2,3-Dihydro-1H-Pyrrolo[3,4-C]Pyridine dihydrochloride

(CAS-No. 6000-50-6, 214 mg, 1.11 mmol) was added to a suspension of raw 4-nitrophenyl {4-[6-oxo-5-(quinolin-5-yl)-1, 4, 5, 6- tetrahydropyridazin-3-yl]phenyl}carbamate (356 mg, 740 mumol) in dichloromethane (14 mL) and N, N-diisopropylethylamine (640 mul, 3.7 mmol). After stirring at r. t. for 2h the mixture was cooled to -20C and the precipitate was filtered off after standing for 12h and washed with cold dichloromethane. The precipitate was stirred in aqueous sodium hydroxide (20 mL, 1M), filtered, washed with water and dried under reduced pressure to give 175 mg (67% purity, 51% yield) of the title compound containing N-{4-[6-oxo-5-(quinolin-5-yl)-1, 6- dihydropyridazin-3-yl] phenyl}-1, 3-dihydro-2H-pyrrolo[3, 4-c]pyridine-2-carboxamide as minor impurity. (0693) LC-MS (Method 2): Rt = 0.78 min; MS (ESIpos): m/z = 463 [M+H]+ (0694) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 3.29 (dd, 1H), 3.42 (dd, 1H), 4.72 (dd, 1H), 4.81 (br d, 4H), 7.43 (d, 1H), 7.52 (d, 1H), 7.56 (dd, 1H), 7.60 - 7.65 (m, 2H), 7.68 - 7.76 (m, 3H), 7.97 (d, 1H), 8.50 (d, 1H), 8.58 - 8.64 (m, 3H), 8.92 (dd, 1H), 11.20 (s, 1H). (CAS-No. 6000-50-6, 45 mg, 232 mumol) was suspended in dichloromethane (1.0 mL) and N, N-diisopropylethylamine (130 mul, 770 mumol) and after stirring for 1 h added to a suspension of raw 4-nitrophenyl {4-[6-oxo-5- (quinolin-5-yl)-5-(trifluoromethyl)-1, 4, 5, 6-tetrahydropyridazin-3-yl]phenyl}carbamate (0860) (intermediate 14-5, 85.0 mg, 155 mumol) in dichloromethane (2.2 mL). After stirring at r. t. for 30 min the mixture was concentrated under reduced pressure and purified by preparative HPLC to give 30 mg (85% purity, 31% yield) of the title compound. (0861) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. Column: Chromatorex C18 10mum 125X30 mm. Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-6 min 15-55% B, 6-8 min 55-100% B, rate 150 mL/min, temperature 25C. (0862) LC-MS (Method 2): Rt = 0.94 min; MS (ESIpos): m/z = 531[M+H]+ (0863) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 3.60 (d, 1H), 4.47 (br d, 1H), 4.82 (br d, 4H), 7.44 (d, 1H), 7.59 (dd, 1H), 7.62 - 7.69 (m, 3H), 7.73 - 7.83 (m, 3H), 8.05 (d, 1H), 8.51 (d, 1H), 8.63 (d, 2H), 8.92 (dd, 1H), 9.11 (br d, 1H), 11.66 (s, 1H). (0864) Chiral LC: Instrument: Agilent HPLC 1260; column: Chiralpak IG 3mu 100x4, 6 mm; eluent A: Hexan + 0.1 vol-% diethylamin; eluent B: ethanol; gradient: 20-50% B in 7min; flow 1.4 mL/min; temperature: 25C; DAD 254 nm: Rt = 2.86 min (37.5%) + 3.12 min (38.1%), racemic mixture. (CAS-No. 6000-50-6, 22.1 mg, 115 mumol) was added to a suspension of raw 4-nitrophenyl{4-[(5R)-6-oxo-5-(quinolin-5-yl)-5- (trifluoromethyl)-1, 4, 5, 6-tetrahydropyridazin-3-yl]phenyl}carbamate (see Intermediate 12-7, 42.0 mg, 76.2 mumol) in dichloromethane (1.6 mL) and N, N-diisopropylethylamine (67 mul, 380 mumol). After stirring at r. t. for 3 h and storage at -20C for 16 h the mixture was concentrated under reduced pressure and purified by preparative HPLC to give 18.6 mg (90% purity, 41% yield of the title compound. (0822) HPLC: Instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 2000, Knauer UV detector Azura UVD 2.1S, Prepcon 5 software. column: Chromatorex C18 10mum 125x30 mm. Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-6 min 15-55% B, 6-8 min 55-100% B, rate 150 mL/min, temperature 25C. (0823) LC-MS (Method 2): Rt = 0.93 min; MS (ESIpos): m/z = 531 [M+H]+ (0824) 1H-NMR (400MHz, DMSO-d6) delta [ppm]: 3.60 (d, 1H), 4.47 (br d, 1H), 4.82 (br d, 4H), 7.44 (d, 1H), 7.59 (dd, 1H), 7.62 - 7.69 (m, 3H), 7.73 - 7.83 (m, 3H), 8.05 (d, 1H), 8.51 (d, 1H), 8.63 (d, 2H), 8.92 (dd, 1H), 9.11 (br d, 1H), 11.66 (s, 1H). (0825) Chiral LC: Instrument: Agilent HPLC 1260; column: Chiralpak IB 3mu 100x4, 6 mm; eluent A: water + 0.1 Vol-% phosphoric acid (85%), eluent B: acetonitril; gradient: 0-7 min 20-90% B ; flow 1.4 mL/min; temperature: 25C; DAD 325 nm: Rt = 2.63 min, ee = 99%. (CAS-No.6000-50-6, 92.2 mg, 478 mumol) was added to a suspension of raw 4-nitrophenyl {4-[5-(5-methyl-1, 3, 4-oxadiazol-2-yl)- 6-oxo-1, 4, 5, 6-tetrahydropyridazin-3-yl]phenyl}carbamate (see Intermediate 7-4, 323 mumol) in dichloromethane (6.6 mL) and N, N-diisopropylethylamine (280 mul, 1.6 mmol). After stirring at r. t. for 3 h the mixture was concentrated under reduced pressure and purified by preparative HPLC to give 52.0 mg (95% purity, 37% yield) of the title compound (0753) HPLC: Instrument: Labomatic HD-3000, pump head HDK-280, gradient module NDB-1000, fraction collector Labomatic Labocol Vario 4000, Knauer UV detector Azura UVD 2.15, Prepcon 5 software. Column: Chromatorex C1810mum 125X30 mm . Eluent A: water + 0.1% ammonia; Eluent B: acetonitrile; gradient: 0-6 min 10-50% B, 6-8 min 50-100% B, rate 150 mL/min, temperature 25C. (0754) LC-MS (Method 2): Rt = 0.67 min; MS (ESIpos): m/z = 418 [M+H]+. (0755) 1H-NMR (400MHz, DMSO-d6): delta [ppm]: 2.51 (s, 3H), 3.28 (dd, 1H), 3.47 (dd, 1H), 4.45 (dd, 1H), 4.82 (br d, 4H), 7.44 (d, 1H), 7.66 (d, 2H), 7.72 (d, 2H), 8.51 (d, 1H), 8.62 (s, 1H), 8.64 (s, 1H) 11.30 (s, 1H).To a solution of 6-(4-aminophenyl)-4-(quinolin-7-yl)pyridazin-3(2H)-one, (800 mg, 2.54 mmol), in tetrahydrofuran, 160 mL, was added 4-nitrophenyl carbonochloridate (615 mg, 3.05 mmol). The reaction mixture was heated at 60 C for 5 hours and concentrated under vacuum. The residue was dissolved in N, N-dimethylformamide, 20 mL and added to 2, 3- dihydro-1H-pyrrolo[3, 4-c]pyridine dihydrochloride (588 mg, 2.54 mmol) and N, N- diisopropylethylamine, (2.21 mL, 12.7 mmol) in dichloromethane (60 mL) and stirred at r.t. for 16 hours. The precipitate was collected by filtration, washed with water and dried to give the desired product, 850 mg (98% purity, 65% yield over two steps).PRODUCTS: (1029) LC-MS (Method 3): Rt = 0.32 min; MS (ESIpos): m/z = 461 [M+H]+ 1H-NMR (400 MHz, DMSO-D6) delta [ppm]: 4.79-4.81 (m, 4H), 7.41 (d, 1H), 7.54-7.57 (m, 1H), 7.68-7.71 (m, 2H), 7.91-7.93 (m, 2H), 8.03-8.05 (m, 1H), 8.15-8.17 (m, 1H), 8.31 (s, 1H), 8.38-8.40 (m, 1H), 8.46-8.48 (m, 1H), 8.58-8.60 (m, 2H), 8.74 (s, 1H), 8.93-8.94 (m, 1H).To a solution of 6-(4-aminophenyl)-4-{1-[(4-methylphenyl)sulfonyl]-1H-indol-5-yl}pyridazin- 3(2H)-one (200 mg, 0.438 mmol) in dichloromethane (16.2 mL) and N, N-dimethylformamide (4.00 mL) was added pyridine (71.0 muL, 0.876 mmol) followed by portion wise addition of 4- nitrophenyl carbonochloridate (106 mg, 0.526 mmol) over 1 minute, and the reaction mixture stirred at r.t. for1 hour. To this reaction mixture was added N, N-diisopropylethylamine (381 muL, 2.19 mmol) followed by To a solution of 6-(4-aminophenyl)-4-{1-[oxan-2-yl]-1H-indazol-4-yl}pyridazin-3(2H)-one (360 mg, 0.929 mmol) in dichloromethane (34.3 mL) under argon was added pyridine (150 muL, 1.86 mmol), followed by portion wise addition of 4-nitrophenyl carbonochloridate (225 mg 1.12 mmol) over 1 minute, and the reaction mixture stirred at r.t. for 5 hours. To this crude reaction mixture was added N, N-diisopropylethylamine (809 muL, 4.65 mmol), followed by 2, 3- dihydro-1H-pyrrolo[3, 4-c]pyridine dihydrochloride (359 mg, 1.86 mmol) under argon and the reaction mixture stirred at r.t. for 5 hours. The reaction mixture was combined with another batch starting from 4-nitrophenyl (4-{6-oxo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]- 1, 6-dihydropyridazin-3-yl}phenyl)carbamate (0.852 mmol), and concentrated to give a residue. The crude residue was triturated with water-ethanol and the precipitate collected by filtration, washed with ethyl acetate, diethyl ether and dried to give the desired product, 580 mg (61% combined yield over two steps, 88% purity). (0950) LC-MS (Method 3): Rt = 0.46 min; MS (ESIneg): m/z = 532 [M-H]- 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.57 (s, 2H), 1.75 (s, 1H), 1.94-2.01 (m, 2H), 2.40- 2.42 (m, 1H), 3.70-3.77 (m, 1H), 3.85-3.88 (m, 1H), 4.80 (d, 4H), 5.87-5.89 (m, 1H), 7.41- 7.42 (m, 1H), 7.47-7.52 (m, 2H), 7.66- 7.74 (m, 2H), 7.80- 7.83 (m, 3H), 8.08- 8.10 (m, 2H), 8.48 (d, 1H), 8.59-8.62 (m, 2H).A solution of 100mg of Intermediate 22 (0.41 minol, 1.00 eq) in DMF (12 mL)was treated with125 mg of N, N?-disuccinimidyl carbonate (0.49 minol, 1.20 eq) and 59.7 mg of 4-dimethylaminopyrdine (0.49 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 94.4 mg of 2, 3-dihydro-I H-pyrrolo[3, 4-c]pyridine dihydrochloride (0.49minol, 1 .20 eq) and 1.70 mL of triethylamine (12.37 minol, 30 eq) in DMF (2 mL) was added.The mixture was stirred over night. THE was removed from under reduced pressure. The remaining solution was poured into water. The solid was removed by filtration, the filtrate was taken to dryness and the residue was purified by preparative reverse phase HPLC to yield 40.3 mg of the desired product (25percent).H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.04 (d, 3H), 1.15 (d, 3H), 1.24 (d, 3H), 2.29 (dd, IH), 2.68 (dd, IH), 3.21 - 3.42 (m, IH), 4.83 (d, 4H), 4.90 (quin, IH), 7.44 (d, IH), 7.60 - 7.72 (m, 2H), 7.72 - 7.83 (m, 2H), 8.50 (d, I H), 8.62 (d, 2H).UPLC-MS (Method 1): RO.78 min; MS (ESIpos): mz [M÷2H] 393.To a solution of Intermediate 47 (400 mg, 1.73 minol, 1.00 eq) in THE (10 mL) was added 4- nitrophenyl chloroformiate (418 mg, 2.08 minol, 1.20 eq) and the mixture was stirred over night at 60 00. The solution was taken to dryness, the residue was resolved in DCM (12 mL) andtreated with DIPEA (0.90 mL, 5.19 minol, 3.00 eq) and 2, 3-dihydro-IH-pyrrolo[3, 4-C]pyridine dihydrochloride (401 mg, 2.08 minol, 1.20 eq). The resulting mixture was stirred over night at room temperature. The mixture was extracted three times with I M aqueous sodium hydroxide solution, the organic layer was washed with water and dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was triturated with MeOHdiethyl ether toyield the desired product (630 mg, 97percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07- 1.09 (m, 6H), 2.85 (s, 2H), 3.31 (s, 3H), 4.82 (d, 4H), 7.44 (d, I H), 7.63 - 7.75 (m, 4H), 8.50 (d, I H), 8.63 (d, 2H).UPLC-MS (Method 2): Rt= 0.69 min; MS (ESIpos): mz [M÷H] 378.A solution of 406 mg of Intermediate 7 (2.00 minol, 1.00 eq) in THE (30 mL) was treated with615 mg of N, N?-disuccinimidyl carbonate (2.40 minol, 1.20 eq) and 293 mg of 4-dimethylaminopyridine (2.40 minol, 1 .20 eq). The mixture was stirred for three days at roomtemperature. A suspension of 463 mg of 2, 3-dihydro-IH-pyrrolo[3, 4-c]pyridine dihydrochloride(2.40 minol, 1.20 eq) and 1.00 mL of triethylamine (7.2Ominol, 3.60 eq) in DMF (2 mL) was added and the resulting suspension as again stirred over night. The mixture was poured into water, the precipitate was collected by filtration and was washed with water to provide after trituration with ethanol 440 mg of the desired product (63percent).1H-NMR (400MHz, DMSO-d6): oe [ppm] = 1.07 (d, 3H), 2.17-2.26 (m, IH), 2.62-2.71 (m, IH), 3.35-3.42 (m, IH), 4.82 (d, 4H), 7.41 -7.46 (m, IH), 7.61 -7.74 (m, 4H), 8.50 (d, IH), 8.61 (d, 2H), 10.85 (s, IH).LC-MS (Method 1): R = 0.57 min; MS (ESIpos): mz = 350 [M÷H].