piperidine-2,3-dione

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Example 8A (13 mg, 0.028 mmol) in DCM (0.5 mL) and DCE (0.5 mL) was added boron trichloride-methyl sulfide complex (30.6 mg, 0.171 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was quenched with ice and MeOH and example 8 isolated via prep HPLC (10 minute gradient from 5 to 100% B; Column: Phenomenex AXIA Luna 100×20 mm 5 μm; Solvent A: 10% ACN-90% H2O-0.1% TFA; Solvent B: 90% ACN-10% H2O-0.1% TFA). The desired fractions were evaporated to dryness to give Example 8 (5 mg, 0.01 mmol, 40% yield). LCMS RT=2.27 min, [M+1]=443.1 {(MeOH/H2O/TFA) Phenom. Luna C18; 50×4.6 mm; 4 min Grad}; HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=11.2 min, 95%}; Xbridge {RT=9.9 min, 96.3%}. 1H NMR (500 MHz, MeOD) δ ppm 2.01-2.06 (m, 3H) 2.19-2.25 (m, 1H) 3.59 (s, 3H) 4.20 (t, J=6.33 Hz, 1H) 5.33 (t, J=5.64 Hz, 1H) 6.74 (d, J=7.43 Hz, 1H) 6.86 (d, J=7.70 Hz, 1H) 7.10 (dd, J=8.25, 1.93 Hz, 1H) 7.14 (d, J=7.43 Hz, 1H) 7.18 (t, J=7.57 Hz, 1H) 7.24 (t, J=7.29 Hz, 1H) 7.34 (d, J=2.20 Hz, 1H) 7.39 (d, J=7.43 Hz, 1H) 7.43-7.46 (m, 1H). The reaction mixture was quenched with ice and MeOH and example 8

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

Procedure: The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).

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

Procedure: The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Example 8A (13 mg, 0.028 mmol) in DCM (0.5 mL) and DCE (0.5 mL) was added boron trichloride-methyl sulfide complex (30.6 mg, 0.171 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was quenched with ice and MeOH and example 8 isolated via prep HPLC (10 minute gradient from 5 to 100% B; Column: Phenomenex AXIA Luna 100×20 mm 5 μm; Solvent A: 10% ACN-90% H2O-0.1% TFA; Solvent B: 90% ACN-10% H2O-0.1% TFA). The desired fractions were evaporated to dryness to give Example 8 (5 mg, 0.01 mmol, 40% yield). LCMS RT=2.27 min, [M+1]=443.1 {(MeOH/H2O/TFA) Phenom. Luna C18; 50×4.6 mm; 4 min Grad}; HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=11.2 min, 95%}; Xbridge {RT=9.9 min, 96.3%}. 1H NMR (500 MHz, MeOD) δ ppm 2.01-2.06 (m, 3H) 2.19-2.25 (m, 1H) 3.59 (s, 3H) 4.20 (t, J=6.33 Hz, 1H) 5.33 (t, J=5.64 Hz, 1H) 6.74 (d, J=7.43 Hz, 1H) 6.86 (d, J=7.70 Hz, 1H) 7.10 (dd, J=8.25, 1.93 Hz, 1H) 7.14 (d, J=7.43 Hz, 1H) 7.18 (t, J=7.57 Hz, 1H) 7.24 (t, J=7.29 Hz, 1H) 7.34 (d, J=2.20 Hz, 1H) 7.39 (d, J=7.43 Hz, 1H) 7.43-7.46 (m, 1H). The reaction mixture was quenched with ice and MeOH and example 8

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

Procedure: The ester (compound D, Scheme 1) can be treated with NIS in DMF to provide the C6 iodide (B). The resulting iodide (B) can be converted to trifluoromethylpyridinedione (C) by the treatment with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of copper (I) iodide in a solvent such as DMF. The ester (C) can be hydrolyzed using an aqueous hydroxide base such as lithium hydroxide or sodium hydroxide with a co-solvent such as tetrahydrofuran or methanol to provide the acid (D). The acid (D) can be coupled to an amine (RNH2) using standard peptide coupling conditions such as PyBOP/DIPEA or EDC/HOBT/DIPEA in a solvent such as dichloromethane or THF to produce the amide (E). The methoxy group on amide (E) could be cleaved using boron tribromide-methyl sulfide complex, boron tribromide solution in dichloromethane or boron trichloride to provide the pyridinedione (F).

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