 mmol) of Lindlar catalyst (PdCaCO3) is added. After purification on a column of silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.330 g of pure product is obtained in the form of a white powder. obtained in step 11.5 After purification on a column of silica gel eluting with a 98/2/0.2 mixture of dichloromethane, methanol and 28% aqueous ammonia

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

Procedure: 4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride using methods B, C, D, and E. HPLC: 98%. MS: m/z=453 [M+H]+. 1H-NMR (DMSO-d6) δ 7.96 (s, 1H), 7.87 (d, 2H), 7.29-7.23 (m, 6H), 6.31-6.22 (m, 1H), 6.07 (d, 1H), 5.67-5.46 (m, 4H), 4.40 (q, 1H), 4.25 (s, 1H), 4.08 (s, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 2.47-2.40 (m, 2H), 2.14-2.09 (m, 2H).

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

Procedure: (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl) boronic acid and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride according to general scheme 3 using methods S1, S2, S3, and S4D. HPLC purity: 99%. MS: m/z=485 [M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.13-7.50 (m, 9H), 6.75 (m, 1H), 6.46 (dd, 1H), 4.59 (m, 1H), 4.35 (d, 2H), 4.11 (d, 2H), 3.91 (m, 2H), 2.82 (d, 6H), 2.61 (m, 2H), 2.29 (m, 2H).

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

Procedure: 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid and acryloyl chloride according to general scheme 3 using methods S1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z=428 [M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.13-7.50 (m, 9H), 6.25 (m, 2H), 5.71 (m, 1H), 4.59 (m, 1H), 4.35 (d, 2H), 4.11 (d, 2H), 2.61 (m, 2H), 2.29 (m, 2H).

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

Procedure: N4-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine (10.5 mg, 11.2%) was prepared from 5,6-dichloropyrimidin-4-amine, 6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester, (4-phenoxyphenyl)boronic acid and 2-chloro-ethanesulfonyl chloride according to general scheme 3 using methods S1, S2, S3, and S4C. HPLC purity 95%. MS: m/z=501 [M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.10-7.47 (m, 9H), 6.70 (m, 1H), 6.19 (d, 1H), 6.01 (d, 1H), 4.62 (m, 1H), 3.58 (s, 2H), 3.13 (s, 2H), 2.37 (m, 2H), 1.81 (m, 2H).

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

Procedure: 1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)boronic acid and acrylic acid according to general scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z=416 [M+H]+. 1H NMR (CD3OD) δ 8.77 (m, 2H), 8.23 (s, 1H), 8.00 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H), 6.26 (m, 2H), 5.75 (m, 3H), 4.54 (m, 1H), 4.27 (d, 2H), 4.11 (d, 2H), 2.59 (m, 2H), 2.26 (m, 2H).

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

Procedure: 1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one was prepared from 5,6-dichloropyrimidin-4-amine, (1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate and propiolic acid according to general scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 95%. MS: m/z=414 [M+H]+. 1H NMR (CD3OD) δ 8.21 (s, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 7.41 (m, 5H), 5.42 (s, 2H), 4.54 (s, 1H), 4.31 (d, 2H), 4.08 (d, 2H), 3.88 (d, 1H), 2.61 (m, 2H), 2.30 (m, 2H).

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

Procedure: 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid and but-2-ynoic acid according to general scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z=440 [M+H]+. 1H NMR (CD3OD) δ 8.24 (s, 1H), 7.16-7.45 (m, 9H), 4.57 (s, 1H), 4.27 (d, 2H), 4.05 (d, 2H), 2.61 (m, 2H), 2.27 (m, 2H), 2.00 (m, 3H).