tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) dissolved in DMF (5 ml) was added Et3N (1.3 ml, 9.8 mmol) followed by commercially available 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.5 g, 7.2 mmol). The reaction mixture was heated for 16 hours at 110° C. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) and extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 1.5 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL) dried over Na2SO4 filtered concentrated in vacuo to provide 1.5 g crude The product was purified by flash chromatography on silica

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

Procedure: Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-5-methoxy-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester. Prepared in a sequence similar to the sequence

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

Procedure: Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-5-methoxy-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester. Prepared in a sequence similar to the sequence

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

Procedure: Prepared in a sequence similar to the sequence described for intermediates 1 and 2, starting from 4-chloro-1H-pyrrolo[2,3-b]pyridine and 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester. Prepared in a sequence similar to the sequence

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

Procedure: Prepared in a way similar to Intermediate 1, using 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, instead of 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.

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

Procedure: Prepared in a way similar to Intermediate 1, using 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, instead of 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.

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

Procedure: Prepared in a way similar to Intermediate 1, using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, instead of 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) dissolved in DMF (5 ml) was added Et3N (1.3 ml, 9.8 mmol) followed by commercially available 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.5 g, 7.2 mmol). The reaction mixture was heated for 16 hours at 110° C. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) and extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 1.5 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL) dried over Na2SO4 filtered concentrated in vacuo to provide 1.5 g crude The product was purified by flash chromatography on silica

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an off-white powder. HPLC (Condition 4) tR=4.44 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=475 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.27-0.54 (m, 4H) 2.82 (br. s, 2H) 2.96-3.20 (m, 5H) 6.64 (br. s, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.29 (br. s, 1H) 8.71 (br. s, 1H) 10.37 (br. s, 1H) 13.00 (br. s, 1H). to afford an off-white powder

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an off-white powder. HPLC (Condition 4) tR=4.44 min, UPLC-MS (Condition 3) tR=0.81 min, m/z=475 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.27-0.54 (m, 4H) 2.82 (br. s, 2H) 2.96-3.20 (m, 5H) 6.64 (br. s, 1H) 7.32 (d, J=8.21 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.29 (br. s, 1H) 8.71 (br. s, 1H) 10.37 (br. s, 1H) 13.00 (br. s, 1H). to afford an off-white powder

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to afford an amorphous white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=459.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.46-0.85 (m, 4H) 3.04 (br. s, 2H) 3.16-3.37 (m, 5H) 6.67 (br. s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=9.38 Hz, 3H) 8.34 (br. s, 1H) 8.75 (s, 1H) 10.43 (s, 1H) 12.96-13.19 (m, 1H). to afford an amorphous white powder