4-N,4-N-diethylcyclohexane-1,4-diamine

Conditions: temp:70.01; pressure:0.00; stir:

Procedure: Dilution of the aliquot (2 uL) with DMSO (200 uL).

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

Procedure: Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J1=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J1=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J1=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J1=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Into a 5 mL screw-cap vial The vial was sealed The plug was washed with 1 N aqueous potassium hydrogensulfate and water Elution with acetonitrile and evaporation of the solvent afforded a brown oil which the reaction mixture was concentrated The residue was dissolved in 2 mL of methanol 200 μL ethylenediamine were added The mixture was diluted with 2 mL of DMSO purified by reverse-phase HPLC

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

Procedure: Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J1=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J1=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J1=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J1=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Into a 5 mL screw-cap vial The vial was sealed The plug was washed with 1 N aqueous potassium hydrogensulfate and water Elution with acetonitrile and evaporation of the solvent afforded a brown oil which the reaction mixture was concentrated The residue was dissolved in 2 mL of methanol 200 μL ethylenediamine were added The mixture was diluted with 2 mL of DMSO purified by reverse-phase HPLC

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

Procedure: Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (116 mg, 0.408 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (138 mg, 0.812 mmol) to afford the desired product (157 mg, 51%) as an off-white solid: ESI MS m/z 418 [C21H28BrN3O+H]+.

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

Procedure: Following general procedure B, 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (161 mg, 0.500 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (170 mg, 1.00 mmol) to afford the desired product (197 mg, 87%) as a white solid: ESI MS m/z 454 [C20H28BrN3O2S+H]+.

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

Procedure: Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.01 g, 3.25 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (660 mg, 3.90 mmol) to afford the desired product (1.12 g, 78%) as a yellow wax: ESI MS m/z 523 [C23H30BrN3O+H]+.

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

Procedure: Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (1.01 g, 3.25 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (660 mg, 3.90 mmol) to afford the desired product (1.12 g, 78%) as a yellow wax: ESI MS m/z 523 [C23H30BrN3O+H]+.

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

Procedure: Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Into a 5 mL screw-cap vial The vial was sealed The plug was washed with 1 N aqueous potassium hydrogensulfate and water Elution with acetonitrile and evaporation of the solvent afforded a brown oil which the reaction mixture was concentrated The residue was dissolved in 2 mL of methanol 200 μL ethylenediamine were added The mixture was diluted with 2 mL of DMSO purified by reverse-phase HPLC