1-(1H-indol-4-yl)-N-methylmethanamine

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

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

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

Procedure: A tube was charged with 116 (280 mg, 1.75 mmol), 53 (412 mg, 1.75 mmol), DIPEA (678 mg, 5.25 mmol) and IPA (5 mL), sealed and heated at 120° C. for 14 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40. sealed The mixture was concentrated in vacuo the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40

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

Procedure: To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added 1H-indole-4-carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (1H-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z=161.3 [M+1]+. The reaction was cooled in an ice bath The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h The solvent was removed under reduced pressure

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

Procedure: To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added 1H-indole-4-carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (1H-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z=161.3 [M+1]+. The reaction was cooled in an ice bath The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h The solvent was removed under reduced pressure

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

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

Procedure: According to the procedure of Example 35g, (1H-indol-4-ylmethyl)-methyl-amine (223 mg, 1.39 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (359 mg, 1.41 mmol), were coupled to give crude product. Purification by column chromatography gave the title compound (369 mg, 73%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.20-11.14 (m, 1H), 10.65-10.62 (m, 1H), 8.38-8.32 (m, 1H), 8.08-7.99 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.21 (m, 3H), 7.09-7.03 (m, 1H), 6.89-6.76 (m, 1H), 6.51 (s, 1H), 5.06-4.88 (m, 2H), 3.04-2.83 (m, 5H), 2.56-2.52 (m, 2H); ESI MS m/z 361 [C21H20N4O2+H]+. to give crude product Purification by column chromatography

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

Procedure: 1H-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (1H-indol-4-ylmethyl)-methyl-amine (229 mg, 94%) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, 1H), 3.88 (s, 2H), 2.30 (s, 3H). The solution was concentrated to an orange solid dissolved in anhydrous methanol (7 ml) the mixture was stirred overnight at room temperature the solution was concentrated Sodium hydroxide (10 ml, 1N) was added the aqueous layer was extracted with ethyl acetate (3×20 ml) Combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: According to the procedure of Example 35g, (1H-indol-4-ylmethyl)-methyl-amine (223 mg, 1.39 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride (359 mg, 1.41 mmol), were coupled to give crude product. Purification by column chromatography gave the title compound (369 mg, 73%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 11.20-11.14 (m, 1H), 10.65-10.62 (m, 1H), 8.38-8.32 (m, 1H), 8.08-7.99 (m, 1H), 7.59-7.53 (m, 1H), 7.37-7.21 (m, 3H), 7.09-7.03 (m, 1H), 6.89-6.76 (m, 1H), 6.51 (s, 1H), 5.06-4.88 (m, 2H), 3.04-2.83 (m, 5H), 2.56-2.52 (m, 2H); ESI MS m/z 361 [C21H20N4O2+H]+. to give crude product Purification by column chromatography

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

Procedure: 1H-Indole-4-carbaldehyde (219 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to an orange solid and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.0 mg, 1.53 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (1H-indol-4-ylmethyl)-methyl-amine (229 mg, 94%) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ 11.03 (bs, 1H), 7.29-7.24 (m, 2H), 7.03-6.93 (m, 2H), 6.51-6.50 (m, 1H), 3.88 (s, 2H), 2.30 (s, 3H). The solution was concentrated to an orange solid dissolved in anhydrous methanol (7 ml) the mixture was stirred overnight at room temperature the solution was concentrated Sodium hydroxide (10 ml, 1N) was added the aqueous layer was extracted with ethyl acetate (3×20 ml) Combined organic layers were dried over MgSO4 filtered concentrated

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

Procedure: A tube was charged with 116 (280 mg, 1.75 mmol), 53 (412 mg, 1.75 mmol), DIPEA (678 mg, 5.25 mmol) and IPA (5 mL), sealed and heated at 120° C. for 14 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40. sealed The mixture was concentrated in vacuo the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40

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

Procedure: To a solution of methanamine (536 mg, 17.24 mmol) in MeOH (10 mL) was added 1H-indole-4-carbaldehyde (500 mg, 3.45 mmol). The reaction mixture was stirred at RT for 14 h. The reaction was cooled in an ice bath and NaBH4 (130 mg, 3.45 mmol) was added in several portions. The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h. The solvent was removed under reduced pressure to afford 300 mg (54.5%) of (1H-indol-4-yl)-N-methylmethanamine (116) which was used in the next step without further purification: MS (ESI) m/z=161.3 [M+1]+. The reaction was cooled in an ice bath The reaction was stirred at 0° C. for 5 min then stirred at RT for 4 h The solvent was removed under reduced pressure