1H-indol-2-ylmethanamine

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

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3×). The combined extracts were washed with H2O (1×), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°). The mixture was evaporated to dryness in vacuo the residue treated with H2O extracted with EtOAc (3×) The combined extracts were washed with H2O (1×) dried over MgSO4 filtered to give an orange oil which

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3×). The combined extracts were washed with H2O (1×), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°). The mixture was evaporated to dryness in vacuo the residue treated with H2O extracted with EtOAc (3×) The combined extracts were washed with H2O (1×) dried over MgSO4 filtered to give an orange oil which

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3x). The combined extracts were washed with H2O (1X), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°). The mixture was evaporated to dryness in vacuo the residue treated with H2O extracted with EtOAc (3x) The combined extracts were washed with H2O (1X) dried over MgSO4 filtered to give an orange oil which

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3x). The combined extracts were washed with H2O (1X), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°). The mixture was evaporated to dryness in vacuo the residue treated with H2O extracted with EtOAc (3x) The combined extracts were washed with H2O (1X) dried over MgSO4 filtered to give an orange oil which

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

Procedure: EDC (1.53 g, 7.99 mmol) was added to a solution of methyl (±)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (2.13 g, 7.26 mmol), 2-aminomethylindole (1.06 g, 7.26 mmol), HOBT.H2O (1.08 g, 7.99 mmol) and diisopropylethylamine (1.53 mL, 8.71 mmol) in anhydrous DMF (10 mL) at RT. After 20 h the reaction was concentrated on the rotavap (high vacuum). The residue was taken up in EtOAc and washed sequentially with H2O and 10% Na2CO3 (2×30 mL). Drying (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2Cl2) gave the title compound (1.8 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, 1H), 7.95 (s, 1H), 7.59 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.33 (d, 1H), 7.01 (t, 1H), 6.93 (t, 1H), 6.55 (d, 1H), 6.33 (br, 1H), 6.25 (s, 1H), 5.49 (d, 1H), 5.14 (t, 1H), 4.56 (d, 2H), 3.82 (d, 1H), 3.61 (s, 3H), 2.92 (s, 3H), 2.75 (dd, 1H), 2.53 (d, 1H); MS(ES) m/e 421.2 (M+H)+. at RT After 20 h the reaction was concentrated on the rotavap (high vacuum) washed sequentially with H2O and 10% Na2CO3 (2×30 mL) Drying (MgSO4), concentration, and silica gel chromatography (2% MeOH/CH2Cl2)

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

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

Procedure: Compound 963 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, 2-aminomethylindole, and 1-(2-hydroxyethyl)-1H-indole-5-carboxylic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.42 (s, 1H), 8.31 (dd, J=1.0, 5.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 2H), 8.06 (t, J=5.5 Hz, 1H), 7.87 (dd, J=1.5, 9 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.66 (d, J=9 Hz, 2H), 7.62 (d, J=2 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J=3 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.11 (ddd, J=1, 7, 9 Hz, 1H) 7.03 (ddd, J=1, 7, 8.5 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 6.56 (d, J=3.5 Hz, 1H), 4.82 (d, J=5.5 Hz, 2H), 4.35 (t, J=5.5 Hz, 2H), 3.92 (q, J=5 Hz, 2H), 3.31 (d, J=5 Hz, 1H).

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

Procedure: Following the procedure as described in Example 22, making variation only as required to use (1H-indol-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 22% yield: 1H NMR (300 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.73 (t, J=5.6 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.45-7.29 (m, 7H), 7.01-6.87 (m, 2H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.25-6.22 (m, 2H), 5.16 (s, 2H), 4.53 (d, J=5.6 Hz, 2H), 2.56 (s, 3H); MS (ES+) m/z 471.2 (M+1).

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

Procedure: (R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-indol-2-yl)methanamine (10.17 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 ODS 5u 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.3 min) to provide (R/S)-N-((1H-indol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.02 mmol, 43.7% yield): LCMS=560.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.20 (2 H, m), 7.55-7.75 (9 H, m), 7.27-7.46 (2 H, m), 6.92-7.08 (2 H, m), 6.29 (1 H, s), 5.20 (1 H, s), 4.48-4.64 (2 H, m); HPLC peak RT=10.7 min (Method A). was purified by prep HPLC (YMC S5 ODS 5u 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.3 min)

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

Procedure: LAH (42 mL, 1M solution in THF) was added dropwise through a syringe to a solution of 2-cyanoindole (2.0 g, 14.1 mmol) in anhydrous THF (20 mL) with cooling, and the resulting solution was stirred at RT under argon for 5 h. H2O was added dropwise with cooling to destroy excess LAH, and the colorless precipitate was removed by filtration and washed with THF. The filtrate was dried (K2CO3) and concentrated to afford the title compound (2.11 g, quantitative) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, 1H), 7.29 (d, 1H), 6.97 (t, 1H), 6.91 (t, 1H), 6.20 (s, 1H), 3.82 (s, 2H), 2. 18 (br, 1H). with cooling with cooling to destroy excess LAH the colorless precipitate was removed by filtration washed with THF The filtrate was dried (K2CO3) concentrated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(RS)-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (150 mg, 0.520 mmol) and 2-aminomethylindole (75.9 mg, 0.520 mmol) were combined in 1,2-dimethoxyethane (3 ml) and the mixture stirred 20 min. at 25° C. The mixture was evaporated to dryness in vacuo and the residue treated with H2O and extracted with EtOAc (3×). The combined extracts were washed with H2O (1×), dried over MgSO4, filtered and stripped to dryness in vacuo to give an orange oil which, after chromatography on silica gel (4% MeOH in CH2Cl2) provided the title compound as a white solid from ether: (m.p. 200°-202°). The mixture was evaporated to dryness in vacuo the residue treated with H2O extracted with EtOAc (3×) The combined extracts were washed with H2O (1×) dried over MgSO4 filtered to give an orange oil which