1H-azepine

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

Procedure: The product from Example 44E and azepine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+;

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

Procedure: The product from Example 1C and azepine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;

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

Procedure: To a solution of azepine compound prepared in example 7′ (5-(3-cyano-propyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, 100 mg) in DMF (2.0 mL) was added DIEA (181 μL) followed by 4-bromomethyl-5-methyl-[1,3]-dioxol-2-one (194 mg, prepared as described in J. Alexander, et al. J. Med. Chem, 1996, 39, 480-486). After stirring overnight EtOAc (30 mL) was added, the organic solution washed with brine (20 mL), dried over Na2SO4 and the solvents removed under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm) to provide the title compound (6 mg) of as a white solid. was added the organic solution washed with brine (20 mL) dried over Na2SO4 the solvents removed under reduced pressure The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm)

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

Procedure: To a solution of azepine compound prepared in example 7′ (5-(3-cyano-propyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, 100 mg) in DMF (2.0 mL) was added DIEA (181 μL) followed by 4-bromomethyl-5-methyl-[1,3]-dioxol-2-one (194 mg, prepared as described in J. Alexander, et al. J. Med. Chem, 1996, 39, 480-486). After stirring overnight EtOAc (30 mL) was added, the organic solution washed with brine (20 mL), dried over Na2SO4 and the solvents removed under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm) to provide the title compound (6 mg) of as a white solid. was added the organic solution washed with brine (20 mL) dried over Na2SO4 the solvents removed under reduced pressure The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm)

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

Procedure: The product from Example 44E and azepine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+;

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

Procedure: The product from Example 1C and azepine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;

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

Procedure: This compound was prepared as the hydrochloride salt using 5-[4-(3-chloropropoxy)-phenyl]-2-methyl-2H-pyridazin-3-one and azepine using the procedure described in Example 91 Step 5; Mp 247-8° C.; MS m/z 342 (M+H).

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

Procedure: The product from Example 1C and azepine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;

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

Procedure: To a solution of azepine compound prepared in example 7′ (5-(3-cyano-propyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, 100 mg) in DMF (2.0 mL) was added DIEA (181 μL) followed by 4-bromomethyl-5-methyl-[1,3]-dioxol-2-one (194 mg, prepared as described in J. Alexander, et al. J. Med. Chem, 1996, 39, 480-486). After stirring overnight EtOAc (30 mL) was added, the organic solution washed with brine (20 mL), dried over Na2SO4 and the solvents removed under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm) to provide the title compound (6 mg) of as a white solid. was added the organic solution washed with brine (20 mL) dried over Na2SO4 the solvents removed under reduced pressure The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm)

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

Procedure: 1,1-Carbonydiimidazole (0.80 g, 4.9 mmol) was added to a solution of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-3-phenylbutanoic acid dihydrochloride (2.00 g, 4.68 mmol) and triethylamine (0.95 g, 9.4 mmol) in dichloromethane (20 ml). After the cessation of gas evolution, a solution of azepine (0.51 g, 5.2 mmol) in dichloromethane (7 ml) was added and stirring continued overnight. The reaction mixture was concentrated under reduced pressure and the crude product chromatographed on silica gel, eluting with ethyl acetate: hexane (5:1) to afford an oil. The oil was dissolved in methyl acetate and acidified with ethereal hydrogen chloride to afford the title compound dihydrochloride hemihydrate as a colourless powder (1.08 g), m.p. 201.5-202.2 (dec.). The reaction mixture was concentrated under reduced pressure the crude product chromatographed on silica gel eluting with ethyl acetate: hexane (5:1) to afford an oil

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

Procedure: 1,1-Carbonydiimidazole (0.80 g, 4.9 mmol) was added to a solution of 4-[4-(2-methoxyphenyl)piperazin-1-yl]-3-phenylbutanoic acid dihydrochloride (2.00 g, 4.68 mmol) and triethylamine (0.95 g, 9.4 mmol) in dichloromethane (20 ml). After the cessation of gas evolution, a solution of azepine (0.51 g, 5.2 mmol) in dichloromethane (7 ml) was added and stirring continued overnight. The reaction mixture was concentrated under reduced pressure and the crude product chromatographed on silica gel, eluting with ethyl acetate: hexane (5:1) to afford an oil. The oil was dissolved in methyl acetate and acidified with ethereal hydrogen chloride to afford the title compound dihydrochloride hemihydrate as a colourless powder (1.08 g), m.p. 201.5-202.2 (dec.). The reaction mixture was concentrated under reduced pressure the crude product chromatographed on silica gel eluting with ethyl acetate: hexane (5:1) to afford an oil

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

Procedure: Prepared from the product of Example 12 and azepine.