Spirocyclic degronimers for target protein degradation

[0833] Representative example 1: 2,6-diazaspiro[3.5]nonane-5,7-dione

[0834]

[0835] 3-(3-Methoxy-3-oxopropyl)azetidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl ester:

[0836]

[0837] Azetidine-1,3-dicarboxylic acid 1-(tert-butyl)3-methyl ester (1 equivalent) was dissolved in dry tetrahydrofuran and cooled to -78°C. Then a solution of lithium hexamethyldisilazide (1.0 M in tetrahydrofuran) (1.1 equivalents) was added dropwise and the solution was stirred for 1 hour. Then methyl 3-bromopropionate (1 equivalent) was added dropwise. The reaction was allowed to stir for 30 minutes and then gradually warmed to room temperature. When the reaction was judged to be complete based on TLC or LCMS analysis, it was quenched with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layer was washed with brine and dried over sodium sulfate, and then c

[0860] Representative example 2: 2-((2-hydroxyethyl)sulfonyl)-2,6-diazaspiro[3.5]nonane-5,7-dione

[0861]

[0862] 1-(Vinylsulfonyl)azetidine-3-carboxylic acid methyl ester:

[0863]

[0864] The Boc protected azetidine is dissolved in dioxane. HCl (4N in dioxane) was added and the solution was stirred at room temperature for 12 hours. Then the solvent was evaporated under reduced pressure. Then azetidine (1 equivalent) was dissolved in DCM and cooled to -40°C. Add triethylamine (1.5 equivalents), then DMAP (0.1 equivalents). A solution of vinylsulfonyl chloride (1.2 equivalents) in DCM was slowly added dropwise. The mixture was stirred until the starting material was consumed as judged by TLC or LCMS analysis. The reaction was then warmed to room temperature and filtered through silica gel. The filtrate was concentrated under reduced pressure and the crude material was purified on silica gel.

[0865] 1-((2-((tert-butyldimethylsilyl)oxy)ethyl)sulfonyl)azetidine-3-carboxylic aci

[0876] Representative example 3: 2-(2-hydroxyethyl)-2-methyl-1-oxa-6-azaspiro[3.5]nonane-5,7-dione:

[0877]

[0878] To a solution of 4-butenoic acid (1 equivalent) in dichloromethane at 0°C was added trimethylamine (2 equivalents), isobutyl chloroformate (1.1 equivalents) and N,O-dimethylhydroxylamine (1.05 Equivalent), then trimethylamine (2 equivalents). The reaction was stirred overnight at room temperature. Then it was treated with saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3x). The combined organic layer was washed with brine and dried over sodium sulfate, then concentrated. The crude material was purified on silica gel (Goncalves-Martin, M. et al., Synlett, 2009, 17, ). The Weinreb amide was then dissolved in dry tetrahydrofuran and cooled to 0°C. Then vinyl Grignard reagent (0.7M in THF, 1.2 equivalents) was added dropwise. After 1 hour, the reaction was quenched with satura