1,4-thiazinane 1-oxide;hydrochloride

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

Procedure: To a solution of thiomorpholine 1-oxide hydrochloride (340 mg) and triethylamine (0.31 mL) in N,N-dimethylformamide (25 mL) were added [2-(7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-hydroxybenzotriazole (300 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (420 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 80:20, volume ratio), and the obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (354 mg, yield 58%) as colorless crystals. melting point 194-196° C. cooling cooling the mixture was extracted with ethyl acetate The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate filtered concentrated under reduced pressure the obtained pale-yellow crystals were recrystallized from tetrahydrofuran-ethyl acetate

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

Procedure: To a solution of thiomorpholine 1-oxide hydrochloride (140 mg) and triethylamine (0.125 mL) in N,N-dimethylformamide (15 mL) were added [2-(7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-hydroxybenzotriazole (121 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (172 mg) under ice-cooling, and the mixture was stirred under ice-cooling and then at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0 to 75:25, volume ratio), and the obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane to give the title compound (104 mg, yield 42%) as colorless crystals. cooling cooling the mixture was extracted with ethyl acetate The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate filtered concentrated under reduced pressure the obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (280 mg), trifluoroacetic acid (3.5 mL) and water (10.5 mL) was added concentrated sulfuric acid (3.5 mL), and the mixture was stirred at 60° C. for 3.5 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (10 mL), thiomorpholine 1-oxide hydrochloride (103 mg) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (233 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (methanol:ethyl acetate=0:100-10:90), and the obtained crude product was further purified by preparative HPLC to give the title compound (56 mg, yield 18%) as a white solid. MS: 581 (MH+). The excess trifluoroacetic acid was evaporated under reduced pressure The reaction mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The obtained crude product the mixture was stirred at room temperature for 15 min the mixture was stirred at room temperature for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure the obtained crude product was further purified by preparative HPLC

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

Procedure: To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1-oxide hydrochloride (310 mg), triethylamine (200 μL) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate:methanol=90:10. The obtained colorless oil was purified by preparative HPLC to give the title compound (230 mg, yield 35%) as white crystals. melting point 204° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated to give a colorless oil from a fraction eluted with ethyl acetate The obtained colorless oil was purified by preparative HPLC

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

Procedure: TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.27 mmol) and DIPEA (0.286 mL, 1.64 mmol) at room temperature and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-6-(1-oxo-1,4-thiazinane-4-carbonyl)chromen-4-one (87 mg, 57%) as a pale beige solid. stirring was continued for 3 h washed with water, brine dried over MgSO4 concentrated The residue was purified by preparative HPLC The fractions were evaporated to dryness the residue was dissolved in DCM dried over MgSO4 concentrated The remaining solid was triturated with diethyl ether filtered washed with diethyl ether dried under vacuum at 50° C.

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

Procedure: TBTU (176 mg, 0.55 mmol) was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.27 mmol) and DIPEA (0.286 mL, 1.64 mmol) at room temperature and stirred for 2.5 h. Thiomorpholine 1-oxide hydrochloride (85 mg, 0.55 mmol) was added to the reaction mixture and stirring was continued for 3 h. The reaction mixture was diluted with DCM, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-6-(1-oxo-1,4-thiazinane-4-carbonyl)chromen-4-one (87 mg, 57%) as a pale beige solid. stirring was continued for 3 h washed with water, brine dried over MgSO4 concentrated The residue was purified by preparative HPLC The fractions were evaporated to dryness the residue was dissolved in DCM dried over MgSO4 concentrated The remaining solid was triturated with diethyl ether filtered washed with diethyl ether dried under vacuum at 50° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (280 mg), trifluoroacetic acid (3.5 mL) and water (10.5 mL) was added concentrated sulfuric acid (3.5 mL), and the mixture was stirred at 60° C. for 3.5 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (10 mL), thiomorpholine 1-oxide hydrochloride (103 mg) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (233 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100-10:90), and the obtained crude product was further purified by preparative HPLC to give the title compound (56 mg, yield 18%) as a white solid. MS: 581 (MH+). The excess trifluoroacetic acid was evaporated under reduced pressure The reaction mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The obtained crude product the mixture was stirred at room temperature for 15 min the mixture was stirred at room temperature for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100-10:90) the obtained crude product was further purified by preparative HPLC

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

Procedure: To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1-oxide hydrochloride (310 mg), triethylamine (200 μL) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate:methanol=90:10. The obtained colorless oil was purified by preparative HPLC to give the title compound (230 mg, yield 35%) as white crystals. melting point 204° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated to give a colorless oil from a fraction eluted with ethyl acetate The obtained colorless oil was purified by preparative HPLC

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

Procedure: To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1-oxide hydrochloride (310 mg), triethylamine (200 μL) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate:methanol=90:10. The obtained colorless oil was purified by preparative HPLC to give the title compound (230 mg, yield 35%) as white crystals. melting point 204° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated to give a colorless oil from a fraction eluted with ethyl acetate The obtained colorless oil was purified by preparative HPLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (280 mg), trifluoroacetic acid (3.5 mL) and water (10.5 mL) was added concentrated sulfuric acid (3.5 mL), and the mixture was stirred at 60° C. for 3.5 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (10 mL), thiomorpholine 1-oxide hydrochloride (103 mg) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (233 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100-10:90), and the obtained crude product was further purified by preparative HPLC to give the title compound (56 mg, yield 18%) as a white solid. MS: 581 (MH+). The excess trifluoroacetic acid was evaporated under reduced pressure The reaction mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The obtained crude product the mixture was stirred at room temperature for 15 min the mixture was stirred at room temperature for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (methanol:ethyl acetate=0:100-10:90) the obtained crude product was further purified by preparative HPLC

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

Procedure: To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1-oxide hydrochloride (310 mg), triethylamine (200 μL) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate:methanol=90:10. The obtained colorless oil was purified by preparative HPLC to give the title compound (230 mg, yield 35%) as white crystals. melting point 204° C. the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with saturated brine dried (MgSO4) concentrated to give a colorless oil from a fraction eluted with ethyl acetate The obtained colorless oil was purified by preparative HPLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (280 mg), trifluoroacetic acid (3.5 mL) and water (10.5 mL) was added concentrated sulfuric acid (3.5 mL), and the mixture was stirred at 60° C. for 3.5 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (10 mL), thiomorpholine 1-oxide hydrochloride (103 mg) and triethylamine (0.1 mL) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (233 mg) was added, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (methanol:ethyl acetate=0:100-10:90), and the obtained crude product was further purified by preparative HPLC to give the title compound (56 mg, yield 18%) as a white solid. MS: 581(MH+). The excess trifluoroacetic acid was evaporated under reduced pressure The reaction mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure The obtained crude product the mixture was stirred at room temperature for 15 min the mixture was stirred at room temperature for 16 hr the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over magnesium sulfate filtrated the filtrate was concentrated under reduced pressure the obtained crude product was further purified by preparative HPLC