5-chloro-2,8,9-triazabicyclo[4.3.0]nona-1,3,5,7-tetraene

Step B: Step E: Preparation of 4-chloro-lH-pyrazolo[3, 4-b]pyridine: 4-Chloro-l-(4- methoxybenzyl)-lH-pyrazolo[3, 4-b]pyridine (1.51 g, 5.50 mmol) was dissolved in neat TFA (8.48 mL, 110 mmol), and the reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was then concentrated to an oil, and MeOH was added to give a thick precipitate that was filtered and washed with MeOH. The filtrate, which contained the desired product, was concentrated to an oil that was dried in vacuo overnight to yield a waxy solid. The crude solid was partitioned between EtOAc and saturated NaHCOA solution of 4-chloro- l-(4-methoxybenzyl)- lH-pyrazolo[3, 4-b]pyridine (4) (8.2 g, 32 mmol) in TFA (50 mL) was heated to 75°C for 2 hrs. The reaction mixture was concentrated to give the crude product which was partitioned between DCM (200 mL) and sat. NaHC0In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 20 mL of trifluoroacetic acid and 4.923 g (0.0178 mol) of BCD-BTK-124-6. Boil the resulting mixture for 2 hours; use the TLC method to ensure the completeness of the reaction. After that, distill off most of the trifluoroacetic acid using a rotary evaporator; neutralize the residue to pH 7 with a solution of sodium bicarbonate. Extract the aqueous solution with 20 mL of ethyl acetate three times; wash the combined extract with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : ethyl acetate (from 9:1 to 8:2). Yield: 0.63 g (55percent).1H-Pyrazolo[3, 4-b]pyridine 7N-oxide m-chlorobenzoate (1.25 g, 7.18 mmol) was dissolved in DMF (5.0 mL), and methanesulfonyl chloride (d = 1.477, 0.82 mL, 10.6 mmol) was dropwise added thereto under an argon atmosphere. The resulting mixture was stirred at 70°C for 60 minutes. After termination of the reaction by adding water (2 mL) thereto, the mixture was neutralized with a 1 N sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (100 mL) twice, and the organic layer was dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel (Fuji Silysia, BW300, 70g, n-hexane : ethyl acetate = 1:1) to give 4-chloro-1H-pyrazolo[3, 4-b]pyridine (379 mg, yield: 23percent). A mixture of N-(3-(lH-l, 2, 3-triazol-l-yl)phenyl)-N-methyl-4-(5-(4, 4, 5, 5- tetramethyl-l , 3, 2-dioxaborolan-2-yl)pyridin-3-yl)benzamide (crude), 4-chloro-lH- pyrazolo[3, 4-b]pyridine (70 mg, 0.50 mmol), Pd(dppf)Cl2 (34 mg, 0.046 mmol) and Na2C03 (146 mg, 1.38 mmol) in dioxane (4 mL) and water (1 mL) was degassed and purged with N2 for 3 times. And the resulting reaction mixture was stirred at 100 C for 16 hours under N2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 33% (Rt = 0.690 min; MS Calcd: 472.2; MS Found: 495.2 [M+Na]+). The reaction mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc/THF (30 mL x3, 1/1). The combined organic layer was washed with water (20 mL x2), brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi Flash (0% to 10% MeOH in DCM), and further purified by prep-HPLC (0.225% FA as an additive) to give N-(3-(lH-l, 2, 3-triazol-l-yl)phenyl)-4-(5-(lH- pyrazolo[3, 4-b]pyridin-4-yl)pyridin-3-yl)-N-methylbenzamide (20.1 mg, yield: 9% for two steps) as an off-white solid. NMR (400 MHz, DMSO-rie) d 3.49 (3H, s), 7.30 (1H, d , J= 8.0 Hz), 1 AT -1.56 (4H, m), 7.78 (1H, d , J= 8.0 Hz), 7.85 (2H, d, J= 8.0 Hz), 7.97-8.00 (2H, m), 8.42 (1H, s), 8.45 (1H, t , J= 2.0 Hz), 8.63 (1H, d, J= 4.8 Hz), 8.81 (1H, s), 9.02 (1H, s), 9.06 (1H, s), 13.89 (1H, brs).A mixture of tert-butyl (4-(5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin- 3-yl)phenyl)carbamate (crude), 4-chloro-lH-pyrazolo[3, 4-b]pyridine (88 mg, 0.570 mmol), Pd(dppf)Cl2 (42 mg, 0.057 mmol) and Na2C03 (181 mg, 1.71 mmol) in dioxane (4 mL) and water (1 mL) was degassed and purged with N2 for 3 times. And the resulting reaction mixture was stirred at 100 C for 16 hours under N2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 47% (Rt = 0.832 min; MS Calcd: 387.2; MS Found: 388.0 [M+H]+). The reaction mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc (30 mL x3). The combined organic layer was washed with water (20 mL), brine (40 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi Flash (20% to 100% EtOAc in PE) to give tert-butyl (4-(5-(lH-pyrazolo[3, 4-b]pyridin-4-yl)pyridin-3-yl)phenyl)carbamate (200 mg, yield: 91% for two steps) as ayellow solid.A mixture of 2-(7-azabicyclo[2.2. l]heptan-7-yl)-2-oxo-N-(4-(5-(4, 4, 5, 5- tetramethyl-l , 3, 2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)acetamide (crude), 4-chloro-lH- pyrazolo[3, 4-b]pyridine (19 mg, 0.12 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol) and Na2CCh (39 mg, 0.369 mmol) in dioxane (3 mL) and water (1 mL) was degassed and purged with N2 for 3 times. And the resulting reaction mixture was stirred at 100 C for 16 hours under N2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 27% (Rt = 0.826 min; MS Calcd: 438.2; MS Found: 439.2 [M+H]+). The reaction mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc/THF (30 mL x3, 1/1). The combined organic layer was washed with water (20 mL x2), brine (30 mL), dried over anhydrous Na2SCh. filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.225% FA as an additive) to give N-(4-(5-(lH-pyrazolo[3, 4- b]pyridin-4-yl)pyridin-3-yl)phenyl)-2-(7-azabicyclo[2.2. l]heptan-7-yl)-2-oxoacetamide (9.1 mg, yield: 16% for two steps) as an off-white solid. NMR (400 MHz, DMSO-rie) d 1.49-1.61 (4H, m), 1.65-1.74 (2H, m), 1.78-1.86 (2H, m), 4.60 (1H, t, J= 4.8 Hz), 4.89 (1H, t, J= 4.8 Hz), 7.59 (1H, d, J= 4.8 Hz), 7.90-7.94 (4H, m), 8.45 (1H, s), 8.50 (1H, t, J= 2.0 Hz), 8.66 (1H, d, J= 4.8 Hz), 9.04-9.09 (2H, m), 10.82 (1H, brs), 13.90 (1H, brs).A mixture of 2-(2-azabicyclo[2.2. l]heptan-2-yl)-2-oxo-N-(4-(5-(4, 4, 5, 5- tetramethyl-l , 3, 2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)acetamide (crude), 4-chloro-lH- pyrazolo[3, 4-b]pyridine (23 mg, 0.15 mmol), Pd(dppf)Cl2 (11 mg, 0.015 mmol) and Na2C03 (48 mg, 0.45 mmol) in dioxane (3 mL) and water (0.8 mL) was degassed and purged with N2 for 3 times. And the resulting reaction mixture was stirred at 100 C for 16 hours under N2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 17% (Rt = 0.834 min; MS Calcd: 438.2; MS Found: 339.0 [M+H]+). The reaction mixture was diluted with water (20 mL). The aqueous layer was extracted with EtOAc/THF (30 mL x3, 1/1). The combined organic layer was washed with water (20 mL x2), brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by Combi Flash (0% to 10% MeOH in DCM) and further purified by prep-HPLC (0.225% FA as an additive), and then lyophilizated to give N-(4-(5-(lH-pyrazolo[3, 4- b]pyridin-4-yl)pyridin-3-yl)phenyl)-2-(2-azabicyclo[2.2. l]heptan-2-yl)-2-oxoacetamide (5.1 mg, yield: 8% for two steps) as an off-white solid. NMR (400 MHz, DMSO-rie) d 1.37-1.51 (2H, m), 1.58-1.76 (4H, m), 2.61 (1H, s), 3.09 (0.5H, d, J= 11.6 Hz), 3.42-3.46 (0.5H, m), 3.51 (0.5H, d, J= 11.2 Hz), 3.69 (0.5H, d , J = 8.0 Hz), 4.55 (0.5H, s), 4.72 (0.5H, s), 7.58 (1H, d, J= 4.4 Hz), 7.86-7.96 (4H, m), 8.44 (1H, s), 8.48 (1H, s), 8.66 (1H, d, .7= 4.8 Hz), 8.98-9.11 (2H, m), 10.74-10.82 (1H, m), 13.89 (1H, brs).The compound

Molecular Weight:153.57
XLogP3:1.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:153.0093748
Monoisotopic Mass:153.0093748
Topological Polar Surface Area:41.6
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes