3-piperidin-4-yl-1,4-dihydroquinazolin-2-one;hydrochloride

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

Procedure: A solution of N-t-butyloxycarbonyl-(3R)-3-amino-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (40.0 mg, 0.114 nmol) in dimethylformamide (1.5 mL) was stirred with sodium hydride (6.83 mg, 0.17 mmol, 60% dispersion in oil) for 15 min, then N-(4-bromobutyl)-phthalimide (32.1 mg, 0.114 mmol) was added. The reaction was stirred overnight and worked up with methylene chloride and water. The crude product was dissolved in methylene chloride (4.5 mL) containing trifluoroacetic acid (1.5 mL) and stirred for 1 h. The solvents were removed in vacuo, and the crude product dissolved in tetrahydrofuran (1 mL) along with p-nitrochloroformate (14.5 mg, 0.072 mmol) and triethylamine (0.20 mL, 0.14 mmol). After stirring for 2 h, 3-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (19.3 mg, 0.072 mmol) and triethylamine (0.020 mL, 0.14 nmol) was added and the reaction stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), to yield the title compound (19 mg). MS 710.3123 (M+1) stirred for 1 h The solvents were removed in vacuo After stirring for 2 h the reaction stirred overnight The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Hydroxy-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (40 mg, 0.12 mmol) and p-nitrophenylchloroformate (24.1 mg, 0.12 mmol) were dissolved in tetrahydrofuran (1 mL) under argon, and cooled to 0° C. Triethylamine (15 uL, 0.11 mmol) was added and the reaction stirred for 1.5 h. Additional triethylamine was added (33 uL, 0.24 mmol) along with 3-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (32 mg, 0.12 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and the residue triturated with methanol. The triturated solid was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), to yield the title compound (29 mg). MS 592.2181 (M+1) The reaction was warmed to room temperature stirred overnight The reaction was concentrated the residue triturated with methanol The triturated solid was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Hydroxy-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (40 mg, 0.12 mmol) and p-nitrophenylchloroformate (24.1 mg, 0.12 mmol) were dissolved in tetrahydrofuran (1 mL) under argon, and cooled to 0° C. Triethylamine (15 uL, 0.11 mmol) was added and the reaction stirred for 1.5 h. Additional triethylamine was added (33 uL, 0.24 mmol) along with 3-(4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (32 mg, 0.12 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and the residue triturated with methanol. The triturated solid was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), to yield the title compound (29 mg). MS 592.2181 (M+1) The reaction was warmed to room temperature stirred overnight The reaction was concentrated the residue triturated with methanol The triturated solid was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3R)-3-amino-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine oxalic acid salt (27.6 mg, 0.0747 mmol) and p-nitrophenylchloroformate (15.1 mg, 0.0747 mmol) was dissolved in tetrahydrofuran (0.5 mL), and cooled to 0° C. under argon. Triethylamine (10.4 uL, 0.0747 mmol) was added and the reaction stirred for 1 h. Additional triethylamine (26.0 uL, 0.186 mmol) was added, along with 3-(4-piperidinyl)-3,4 dihydroquinazolin-2(1H)-one hydrochloride (20.0 mg, 0.0747 mmol) in dimethylsulfoxide (0.5 mL). The reaction was allowed to warm to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), isolating 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (10.0 mg) MS 537 (M+1) and 4-(2-oxo-1,4-dihydro-4-hydroxyquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (5 mg) MS 535 (M−17). to warm to room temperature stirred overnight The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (3R)-3-amino-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine oxalic acid salt (27.6 mg, 0.0747 mmol) and p-nitrophenylchloroformate (15.1 mg, 0.0747 mmol) was dissolved in tetrahydrofuran (0.5 mL), and cooled to 0° C. under argon. Triethylamine (10.4 uL, 0.0747 mmol) was added and the reaction stirred for 1 h. Additional triethylamine (26.0 uL, 0.186 mmol) was added, along with 3-(4-piperidinyl)-3,4 dihydroquinazolin-2(1H)-one hydrochloride (20.0 mg, 0.0747 mmol) in dimethylsulfoxide (0.5 mL). The reaction was allowed to warm to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), isolating 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (10.0 mg) MS 537 (M+1) and 4-(2-oxo-1,4-dihydro-4-hydroxyquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (5 mg) MS 535 (M−17). to warm to room temperature stirred overnight The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)

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

Procedure: (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (58 mg, 0.15 mmol) was dissolved in a mixture containing methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added to the mixture. Reaction stirred at room temperature for 15 hours. Reaction was quenched with 1N hydrochloric acid (0.5 mL). Mixture was concentrated in vacuo. Residue was dissolved in DMF (2 mL). N,N-Diisopropylethylamine was added to the mixture followed by o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium Tetrafluoroborate (60 mg, 0.19 mmol). Mixture stirred at room temperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (50 mg, 0.19 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Reaction mixture was purified by preparatory HPLC. Desired fractions were identified. Acetonitrile was removed from the fractions in vacuo. Remaining aqueous was made basic with sodium bicarbonate. Mixture was extracted twice with ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 28% yield. MS m/e (M+H)+=587.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.75 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 6.84 (m, 2H), 6.77 (d, J=7.93, 1H), 5.23 (d, J=15.16, 1H), 4.76 (m, 1H), 4.69 (dd, J1=15.26, J2=5.19, 1H), 4.53 (d, J=13.43, 1H), 4.47 (d, J=15.26, 1H), 4.40 (m, 1H), 4.29 (d, J=3.97, 2H), 4.08 (m, 1H), 3.89 (d, J=9.77, 1H), 3.15 (m, 2H), 3.00 (m, 1H), 2.91 (m, 3H), 2.60 (m, 1H) 2.44 (m, 2), 1.80 (m, 1H), 1.60 (m, 3H). Reaction Reaction was quenched with 1N hydrochloric acid (0.5 mL) Mixture was concentrated in vacuo Residue was dissolved in DMF (2 mL) N,N-Diisopropylethylamine was added to the mixture Mixture stirred at room temperature for 30 minutes Reaction stirred at room temperature for 3 hours Reaction mixture was purified by preparatory HPLC Acetonitrile was removed from the fractions in vacuo Mixture was extracted twice with ethyl acetate Combined extracts were dried (magnesium sulfate) filtered concentrated in vacuo

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

Procedure: (S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (90 mg, 0.23 mmol) and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (75 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield. MS m/e (M+H)+=598.2. 1H NMR (500 MHz, DMSO-D6): δ=13.47 (s, 1H), 9.19 (s, 1H), 8.31 (s, 2H), 8.23 (s, 1H), 7.22 (s, 1H), 7.12 (s, 3H), 6.99 (m, 1H), 6.84 (m, 2H), 6.77 (s, 1H), 5.40 (d, J=15.26, 1H), 4.65 (m, 3H), 4.54 (d, J=10.38, 1H), 4.40 (m, 1H), 4.30 (s, 1H), 4.22 (s, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 3.14 (m, 2H), 3.03 (m, 1H), 2.93 (m, 1H), 2.60 (m, 1H), 1.78 (m, 1H), 1.58 (m, 3H).

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

Procedure: To a solution of (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester (50 mg, 0.132 mmol) in methanol and chloroform (0.5 mL) was added 10% palladium on carbon (20 mg) under nitrogen atmosphere. The reaction mixture was brought to hydrogen atmosphere (1 atm) and stirred for 3 h. The catalyst was filtered and the solvent was evaporated to give 7-amino-4,9-dimethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one, hydrochloride in almost quantitative yield. To the amine salt in dichloromethane was added disuccinimidyl carbonate (37 mg, 0.145 mmol) and triethylamine (0.11 mL, 0.8 mmol) at room temperature. After 120 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, hydrochloride (39 mg, 0.145 mmol) was added and stirring continued for 12 h. The solvent was evaporated and the crude product was purified by Prep HPLC to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide in 59% overall yield. MS (ESI) 502 (M+H); Rf=1.31. continued for 12 h The solvent was evaporated the crude product was purified by Prep HPLC

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

Procedure: (S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (58 mg, 0.15 mmol) was dissolved in a mixture containing methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added to the mixture. Reaction stirred at room temperature for 15 hours. Reaction was quenched with 1N hydrochloric acid (0.5 mL). Mixture was concentrated in vacuo. Residue was dissolved in DMF (2 mL). N,N-Diisopropylethylamine was added to the mixture followed by o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium Tetrafluoroborate (60 mg, 0.19 mmol). Mixture stirred at room temperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (50 mg, 0.19 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Reaction mixture was purified by preparatory HPLC. Desired fractions were identified. Acetonitrile was removed from the fractions in vacuo. Remaining aqueous was made basic with sodium bicarbonate. Mixture was extracted twice with ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 28% yield. MS m/e (M+H)+=587.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.75 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 6.84 (m, 2H), 6.77 (d, J=7.93, 1H), 5.23 (d, J=15.16, 1H), 4.76 (m, 1H), 4.69 (dd, J1=15.26, J2=5.19, 1H), 4.53 (d, J=13.43, 1H), 4.47 (d, J=15.26, 1H), 4.40 (m, 1H), 4.29 (d, J=3.97, 2H), 4.08 (m, 1H), 3.89 (d, J=9.77, 1H), 3.15 (m, 2H), 3.00 (m, 1H), 2.91 (m, 3H), 2.60 (m, 1H) 2.44 (m, 2H), 1.80 (m, 1H), 1.60 (m, 3H). Reaction Reaction was quenched with 1N hydrochloric acid (0.5 mL) Mixture was concentrated in vacuo Residue was dissolved in DMF (2 mL) N,N-Diisopropylethylamine was added to the mixture Mixture stirred at room temperature for 30 minutes Reaction stirred at room temperature for 3 hours Reaction mixture was purified by preparatory HPLC Acetonitrile was removed from the fractions in vacuo Mixture was extracted twice with ethyl acetate Combined extracts were dried (magnesium sulfate) filtered concentrated in vacuo

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

Procedure: (S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (90 mg, 0.23 mmol) and 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (75 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield.

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

Procedure: To a solution of (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester (50 mg, 0.132 mmol) in methanol and chloroform (0.5 mL) was added 10% palladium on carbon (20 mg) under nitrogen atmosphere. The reaction mixture was brought to hydrogen atmosphere (1 atm) and stirred for 3 h. The catalyst was filtered and the solvent was evaporated to give 7-amino-4,9-dimethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one, hydrochloride in almost quantitative yield. To the amine salt in dichloromethane was added disuccinimidyl carbonate (37 mg, 0.145 mmol) and triethylamine (0.11 mL, 0.8 mmol) at room temperature. After 120 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, hydrochloride (39 mg, 0.145 mmol) was added and stirring continued for 12 h. The solvent was evaporated and the crude product was purified by Prep HPLC to give 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid (4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide in 59% overall yield. MS (ESI) 502 (M+H); Rf=1.31. continued for 12 h The solvent was evaporated the crude product was purified by Prep HPLC

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

Procedure: In this example, 4.00 g 4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine mono-hydrochloride, 3.44 g of α-bromo-p-methoxyacetophenone, 4.2 ml of triethylamine and 60 ml of methanol are mixed and stirred at room temperature overnight. Then, the white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 4.71 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 3.79 g of the desired product. Then, the white crystals deposited are separated by filtration successively washed with methanol and water dried to obtain 4.71 g of a crude product The crude product is recrystallized from a mixed solvent of chloroform and ethanol