tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate

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

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

Conditions: temp:102.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2 L round-bottom flask was charged with tert-butyl 2,6-diazaspiro[3,3]heptane-6-carboxylate (64.3 g, 0.32 mol), cesium carbonate (317.0 g, 0.97 mol), 2-chloropyrimidine (45.5 g, 0.4 mol), and DMF (759.0 mL). The reaction mixture was heated to 100-105° C. for 20 min. The reaction mixture was cooled to ambient temperature, diluted with water (759.0 mL) and EtOAc (759.0 mL). The organic layer was washed with water (2×500.0 mL) and brine (500.0 mL). The organic layer was dried over sodium sulfate and filtered through Celite™. The filtrate was concentrated under reduced pressure. Column chromatography of the resulting crude product on silica gel, eluting with EtOAc and heptane (50-100%) afforded the desired product. The reaction mixture was cooled to ambient temperature The organic layer was washed with water (2×500.0 mL) and brine (500.0 mL) The organic layer was dried over sodium sulfate filtered through Celite™ The filtrate was concentrated under reduced pressure Column chromatography of the resulting crude product on silica gel, eluting with EtOAc and heptane (50-100%)

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

Procedure: Following amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (199 mg, 0.5 mmol, 1.0 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.5 mmol, 1.0 eq) were combined and gave tert-butyl 6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (214 mg, 0.37 mmol) in 74% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.79 (s, 1H) 8.53-8.66 (m, 2H) 8.08 (dd, J=8.84, 2.27 Hz, 1H) 6.53 (s, 1H) 4.74-4.92 (m, 1H) 4.20-4.61 (m, 4H) 4.07-4.16 (m, 4H) 3.18 (br s, 6H) 2.47-2.65 (m, 2H) 2.03-2.20 (m, 4H) 1.68-1.85 (m, 3H) 1.46 (s, 9H). MS (m/z, MH+): 575.6

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

Procedure: Following amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (199 mg, 0.5 mmol, 1.0 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.5 mmol, 1.0 eq) were combined and gave tert-butyl 6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (214 mg, 0.37 mmol) in 74% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.79 (s, 1H) 8.53-8.66 (m, 2H) 8.08 (dd, J=8.84, 2.27 Hz, 1H) 6.53 (s, 1H) 4.74-4.92 (m, 1H) 4.20-4.61 (m, 4H) 4.07-4.16 (m, 4H) 3.18 (br s, 6H) 2.47-2.65 (m, 2H) 2.03-2.20 (m, 4H) 1.68-1.85 (m, 3H) 1.46 (s, 9H). MS (m/z, MH+): 575.6

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 2,6-diazaspiro[3.3]heptane-2-carboxylate to afford a white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=461 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.30 (br. s, 2H) 3.63 (s, 4H) 3.75-3.92 (m, 4H) 6.41 (d, J=2.35 Hz, 1H) 7.26-7.35 (m, 2H) 7.77 (br. s, 1H) 7.81-7.89 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.22 (s, 1H). to afford a 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 2,6-diazaspiro[3.3]heptane-2-carboxylate to afford a white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=461 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.30 (br. s, 2H) 3.63 (s, 4H) 3.75-3.92 (m, 4H) 6.41 (d, J=2.35 Hz, 1H) 7.26-7.35 (m, 2H) 7.77 (br. s, 1H) 7.81-7.89 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.22 (s, 1H). to afford a white powder

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 25 mL pear-shaped flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 40 h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e. to give a light yellow solution Cooled to 25° C. extracted with EtOAc (3×50 mL) washed with sat NaCl (1×50 mL) dried over Na2SO4 concentrated in vacuo

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

Procedure: Following the procedures as described in Example 124 and starting with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 2-bromo-6-fluoropyridine, 6-chloro-1H-pyrazolo[4,3-c]pyridine, and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 268 was obtained as a yellow solid (87 mg, 26%) over four steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.10 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.69-7.71 (t, J=9 Hz, 1H), 7.20-7.21 (d, J=9 Hz, 1H), 6.30-6.31 (d, J=9 Hz, 1H), 4.24 (s, 3H), 4.08 (s, 1H), 3.86-3.93 (m, 3H), 3.79-3.83 (m, 2H), 3.35-3.42 (m, 3H); MS (ESI) m/z: 373 [M+H]+.

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

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

Procedure: Following the procedures as described in Example 124 and starting with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 2-bromo-6-fluoropyridine, 6-chloro-1H-pyrazolo[4,3-c]pyridine, and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 268 was obtained as a yellow solid (87 mg, 26%) over four steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.10 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.69-7.71 (t, J=9 Hz, 1H), 7.20-7.21 (d, J=9 Hz, 1H), 6.30-6.31 (d, J=9 Hz, 1H), 4.24 (s, 3H), 4.08 (s, 1H), 3.86-3.93 (m, 3H), 3.79-3.83 (m, 2H), 3.35-3.42 (m, 3H); MS (ESI) m/z: 373 [M+H]+.

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