牛磺酰胺盐酸盐

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), 2-amino-ethanesulfonic acid amide HCl salt (30 mg, 0.24 mmol), and NaOMe (13 mg, 0.23 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 1, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 5.8 mg of the title compound. MS: (−) m/z 426.24 (M−1). The mixture was concentrated to dryness the residue was partitioned between EtOAc and water 1 M HCl was added the aqueous layer was extracted with additional EtOAc dried over MgSO4 concentrated The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), 2-amino-ethanesulfonic acid amide HCl salt (30 mg, 0.24 mmol), and NaOMe (13 mg, 0.23 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 1, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 5.8 mg of the title compound. MS: (−) m/z 426.24 (M−1). The mixture was concentrated to dryness the residue was partitioned between EtOAc and water 1 M HCl was added the aqueous layer was extracted with additional EtOAc dried over MgSO4 concentrated The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.097 mmol), 2-amino-ethanesulfonic acid amide HCl salt (24 mg, 0.19 mmol), and NaOMe (9.9 mg, 0.18 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between 1 M HCl and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 21 mg of the title compound. MS: (+) m/z 403.25 (M+1). Solvent was evaporated in vacuo the residue was partitioned between 1 M HCl and EtOAc The aqueous layer was extracted with additional EtOAc dried over MgSO4 After evaporating the solvent the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2)

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.097 mmol), 2-amino-ethanesulfonic acid amide HCl salt (24 mg, 0.19 mmol), and NaOMe (9.9 mg, 0.18 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between 1 M HCl and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 21 mg of the title compound. MS: (+) m/z 403.25 (M+1). Solvent was evaporated in vacuo the residue was partitioned between 1 M HCl and EtOAc The aqueous layer was extracted with additional EtOAc dried over MgSO4 After evaporating the solvent the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 250 mg, 0.83 mmol) in THF (4 mL) was treated with sodium hydroxide (1N NaOH, 0.92 mL, 0.92 mmol). After 2 hours, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was co-evaporated with toluene (5 mL), re-dissolved in DMF (4 mL), and treated with 2-aminoethanesulfonamide hydrochloride (201 mg, 1.30 mmol), TEA (1.2 mL, 8.3 mmol) and HATU (475 mg, 1.30 mmol). After 16 hours, the reaction mixture was diluted with water (20 mL), extracted with DCM (3×10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in DMF/methanol and purified using reverse phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100 mm, 30 to 100% B over 15 minutes with 10 minute hold time, solvent A: 90% water/ACN/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254). The pooled fractions were lyophilized to Compound A1a, (170 mg, 45% yield) as a white solid. HPLC: RT=0.75 (LCMS Method O). MS (ES): m/z=379.7 [M+H]+. 1H NMR (400 MHz, DMF-d7) δ 8.40 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 6.97 (s, 2H), 3.82-3.61 (m, 2H), 3.46 (s, 3H), 3.33 (dd, J=7.9, 6.4 Hz, 3H). the reaction mixture was concentrated to dryness under reduced pressure re-dissolved in DMF (4 mL) After 16 hours extracted with DCM (3×10 mL) dried over Na2SO4 concentrated under reduced pressure The residue was dissolved in DMF/methanol purified phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100 mm, 30 to 100% B over 15 minutes with 10 minute hold time, solvent A: 90% water/ACN/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254) RT=0.75 (LCMS Method O)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 250 mg, 0.83 mmol) in THF (4 mL) was treated with sodium hydroxide (1N NaOH, 0.92 mL, 0.92 mmol). After 2 hours, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was co-evaporated with toluene (5 mL), re-dissolved in DMF (4 mL), and treated with 2-aminoethanesulfonamide hydrochloride (201 mg, 1.30 mmol), TEA (1.2 mL, 8.3 mmol) and HATU (475 mg, 1.30 mmol). After 16 hours, the reaction mixture was diluted with water (20 mL), extracted with DCM (3×10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in DMF/methanol and purified using reverse phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100 mm, 30 to 100% B over 15 minutes with 10 minute hold time, solvent A: 90% water/ACN/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254). The pooled fractions were lyophilized to Compound A1a, (170 mg, 45% yield) as a white solid. HPLC: RT=0.75 (LCMS Method O). MS (ES): m/z=379.7 [M+H]+. 1H NMR (400 MHz, DMF-d7) δ 8.40 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 6.97 (s, 2H), 3.82-3.61 (m, 2H), 3.46 (s, 3H), 3.33 (dd, J=7.9, 6.4 Hz, 3H). the reaction mixture was concentrated to dryness under reduced pressure re-dissolved in DMF (4 mL) After 16 hours extracted with DCM (3×10 mL) dried over Na2SO4 concentrated under reduced pressure The residue was dissolved in DMF/methanol purified phase HPLC (Phenomemenx Luna AXIA 5 micron C18, 21.2×100 mm, 30 to 100% B over 15 minutes with 10 minute hold time, solvent A: 90% water/ACN/0.1% TFA, solvent B:90% ACN/water/0.1% TFA, Flow rate 20 mL/min; detector at 254) RT=0.75 (LCMS Method O)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (2.15 mL, 17.1 mmol), triethylamine (2.2 mL, 15.6 mmol), 2-aminoethanesulfonamide-hydrochloric acid (2.5 g, 15.6 mmol), and 4 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (40 mL) was stirred at ambient temperature for 20 h. This material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (2.0 g, 20.7 mmol) was added and the mixture was warmed to 50° C. Iodine (3.95 g, 15.6 mmol) was added and the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 50 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.5 g, 1.9 mmol, 12.2% yield) which was carried on without further purification. MS (DCI/NH3) m/z 264 (M+H)+. This material was filtered through Celite with acetonitrile (additional 25 mL) the mixture was warmed to 50° C the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with CH2Cl2 (3×10 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (2.15 mL, 17.1 mmol), triethylamine (2.2 mL, 15.6 mmol), 2-aminoethanesulfonamide-hydrochloric acid (2.5 g, 15.6 mmol), and 4 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (40 mL) was stirred at ambient temperature for 20 h. This material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (2.0 g, 20.7 mmol) was added and the mixture was warmed to 50° C. Iodine (3.95 g, 15.6 mmol) was added and the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 50 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.5 g, 1.9 mmol, 12.2% yield) which was carried on without further purification. MS (DCI/NH3) m/z 264 (M+H)+. This material was filtered through Celite with acetonitrile (additional 25 mL) the mixture was warmed to 50° C the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with CH2Cl2 (3×10 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H, s), 8.58 (1H, s), 8.23 (1H, d), 7.77-7.88 (3H, m), 7.30-7.52 (5H, m), 7.26 (2H, s), 7.20 (1H, d), 7.08 (2H, d), 6.81 (1H, d), 5.14 (2H, s), 4.44 (2H, s), 3.34-3.60 (2H, m), 3.25-3.45 (2H,obscured by water); m/z (M+1+) 530. On completion of the reaction to give the crude product as a precipitate collected by filtration Treatment with triethylamine followed by purification by silica gel chromatography eluting with 3-10% MeOH/CHCl3

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Starting materials: methyl 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carboxylate and 2-aminoethanesulfonamide hydrochloride, but the reaction mixture was heated at 80° C. for 22 h. After the first 2 h, an additional 6 eqv. of trimethylaluminium was added to the reaction mixture. The mixture was cooled, diluted with a saturated sodium hydrogen carbonate solution (10 mL) and concentrated in vacuo. The residue was suspended in methanol/dichloromethane, (1:1), silica gel (˜2 g) was added and the mixture was re-concentrated in vacuo, resulting in a fine yellow powder that was purified on a silica gel column using dichloromethane/methanol/aqueous NH3, (first 100:10:1, then 70:10:1), as the eluent to afford the title compound as a base in 40% yield: 1H NMR (DMSO-d6, 300 MHz) δ 14.5 (br s, 1H), 11.29 (br s, 1H), 10.69 (s, 1H), 8.61 (br s, 1H), 8.22 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 6.96-6.90 (m, 3H), 4.25 (s, 2H), 3.98-3.64 (m, 14H), 3.36-3.22 (m, 4H), 3.12-3.04 (m, 2H); MS (ES) m/z 460 (M++1). The base was converted to the hydrochloride The mixture was cooled concentrated in vacuo was added the mixture was re-concentrated in vacuo resulting in a fine yellow powder that was purified on a silica gel column

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (2.15 mL, 17.1 mmol), triethylamine (2.2 mL, 15.6 mmol), 2-aminoethanesulfonamide-hydrochloric acid (2.5 g, 15.6 mmol), and 4 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (40 mL) was stirred at ambient temperature for 20 h. This material was filtered through Celite with acetonitrile (additional 25 mL) then potassium thiocyanate (2.0 g, 20.7 mmol) was added and the mixture was warmed to 50° C. Iodine (3.95 g, 15.6 mmol) was added and the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was stirred with 50 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.5 g, 1.9 mmol, 12.2% yield) which was carried on without further purification. MS (DCI/NH3) m/z 264 (M+H)+. This material was filtered through Celite with acetonitrile (additional 25 mL) the mixture was warmed to 50° C the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with CH2Cl2 (3×10 mL) The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H,s), 8.58 (1H,s), 8.23 (1H,d), 7.77-7.88 (3H,m), 7.30-7.52 (5H,m), 7.26 (2H,s), 7.20 (1H,d), 7.08 (2H,d), 6.81 (1H,d), 5.14 (2H,s), 4.44 (2H,s), 3.34-3.60 (2H, m), 3.25-3.45 (2H, obscured by water); m/z (M+1+) 530. On completion of the reaction to give the crude product as a precipitate collected by filtration Treatment with triethylamine followed by purification by silica gel chromatography eluting with 3-10% MeOH/CHCl3