N-(methylsulfamoyl)methanamine

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

Procedure: 13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (63 mg, 0.14 mMol) was dissolved in 1.7 mL of THF and carbonyldiimidazole (31 mg, 0.19 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr then heated to reflux for 1 hr. The reaction was cooled under nitrogen atmosphere and dimethylsulfamide (91 mg, 0.73 mMol) added followed by DBU (23 uL, 0.15 mMol). The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, cooled under nitrogen and stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 103 mg of a crude product as an amorphous yellow film. The crude product was dissolved in methanol and purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=12.16 min to 12.96 min. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.56 (1 H, br. s.), 1.78 (2 H, d, J=10.07 Hz), 2.00 (2 H, br. s.), 2.07 (2 H, br. s.), 2.78-2.91 (1 H, m), 3.09 (6 H, s), 3.94 (3 H, s), 4.43 (1 H, br. s.), 5.91 (1 H, br. s.), 7.03 (1 H, d, J=2.44 Hz), 7.10 (1 H, dd, J=8.55, 2.75 Hz), 7.50 (1 H, d, J=1.53 Hz), 7.55 (1H, d, J=8.55 Hz), 7.65 (1 H, s), 7.69 (1 H, s), 7.89 (1 H, d, J=8.55 Hz), 8.24 (1 H, s), 8.81 (1 H, br. s.). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.65 min, purity 93%; Flow injection Mass Spectrometry: MS m/z 561(MH+), m/z 559(M-H)−. then heated to reflux for 1 hr The reaction was cooled under nitrogen atmosphere The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs cooled under nitrogen stirred at room temperature overnight The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid The organic phase washed with brine dried over magnesium sulfate and volatiles removed in vacuuo

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

Procedure: 13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (63 mg, 0.14 mMol) was dissolved in 1.7 mL of THF and carbonyldiimidazole (31 mg, 0.19 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr then heated to reflux for 1 hr. The reaction was cooled under nitrogen atmosphere and dimethylsulfamide (91 mg, 0.73 mMol) added followed by DBU (23 uL, 0.15 mMol). The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, cooled under nitrogen and stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 103 mg of a crude product as an amorphous yellow film. The crude product was dissolved in methanol and purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=12.16 min to 12.96 min. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.56 (1 H, br. s.), 1.78 (2 H, d, J=10.07 Hz), 2.00 (2 H, br. s.), 2.07 (2 H, br. s.), 2.78-2.91 (1 H, m), 3.09 (6 H, s), 3.94 (3 H, s), 4.43 (1 H, br. s.), 5.91 (1 H, br. s.), 7.03 (1 H, d, J=2.44 Hz), 7.10 (1 H, dd, J=8.55, 2.75 Hz), 7.50 (1 H, d, J=1.53 Hz), 7.55 (1H, d, J=8.55 Hz), 7.65 (1 H, s), 7.69 (1 H, s), 7.89 (1 H, d, J=8.55 Hz), 8.24 (1 H, s), 8.81 (1 H, br. s.). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.65 min, purity 93%; Flow injection Mass Spectrometry: MS m/z 561(MH+), m/z 559(M-H)−. then heated to reflux for 1 hr The reaction was cooled under nitrogen atmosphere The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs cooled under nitrogen stirred at room temperature overnight The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid The organic phase washed with brine dried over magnesium sulfate and volatiles removed in vacuuo

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

Procedure: 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (Peak2-Chiral Isomer B) (100 mg, 0.17 mMol) was dissolved in 1.9 ml of anhydrous THF and carbonyldiimidazole (37.1 mg, 0.23 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr and heated at reflux for 1 hr under nitrogen. The reaction was cooled under nitrogen and dimethyl sulfamide (145 mg, 1.17 mMol) and DBU (27.5 uL, 0.18 mMol) added to the reaction. The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, then cooled to room temperature and analyzed by HPLC for progress. The reaction was heated for an additional 2.5 hrs at 50 C and again monitored by HPLC. Dimethyl sulfamide (100 mg) and DBU (27 uL) were added to the reaction and the reaction heated to reflux for 3 hrs under nitrogen. Heat was removed and the reaction cooled to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and the aqueous phase extracted with ethyl acetate. The organic phases were combined and washed sequentially with 1N aqueous hydrochloric acid, brine then dried over magnesium sulfate. Removal of volatiles in vacuuo left 209 mg of crude product which was purified by reverse phase HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=15 min; Flow rate=45 ml/min; Column=Waters Sunfire 30 mm×100 mm; Peak collection 8.2 min to 9.1 min.; The title compound was isolated as a colorless solid, 71.2 mg (60%). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.25 (q, J=12.82 Hz, 1.2 H) 1.31-1.53 (m, 2.1 H) 1.58-1.85 (m, 3.2 H) 1.86-2.12 (m, 4.2 H) 2.54-2.76 (m, 2.1 H) 2.81-2.99 (m, 3.3 H) 2.99-3.12(m, 7.3 H) 3.14-3.24(m, 1 H) 3.34-3.61 (m, 3.1 H) 3.60-3.73 (m, 5.3H) 3.72-3.82 (m, 0.9 H) 3.84 (s, 0.6 H) 3.90 (s, 2.5 H) 4.02 (dd, J=14.95, 6.10 Hz, 0.9 H) 4.77-4.92 (m, 1.3 H) 6.78-6.87 (m, 1 H) 6.88-7.05 (m, 2 H) 7.30-7.51 (m, 1.2 H) 7.64 (dd, J=8.39, 1.37 Hz, 0.8 H) 7.81-7.95 (m, 1.0 H) 8.01-8.21 (m, 1 H) 8.67 (s, 0.2 H) 9.86 (s, 0.8 H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.03 min, purity 99%. Flow injection Mass Spectrometry: MS m/z 704(MH+), 726(M+Na)+, m/z 702(M-H)−. Chiral Purity: Column: Chiralacel OJ-H analytical column 4.6 mm×250 mm; Mobile Phase: 12% methanol in carbon dioxide; Temp: 35° C.; Flow rate: 2.0 ml/min for 40 min; UV monitoring=213 nm; Injection: 5 uL of approximately 1 mg/mL solution in ethanol; Retention time: 32.5 min, purity=100% EE=99.9%. heated at reflux for 1 hr under nitrogen The reaction was cooled under nitrogen The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs cooled to room temperature The reaction was heated for an additional 2.5 hrs at 50 C the reaction heated to reflux for 3 hrs under nitrogen Heat was removed the reaction cooled to room temperature stirred overnight The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid the aqueous phase extracted with ethyl acetate washed sequentially with 1N aqueous hydrochloric acid, brine then dried over magnesium sulfate Removal of volatiles in vacuuo left 209 mg of crude product which was purified by reverse phase HPLC under the following conditions Gradient=15 min Runtime=15 min Peak collection 8.2 min to 9.1 min.

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

Procedure: 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (Peak2-Chiral Isomer B) (100 mg, 0.17 mMol) was dissolved in 1.9 ml of anhydrous THF and carbonyldiimidazole (37.1 mg, 0.23 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr and heated at reflux for 1 hr under nitrogen. The reaction was cooled under nitrogen and dimethyl sulfamide (145 mg, 1.17 mMol) and DBU (27.5 uL, 0.18 mMol) added to the reaction. The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, then cooled to room temperature and analyzed by HPLC for progress. The reaction was heated for an additional 2.5 hrs at 50 C and again monitored by HPLC. Dimethyl sulfamide (100 mg) and DBU (27 uL) were added to the reaction and the reaction heated to reflux for 3 hrs under nitrogen. Heat was removed and the reaction cooled to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and the aqueous phase extracted with ethyl acetate. The organic phases were combined and washed sequentially with 1N aqueous hydrochloric acid, brine then dried over magnesium sulfate. Removal of volatiles in vacuuo left 209 mg of crude product which was purified by reverse phase HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=15 min; Flow rate=45 ml/min; Column=Waters Sunfire 30 mm×100 mm; Peak collection 8.2 min to 9.1 min.; The title compound was isolated as a colorless solid, 71.2 mg (60%). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.25 (q, J=12.82 Hz, 1.2 H) 1.31-1.53 (m, 2.1 H) 1.58-1.85 (m, 3.2 H) 1.86-2.12 (m, 4.2 H) 2.54-2.76 (m, 2.1 H) 2.81-2.99 (m, 3.3 H) 2.99-3.12(m, 7.3 H) 3.14-3.24(m, 1 H) 3.34-3.61 (m, 3.1 H) 3.60-3.73 (m, 5.3H) 3.72-3.82 (m, 0.9 H) 3.84 (s, 0.6 H) 3.90 (s, 2.5 H) 4.02 (dd, J=14.95, 6.10 Hz, 0.9 H) 4.77-4.92 (m, 1.3 H) 6.78-6.87 (m, 1 H) 6.88-7.05 (m, 2 H) 7.30-7.51 (m, 1.2 H) 7.64 (dd, J=8.39, 1.37 Hz, 0.8 H) 7.81-7.95 (m, 1.0 H) 8.01-8.21 (m, 1 H) 8.67 (s, 0.2 H) 9.86 (s, 0.8 H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.03 min, purity 99%. Flow injection Mass Spectrometry: MS m/z 704(MH+), 726(M+Na)+, m/z 702(M-H)−. Chiral Purity: Column: Chiralacel OJ-H analytical column 4.6 mm×250 mm; Mobile Phase: 12% methanol in carbon dioxide; Temp: 35° C.; Flow rate: 2.0 ml/min for 40 min; UV monitoring=213 nm; Injection: 5 uL of approximately 1 mg/mL solution in ethanol; Retention time: 32.5 min, purity=100% EE=99.9%. heated at reflux for 1 hr under nitrogen The reaction was cooled under nitrogen The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs cooled to room temperature The reaction was heated for an additional 2.5 hrs at 50 C the reaction heated to reflux for 3 hrs under nitrogen Heat was removed the reaction cooled to room temperature stirred overnight The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid the aqueous phase extracted with ethyl acetate washed sequentially with 1N aqueous hydrochloric acid, brine then dried over magnesium sulfate Removal of volatiles in vacuuo left 209 mg of crude product which was purified by reverse phase HPLC under the following conditions Gradient=15 min Runtime=15 min Peak collection 8.2 min to 9.1 min.

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[(4-methyl-1-piperazinyl)sulfonyl]-. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[(4-methyl-1-piperazinyl)sulfonyl]-, methyl ester (60 mg, 0.11 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (110 mL) and 2M oxalyl chloride (1.0 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (110 mL); BEMP (60 mg, 0.22 mmol) and dimethylsulfamide (68 mg, 0.55 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (48 mg, 68%) as a yellow paste. MS m/z 643 (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.52 (m, 4H), 1.79 (m, 1H), 1.90-2.11 (m, 5H), 2.56 (s, 3H), 2.79 (m, 1H), 2.87-3.16 (m, 5H), 3.05 (s, 6H), 3.36 (m, 1H), 3.58 (m, 1H), 3.70 (m, 1H), 3.92 (s, 3H), 4.41 (broad d, 1H), 5.28 (broad d, 1H), 7.01 (d, 1H), 7.12 (m, 1H), 7.52 (m, 2H), 7.65 (s, 1H), 7.89 (m, 1H), 8.10 (s, 1H), 9.60 (s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (110 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[(4-methyl-1-piperazinyl)sulfonyl]-. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[(4-methyl-1-piperazinyl)sulfonyl]-, methyl ester (60 mg, 0.11 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (110 mL) and 2M oxalyl chloride (1.0 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (110 mL); BEMP (60 mg, 0.22 mmol) and dimethylsulfamide (68 mg, 0.55 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (48 mg, 68%) as a yellow paste. MS m/z 643 (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.13-1.52 (m, 4H), 1.79 (m, 1H), 1.90-2.11 (m, 5H), 2.56 (s, 3H), 2.79 (m, 1H), 2.87-3.16 (m, 5H), 3.05 (s, 6H), 3.36 (m, 1H), 3.58 (m, 1H), 3.70 (m, 1H), 3.92 (s, 3H), 4.41 (broad d, 1H), 5.28 (broad d, 1H), 7.01 (d, 1H), 7.12 (m, 1H), 7.52 (m, 2H), 7.65 (s, 1H), 7.89 (m, 1H), 8.10 (s, 1H), 9.60 (s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (110 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-(4-morpholinylsulfonyl)-. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(4-morpholinylsulfonyl)-, methyl ester (60 mg, 0.12 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (1.0 mL) and 2M oxalyl chloride (0.24 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL); BEMP (0.14, 0.47 mmol) and dimethylsulfamide (59 mg, 0.47 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (50 mg, 68%) as a yellow paste. MS m/z 613 (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.18-1.70 (m, 5H), 1.77 (m, 2H), 1.87-2.16 (m, 3H), 2.88 (m, 1H), 3.08 (s, 6H), 3.93 (s, 3H), 4.18 (broad m, 1H), 5.67 (broad m, 1H), 7.38 (s, 1H), 7.47 (m, 2H), 7.51 (dd, J=7.6, 8.4 Hz ,1H), 7.61 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.31 (s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-6-(4-morpholinylsulfonyl)-. To a solution of 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-(4-morpholinylsulfonyl)-(45 mg, 0.084 mmol) in CH2Cl2 (1.0 mL) was added 2M oxalyl chloride (0.20 mL) in CH2Cl2. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL); BEMP (0.10 mL, 0.33 mmol) and dimethylsulfamide (42 mg, 0.33 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×20 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (34 mg, 64%) as a yellow paste. MS m/z 645 (MH+). Two rotomers present in NMR. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (m, 1H), 1.32-1.49 (m, 2H), 1.64 (m, 1H), 1.78 (m, 2H), 1.88-2.10 (m, 4H), 2.89 (m, 1H), 2.97-3.15 (m, 9H), 3.36 (m, 2.6H), 3.45 (m, 1.4H), 3.66-3.81 (m, 4H), 3.92 (d, 3H), 3.96 (m, 0.65H), 4.07 (m, 0.35H), 4.72 (m, 0.35H), 4.97 (d, J=15 Hz, 0.65H), 6.92 (m, 0.65H), 6.97 (m, 1.35H), 7.33-7.47 (m, 2H), 7.87 (m, 1H), 7.99 (m, 1H), 8.55 (broad s, 1H). concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×20 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-6-(4-morpholinylsulfonyl)-. To a solution of 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6,7-dihydro-3-methoxy-6-(4-morpholinylsulfonyl)-(45 mg, 0.084 mmol) in CH2Cl2 (1.0 mL) was added 2M oxalyl chloride (0.20 mL) in CH2Cl2. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL); BEMP (0.10 mL, 0.33 mmol) and dimethylsulfamide (42 mg, 0.33 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×20 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (34 mg, 64%) as a yellow paste. MS m/z 645 (MH+). Two rotomers present in NMR. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (m, 1H), 1.32-1.49 (m, 2H), 1.64 (m, 1H), 1.78 (m, 2H), 1.88-2.10 (m, 4H), 2.89 (m, 1H), 2.97-3.15 (m, 9H), 3.36 (m, 2.6H), 3.45 (m, 1.4H), 3.66-3.81 (m, 4H), 3.92 (d, 3H), 3.96 (m, 0.65H), 4.07 (m, 0.35H), 4.72 (m, 0.35H), 4.97 (d, J=15 Hz, 0.65H), 6.92 (m, 0.65H), 6.97 (m, 1.35H), 7.33-7.47 (m, 2H), 7.87 (m, 1H), 7.99 (m, 1H), 8.55 (broad s, 1H). concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×20 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-(4-morpholinylsulfonyl)-. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-(4-morpholinylsulfonyl)-, methyl ester (60 mg, 0.11 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (1.0 mL) and 2M oxalyl chloride (1.0 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL); BEMP (60 mg, 0.22 mmol) and dimethylsulfamide (68 mg, 0.55 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (50 mg, 71%) as a yellow paste. MS 643 m/z (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.15-1.60 (m, 4H), 1.80 (m, 1H), 1.91-2.12 (m, 5H), 2.81 (m, 3H), 3.08 (broad s, 8H), 3.22 (m, 2H), 3.41 (m, 2H), 3.92 (s, 3H), 4.4 (broad d, 1H), 5.36 (broad d, 1H), 7.02 (d, 1H), 7.15 (m, 1H), 7.40 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.90 (m, 1H), 8.11 (s, 1H), 8.58 (s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-(4-morpholinylsulfonyl)-. To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-(4-morpholinylsulfonyl)-, methyl ester (60 mg, 0.11 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (1.0 mL) and 2M oxalyl chloride (1.0 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL); BEMP (60 mg, 0.22 mmol) and dimethylsulfamide (68 mg, 0.55 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (50 mg, 71%) as a yellow paste. MS 643 m/z (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.15-1.60 (m, 4H), 1.80 (m, 1H), 1.91-2.12 (m, 5H), 2.81 (m, 3H), 3.08 (broad s, 8H), 3.22 (m, 2H), 3.41 (m, 2H), 3.92 (s, 3H), 4.4 (broad d, 1H), 5.36 (broad d, 1H), 7.02 (d, 1H), 7.15 (m, 1H), 7.40 (m, 1H), 7.51 (m, 1H), 7.68 (s, 1H), 7.90 (m, 1H), 8.11 (s, 1H), 8.58 (s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.0 mL) to stir at 22° C. for 6 hr the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-(ethylsulfonyl)-To a solution of 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-(ethylsulfonyl)-, methyl ester (80 mg, 0.17 mmol) in 1:1 MeOH/THF (2.0 mL) was added 1M NaOH (2.0 mL). The resulting mixture was stirred at 22° C. for 16 hr. 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white solid. This solid was dissolved in CH2Cl2 (1.5 mL) and 2M oxalyl chloride (1.5 mL) in CH2Cl2 was added. This solution was stirred at 22° C. for 2 hr and concentrated under reduced pressure. The resulting yellow oil was redissolved in CH2Cl2 (1.5 mL); BEMP (94 mg, 0.34 mmol) and dimethylsulfamide (107 mg, 0.86 mmol) were added. The resulting mixture was allowed to stir at 22° C. for 6 hr 1M HCl (15 mL) was added and the aqueous layer was extracted with CHCl3 (2×30 mL). The organic phase was concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (67 mg, 69%) as a yellow paste. MS m/z 556 (MH+). 1H NMR (300 MHz, CDCl3) δ ppm 1.18-1.70 (m, 5H), 1.35 (t, 3H), 1.77 (m, 2H), 1.87-2.16 (m, 3H), 2.88 (m, 1H), 3.08 (s, 6H), 3.15 (q, 2H), 4.18 (broad m, 1H), 5.67 (broad m, 1H), 7.38 (s, 1H), 7.47 (m, 2H), 7.51 (dd, J=7.6, 8.4 Hz,1H), 7.61 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.31 (s, 1H), 8.54 (broad s, 1H). the aqueous layer was extracted with CHCl3 (2×15 mL) The organic phase was dried over Na2SO4 filtered concentrated under reduced pressure to afford a white solid This solution was stirred at 22° C. for 2 hr concentrated under reduced pressure The resulting yellow oil was redissolved in CH2Cl2 (1.5 mL) was added the aqueous layer was extracted with CHCl3 (2×30 mL) The organic phase was concentrated under reduced pressure This oil was purified by reverse-phase prep HPLC