(2R)-3-methylbutan-2-amine

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1,2) gave 30 mg (13%) of the title compound as white crystals.

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1,2) gave 30 mg (13%) of the title compound as white crystals.

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

Procedure: A solution of (R)-3-methylbutan-2-amine (10.50 g) and 2,2-dimethoxyacetaldehyde (18.18 mL) in methanol (50 mL) was added to palladium on carbon (3 g) in water (3.0 mL) at 25° C. The mixture was hydrogenated under 5 bar at 25° C. for 24 h. The reaction mixture was filtered through Celite and concentrated under vacuum to afford (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine as a colourless liquid (16.40 g). 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 2.77 (dd, J=11.9, 5.4 Hz, 1H), 2.66 (dd, J=11.9, 6.0 Hz, 1H), 2.44 (qd, J=6.4, 5.1 Hz, 1H), 1.75-1.63 (m, 1H), 0.96 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H). The reaction mixture was filtered through Celite concentrated under vacuum

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

Procedure: A solution of (R)-3-methylbutan-2-amine (10.50 g) and 2,2-dimethoxyacetaldehyde (18.18 mL) in methanol (50 mL) was added to palladium on carbon (3 g) in water (3.0 mL) at 25° C. The mixture was hydrogenated under 5 bar at 25° C. for 24 h. The reaction mixture was filtered through Celite and concentrated under vacuum to afford (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine as a colourless liquid (16.40 g). 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 2.77 (dd, J=11.9, 5.4 Hz, 1H), 2.66 (dd, J=11.9, 6.0 Hz, 1H), 2.44 (qd, J=6.4, 5.1 Hz, 1H), 1.75-1.63 (m, 1H), 0.96 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H). The reaction mixture was filtered through Celite concentrated under vacuum

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 30 mg (13%) of the title compound as white crystals.

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

Procedure: Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%). were reacted

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

Procedure: 2,2-Dimethoxyacetaldehyde (60% in water, 8.7 mL) was added to (R)-3-methylbutan-2-amine (5.0 g) in methanol (25 mL) and the mixture stirred at ambient temperature overnight. A slurry of palladium on carbon (5%, 1.2 g) in water (10 mL) was added and the mixture was hydrogenated at 5 bar pressure with stirring for 3 hours. The mixture was filtered through Celite and the filter pad washed with methanol (3×100 mL). The combined filtrate and washings were concentrated to a volume of −10 mL and then toluene (200 mL) was added. The mixture was concentrated, more toluene (200 mL) was added and the mixture was concentrated once more to give the titled compound as a yellow oil. Yield 8.0 g. with stirring for 3 hours The mixture was filtered through Celite the filter pad washed with methanol (3×100 mL) The combined filtrate and washings were concentrated to a volume of −10 mL toluene (200 mL) was added The mixture was concentrated more toluene (200 mL) was added the mixture was concentrated once more

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1,2) gave 30 mg (13%) of the title compound as white crystals.

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

Procedure: To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and (2R)-3-methyl-2-butanamine (10.5 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 40%). LC-MS m/z 591 (M+H)+. Separation by HPLC with TFA

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

Procedure: In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(−)-3-methyl-2-butylamine (Fluka) to give the title product. LC-MS (ES+) 734 [(M+H)+].

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

Procedure: Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%). were reacted

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

Procedure: 2,2-Dimethoxyacetaldehyde (60% in water, 8.7 mL) was added to (R)-3-methylbutan-2-amine (5.0 g) in methanol (25 mL) and the mixture stirred at ambient temperature overnight. A slurry of palladium on carbon (5%, 1.2 g) in water (10 mL) was added and the mixture was hydrogenated at 5 bar pressure with stirring for 3 hours. The mixture was filtered through Celite and the filter pad washed with methanol (3×100 mL). The combined filtrate and washings were concentrated to a volume of ˜10 mL and then toluene (200 mL) was added. The mixture was concentrated, more toluene (200 mL) was added and the mixture was concentrated once more to give the titled compound as a yellow oil. Yield 8.0 g. with stirring for 3 hours The mixture was filtered through Celite the filter pad washed with methanol (3×100 mL) The combined filtrate and washings were concentrated to a volume of ˜10 mL toluene (200 mL) was added The mixture was concentrated more toluene (200 mL) was added the mixture was concentrated once more