tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate;hydrochloride

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252 mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA (237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL), extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue. The crude material was purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.47 (m, 7H), 5.31 (s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s, 9H). The reaction mixture was cooled to RT extracted with DCM (20 mL) The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue The crude material was purified by flash chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252 mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA (237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL), extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue. The crude material was purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.47 (m, 7H), 5.31 (s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s, 9H). The reaction mixture was cooled to RT extracted with DCM (20 mL) The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue The crude material was purified by flash chromatography

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

Procedure: Prepared according to the method used in the preparation of 2-(6-fluoro-1H-indol-4-yl)-6-[(S)-1-(hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno-[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-c]pyrazine, followed by BOC-deprotection using TFA:DCM (1:1). The title compound was obtained as a white solid (29 mg, 49%). Prepared

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

Procedure: Prepared according to the method used in the preparation of 2-chloro-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine. The title compound was obtained as a tan solid (209 mg, 84%). Prepared

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

Procedure: Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (70 mg, 71%). Prepared

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

Procedure: To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (4.35 g. 16.6 mmol) and 5-(2H-1,2,3-triazol-2-yl)indan-1-one (SM-1h, 3.3 g, 16.6 mmol) in dichloromethane (50 mL) was added triethylamine (6.94 mL, 49.7 mmol) followed by titanium(IV) isopropoxide (9.81 mL, 33.1 mmol). The reaction was stirred at room temperature overnight and sodium triacetoxyborohydride (4.21 g, 19.8 mmol) was added. After stirring for 4 days, the reaction was quenched with saturated ammonium chloride. The mixture was diluted with 50 mL of dichloromethane and 50 mL water and filtered through a Celite® pad. The aqueous layer was extracted with dichloromethane (30 mL×2). The combined organic layers were washed with brine and dried over MgSO4. The solvent was concentrated and the crude material was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) using an EtOAc/heptanes gradient. The enantiomers were separated via preparative chiral HPLC (Chiralcel OD-H, 250 mm×30 mm, flow-rate—100 g/min, 65/35 CO2/MeOH, with 0.1% IPA) to afford tert-butyl 2-((R)-5-(2H-1,2,3-triazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (6-1a, 1.58 g, 23%) as a white solid. MS (ES+) 410.5 (M+H)+. 1H NMR (CD3OD) δ 1.42 (s, 9H), 1.70-1.73 (m, 4H), 1.92-2.02 (m, 1H), 2.23-2.27 (m, 1H), 2.89-2.92 (m, 2H), 3.09-3.14 (m, 2H), 3.23-3.30 (m, 3H), 3.32-3.36 (m, 3H), 4.02-4.05 (m, 1H), 7.45 (d, 1H), 7.87 (s, 2H), 7.89-7.93 (m, 2H). After stirring for 4 days the reaction was quenched with saturated ammonium chloride The mixture was diluted with 50 mL of dichloromethane and 50 mL water filtered through a Celite® pad The aqueous layer was extracted with dichloromethane (30 mL×2) The combined organic layers were washed with brine dried over MgSO4 The solvent was concentrated the crude material was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) The enantiomers were separated via preparative chiral HPLC (Chiralcel OD-H, 250 mm×30 mm, flow-rate—100 g/min, 65/35 CO2/MeOH, with 0.1% IPA)

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

Procedure: To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (850 mg, 3.23 mmol) and 5-pyrimidin-2-ylindan-1-one (SM-1b, 680 mg, 3.23 mmol) in dichloromethane (10 mL) under nitrogen was added triethylamine (2.5 mL, 17.9 mmol) followed by titanium isopropoxide (2.9 mL, 9.70 mmol). The reaction was stirred at room temperature for 90 minutes and sodium triacetoxyborohydride (2.1 g, 9.9 mmol) was added. After stirring for 4 days, the reaction was quenched with saturated ammonium chloride. The mixture was diluted with 50 mL of dichloromethane and 50 mL of water and filtered through a Celite® pad. The aqueous layer was extracted with dichloromethane (2×30 mL). The combined organics layers were washed with brine and dried over MgSO4. The solvent was removed to give a dark green/brown paste which was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln Nebr.) using a dichloromethane/MeOH gradient to afford the title compound as light brown oil (785 mg, 57.7%). MS (ES+) 421.2 (M+H)+. 1H NMR (CDCl3) δ 1.39 (s, 9H), 1.59-1.69 (m, 4H), 1.75-1.94 (m, 1H), 2.12 (dq, 1H), 2.76-2.92 (m, 1H), 2.95-3.18 (m, 5H), 3.19-3.36 (m, 4H), 3.92 (dd, 1H), 7.09 (t, 1H), 7.33 (d, 1H), 8.18-8.26 (m, 2H), 8.71 (d, 2H). After stirring for 4 days the reaction was quenched with saturated ammonium chloride The mixture was diluted with 50 mL of dichloromethane and 50 mL of water filtered through a Celite® pad The aqueous layer was extracted with dichloromethane (2×30 mL) The combined organics layers were washed with brine dried over MgSO4 The solvent was removed to give a dark green/brown paste which was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln Nebr.)

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

Procedure: Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (70 mg, 71%). Prepared

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252 mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA (237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was cooled to RT, diluted with water (20 mL), extracted with DCM (20 mL). The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue. The crude material was purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.47 (m, 7H), 5.31 (s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s, 9H). The reaction mixture was cooled to RT extracted with DCM (20 mL) The organic phase was concentrated in vacuo to afford the crude product as a yellow oily residue The crude material was purified by flash chromatography