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CAS No. : | 147740-02-1 | MDL No. : | MFCD09607967 |
Formula : | C7H10Cl2N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FZBCVKVGLQRBHY-UHFFFAOYSA-N |
M.W : | 193.07 | Pubchem ID : | 23503616 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 52.7 |
TPSA : | 24.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.46 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.6 |
Log Po/w (MLOGP) : | 0.87 |
Log Po/w (SILICOS-IT) : | 1.79 |
Consensus Log Po/w : | 1.14 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.34 |
Solubility : | 0.879 mg/ml ; 0.00455 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.56 |
Solubility : | 5.34 mg/ml ; 0.0276 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.58 |
Solubility : | 0.51 mg/ml ; 0.00264 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 5.1 6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine Step 1 6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine To 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (as described by Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222 mmols) in DMF (1.2 L) was added 2,4-difluoronitrobenzene (25 mL, 224 mmols). The mixture was heated to 60° C and DIPEA (195 mL, 1.12 mols) was added dropwise from an addition funnel over 2 hrs. After heating overnight the reaction mixture was cooled to rt, poured into water (3 L), filtered and dried in a vacuum oven (50° C.) to provide a yellow-green solid (53.8 g, 94% yield). MS (M+1)=260 m/z. |
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 5.1 6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine Step 1 6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine To 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (as described by Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222 mmols) in DMF (1.2 L) was added 2,4-difluoronitrobenzene (25 mL, 224 mmols). The mixture was heated to 60° C. and DIPEA (195 mL, 1.12 mols) was added dropwise from an addition funnel over 2 hrs. After heating overnight the reaction mixture was cooled to rt, poured into water (3 L), filtered and dried in a vacuum oven (50° C.) to provide a yellow-green solid (53.8 g, 94% yield). MS (M+1)=260 m/z. |
94% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | 5.1 Step 1 Step 1 6,7-Dihydro-6-(2-fluoro-4-nitrophenyl)-5H-pyrrolo[3,4-b]pyridine: To 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride salt (as described by Petersen, et al. (Bayer) EP0520277A2)(42.8 g, 222 mmols) in DMF (1.2 L) was added 2,4-difluoronitrobenzene (25 mL, 224 mmols). The mixture was heated to 60° C. and DIPEA (195 mL, 1.12 mols) was added dropwise from an addition funnel over 2 hrs. After heating overnight the reaction mixture was cooled to rt, poured into water (3 L), filtered and dried in a vacuum oven (50° C.) to provide a yellow-green solid (53.8 g, 94% yield). MS (M+1)=260 m/z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hydrogenchloride; acetone | Z.1.d d) d) 5,7-Dihydro-6H-pyrrolo[3,4-b]pyridine dihydrochloride 8.5 g (44 mmol) of ethyl 5,7-dihydro-1H-pyrrolo-[3,4-b]pyridine-6-carboxylate are refluxed overnight in 90 ml of concentrated hydrochloric acid. The solution is concentrated, the residue is stirred with acetone, and the salt is filtered off with suction and dried in the air. Yield: 7.5 g (88% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; Inert atmosphere; | 92.5 Triethylamine (0.084 ml_, 0.6 mmol) was added to a mixture of 3-(pyridin-2-ylethynyl)-4- (trifluoromethyl)benzoic acid (containing 2 eq. of sodium chloride, 61.2 mg, 0.15 mmol) from step 4, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (36 mg, 0.18 mmol), 1-hydroxy-7- azabenzotriazole (24 mg, 0.18 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (di-HCI salt, 33 mg, 0.17 mmol) in dichloromethane (2.1 ml.) with stirring at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with small amount of water. Solvents were removed and the residue was purified by reverse phase Gilson HPLC (mobile phase: 20-100% acetonitrile (with 0.075% TFA) in water (with 0.075% TFA) to afford the title compound as TFA salt (75 mg, 0.14 mmol; 93% yield). MS (+ESI): m/z 394.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride; 4-(difluoromethoxy)-3-(pyridin-2-ylethynyl)benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: With hydrogenchloride In methanol; water at 20℃; for 0.333333h; | 122.4 Triethylamine (2.3 ml_, 16.7 mmol) was added to a mixture of 4-(difluoromethoxy)-3-(pyridin- 2-ylethynyl)benzoic acid containing two equivalents of sodium chloride (1.7 g, 4.2 mmol) from step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.1 g, 5.5 mmol), 1-hydroxy-7- azabenzotriazole (0.74 g, 5.5 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (di-HCI salt, 0.97g, 5.0 mmol) in dichloromethane (64 ml.) with stirring at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with small amount of water. The solvents were removed and the residue was purified by flash chromatography on SiO2 (gradient elution using dichloromethane/methanol 95/5) to afford a semi-solid, which was dissolved in methanol (50 ml_). Aqueous HCI (2.0 N, 5.0 ml.) was added to this methanol solution. The mixture was then stirred at room temperature for 20 min. Evaporation yielded a semi-solid, which was dried in vacuo at 50 0C for 6 hours to afford the title compound as a light green solid (1.76 g, 91 % yield). MS (+ESI): m/z 392.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine With triethylsilane; trifluoroacetic acid at 60℃; for 5h; Inert atmosphere; Stage #2: With hydrogenchloride In 1,4-dioxane; ethyl acetate at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 4.3 Step 3 : 2-(5-amino-7-methoxy[1.2.4]triazolo[L5-c]quinazolin-2-ylVl -(5,7-dihydro-6/ - pyrrolo [3.4-&]pyridin-6-yI)ethanone Step 3 : 2-(5-amino-7-methoxy[1.2.4]triazolo[L5-c]quinazolin-2-ylVl -(5,7-dihydro-6/ - pyrrolo [3.4-&]pyridin-6-yI)ethanone [0139] A mixture of (5-amino-7-methoxy[l,2,4]triazolo[l,5-c]quinazolin-2-yl)acetic acid (0.050 g, 0.161 mmol), 6,7-dihydro-5H-pyrrolo[3,4-%yridine dihydrochloride (0.047g, 0.24 mmol), DIPEA (0.141 ml, 0.807 mmol), and 1 -propanephosphonic acid cyclic anhydride (0.144 mL, 0.242 mmol) in DCM (5 mL) was stirred at room temperature overnight and then diluted with water and DCM. The organic layer was filtered and concentrated. The residue was purified by preparative reverse phase HPLC (eluting with 10-95 % Acetonitrile Water + 0.1% TFA (20 mL/min) over 10 min.) to give compound, Ex-77 (a light yellow solid), which was characterized by LCMS (M+H) = 376. | |
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 4.C 2-(5-arnino-7-methoxy[l ,2,4]triazolo[1 ,5-c]guinazolin-2-yl)- 1 -(5 ,7-dihydro-6H- pyrrolo[3 ,4-blpyridin-6-yl)ethanone A mixture of (5 -arnino-7-rnethoxy[ 1 ,2,4]triazolo[ 1,5 -cjquinazolin-2-yl)acetic acid (0.050 g, 0.161 mmol), 6,7-dihydro-5H-pyrrolo [3 ,4-b]pyridine dihydrochloride (0 .047g, 0.24 rnrnol), DIPEA (0.141 ml, 0.807 rnrnol), and 1-propanephosphonic acid cyclic anhydride (0.144 rnL, 0.242 mmol) in DCM (5 mL) was stirred at room temperature overnight and then diluted with water and DCM. The organic layer was filtered and concentrated. The residue was purified by preparative reverse phase HPLC (eluting with 10-95 % Acetonitrile/Water + 0.1% TFA (20 mLlrnin) over 10 mm.) to give compound, Ex-77 (a light yellow solid), which was characterized by LCMS (M+H) = 376. | |
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 4.C Step C: 2-(5-amino-7-methoxy[l ,2.41triazolo[l ,5-c1quinazolin-2-yn-l-(5,7- dihydro-6H-pyrrolo[3,4-i?lpyridin-6-yl)ethanone A mixture of (5-amino-7-methoxy[l,2,4]triazolo[ l ,5-c]quinazolin-2-yl)acetic acid (0.050 g, 0.161 mmol), 6,7-dihydro-5H-pyrrolo[3,4-pyridine dihydrochloride (0.047g, 0.24 mmol), DIPEA (0.141 ml, 0.807 mmol), and 1-propanephosphonic acid cyclic anhydride (0.144 mL, 0.242 mmol) in DCM (5 mL) was stirred at room temperature overnight and then diluted with water and DCM. The organic layer was filtered and concentrated. The residue was purified by preparative reverse phase HPLC (eluting with 10-95 % Acetonitrile/Water + 0.1% TFA (20 mL/min) over 10 min.) to give compound, Ex-77 (a light yellow solid), which was characterized by LCMS (M+H) = 376. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In butan-1-ol at 110℃; for 0.5h; Microwave irradiation; | 2.2 Step 2: tert-butyl (R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate A reaction pressure vessel was charged with a mixture of tert-butyl (R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4-chloro- 6-(4- chloro- 1 -methyl- 1 H-pyrazol-5 -yl)-5 -methylpyrimidin-2-yl)phenoxy)propyl (methyl)carbamate (90 mg, 0.13 mmol); 6,7-dihydro -5H-pyrrolo[3,4-b]pyridine dihydrochloride (or any other suitably substituted primary or secondary amine, 0.15 mmol), triethylamine (30 mg, 0.3 mmol) and n-BuOH (2 mL). The vessel was capped, placed in a microwave reactor and irradiated for 30 min. at external temperature of 110 °C. After being cooled down to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered and concentrated to give tert-butyl (R)-2-(tert- butyldimethylsilyloxy)-3-(4-chloro-3- (4-(4-chloro-l -methyl- 1 H-pyrazol-5 -yl)-5-methyl-6- (5H-pyrrolo[3,4-b]pyridin-6(7H) -yl)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate as a yellow solid (120 mg, crude), which was used directly into next step without further purification. ESI-LCMS (m/z): 754.0 found for [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine In dimethyl sulfoxide at 110℃; for 0.5h; Microwave irradiation; | 3.3 Step 3: tert-butyl (2R)-3-(3-(4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrimidin-2-yl)-4-chlorophenoxy)-2-(tert-butyldimethylsilyloxy)propyl(methyl)carbamate A reaction pressure vessel was charged with a mixture of tert-butyl (2R)-3-(3-(4-(4-bromo-l-methyl-lH-pyrazol-5-yl)-6- chloro-5- methylpyrimidin-2-yl)-4-chlorophenoxy)-2-(tert-butyl dimethylsilyloxy)- propyl(methyl)carbamate (120 mg, 0.17 mmol); 6,7-dihydro -5H-pyrrolo[3,4-b]pyridine dihydrochloride (or any other suitably substituted primary or secondary amine, 0.34 mmol), triethylamine (0.5 mL, 3.5 mmol) and DMSO (3 mL). The vessel was capped, placed in a microwave reactor and irradiated for 30 min. at external temperature of 110 °C. After being cooled down to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography over silicagel to give tert-butyl (2R)-3 -(3 -(4-(4-bromo-l -methyl- 1H- pyrazol-5-yl)-5-methyl-6-(5H-pyrrolo [3,4-b]pyridin-6(7H)-yl)pyrimidin-2-yl)-4- chlorophenoxy)-2-(tert-butyldimethyl- silyloxy)propyl(methyl)carbamate (120 mg, 89% yield) as white solid. ESI-LCMS (m/z): 798.2found for [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dimethyl sulfoxide at 110℃; for 0.5h; Microwave irradiation; | 4.2 Step 2: tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-5-methyl-6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate A reaction pressure vessel was charged with a mixture of tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4- chloro-6-(4-iodo-l -methyl- lH-pyrazol-5 -yl)-5-methylp yrimidin-2- yl)phenoxy)propyl(methyl)carbamate (160 mg, 0.2 mmol); 6,7-dihydro -5H-pyrrolo[3,4- b]pyridine dihydrochloride (or any other suitably substituted primary or secondary amine, 0.4 mmol), triethylamine (0.5 mL, 3.5 mmol) and DMSO (3 mL). The vessel was capped, placed in a microwave reactor and irradiated for 30 min. at external temperature of 110 °C. After being cooled down to room temperature, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography over silicagel to give tert-butyl (2R)-2-(tert-butyldimethyl-silyloxy)-3-(4-chloro-3-(4-(4-iodo-l -methyl- 1H- pyrazol-5-yl)-5-methyl-6-(5H- pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrimidin-2- yl)phenoxy)propyl(methyl)carbamate (160 mg, 95% yield ). ESI-LCMS (m/z): 846 found for [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; potassium iodide In butan-1-ol at 140℃; for 2h; Microwave irradiation; | 5.3 Step 3: tert-butyl (R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-5-methyl-6-(5H-pyrrolo[3,4-b]pyridin-6 (7H)-yl)pyrimidin-2-yl)phenoxy)propyl(methyl)carbamate A reaction pressure vessel was charged with a mixture of tert-butyl (R)-2-(tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4- chloro-6-(4-chloro- 1 -ethyl- 1 H-pyrazol-5 -yl)-5 -methylpyrimidin-2-yl)phenoxy)propyl (methyl) carbamate (100 mg, 0.15 mmol); 6,7-dihydro -5H-pyrrolo[3,4-b]pyridine dihydrochloride (or any other suitably substituted primary or secondary amine, 0.35 mmol), KI (30 mg, 0.18 mmol), triethylamine (2 mL) and n-BuOH (4 mL). The vessel was capped, placed in a microwave reactor and irradiated for 2h. at external temperature of 140 °C. After being cooled down to room temperature, 30 mL of water was added and the mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to give tert-butyl (R)-2- (tert-butyldimethylsilyloxy)-3-(4-chloro-3-(4-(4-chloro-l- ethyl- 1 H-pyrazol-5 -yl)-5-methyl- 6-(5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)pyrimidin-2- yl)phenoxy)propyl (methyl) carbamate (128 mg, crude), which was used for next step directly without further purification. ESI- LCMS (m/z): 768.4 found for [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 95℃; for 2h; | 4- (4,6-dichloropyrimidin-2-yl) morpholine10a (400 mg, 1.7 mmol),6,7-dihydro-5H-pyrrolo [3,4-b] pyridine dihydrochloride13a (400 mg, 2.1 mmol)And cesium carbonate (2.2 g, 6.9 mmol)Was added to 15 mL of N-methylpyrrolidone,Stir well,The reaction solution was heated to 95 C,Stirring was continued for 2 hours.The reaction solution was poured into 30 mL of water and treated with acetic acidThe organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, dried over anhydrous sodium sulfate,The filtrate was concentrated under reduced pressure,The title product was obtained 4- (4-Chloro-6- (5H-pyrrolo[3,4-b] pyridine-6 (7H) -yl)Pyrimidin-2-yl) morpholine13b (240 mg, yellow solid),Yield: 44.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - 25℃; | 64.1 Step 7: Intermediate 51- 6-Methylsulfonyl-5,7-dihydropyrrolo[3,4-b]pyridine Methanesulfonyl chloride (479 m, 6.18 mmol) was added dropwise to a solution of DIPEA (2.69 ml, 15.5 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine x 2 HC1 (995 mg, 5.15 mmol) in DCM (10 ml) at -10 °C and the resulting mixture was stirred at rt overnight. Additional DCM was added and the mixture washed with sat. aq. NaHCCh, dried over Na2S04, filtered and concentrated to give the product as a solid (1.02 g, quant.). MS ES+ m/z 199 [M+H]+. |
2 g | With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - 20℃; for 18h; | a; 246.a Step a. A solution of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (CAS Number 147739- 88-6, available from Tyger Scientific) (2.0 g, 10.38 mmol) in DCM (20 ml) was stirred at -10°C. DIPEA (4.02 g, 31.15 mmol) and methanesulphonyl chloride (1.43 g, 12.46 mmol) were added to the reaction mixture at -10°C. The reaction mixture was stirred at rt for 18 h. The resulting reaction mixture was poured into saturated NaHC03 solution (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine (50 ml). The organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure yielding 6-(methylsulfonyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridine (2 g, 10.07 mmol). This material was used for the next step without further purification. LCMS: Method A, 1.479 min, MS: ES+ 199.24; NMR (400 MHz, DMSO-d6) δ ppm 8.48 (dd, J=0.8 Hz, 4.4 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.34 (dd, J=5.2 Hz, 8.0 Hz, 1H), 4.69 (d, J=1.2 Hz, 2 H), 4.63 (d, J= 1.2 Hz, 2 H), 3.03 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C 4.1: trifluoroacetic anhydride; urea hydrogen peroxide adduct / acetonitrile / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C 4.1: trifluoroacetic anhydride; urea hydrogen peroxide adduct / acetonitrile / 2 h / 0 - 20 °C 5.1: oxalyl dichloride; N,N-dimethyl-formamide / N,N-dimethyl-formamide / 48 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C 4.1: trifluoroacetic anhydride; urea hydrogen peroxide adduct / acetonitrile / 2 h / 0 - 20 °C 5.1: oxalyl dichloride; N,N-dimethyl-formamide / N,N-dimethyl-formamide / 48 h / 20 °C 6.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 3 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C 4.1: trifluoroacetic anhydride; urea hydrogen peroxide adduct / acetonitrile / 2 h / 0 - 20 °C 5.1: oxalyl dichloride; N,N-dimethyl-formamide / N,N-dimethyl-formamide / 48 h / 20 °C 6.1: tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; caesium carbonate / 1,4-dioxane / 3 h / 100 °C 7.1: hydrogen bromide; acetic acid / dichloromethane; methanol / 2 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 18 h / -10 - 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 0 - 20 °C 3.1: oxalyl dichloride; N,N-dimethyl-formamide / 15 h / 20 °C 3.2: 4 h / 100 °C 4.1: trifluoroacetic anhydride; urea hydrogen peroxide adduct / acetonitrile / 2 h / 0 - 20 °C 5.1: oxalyl dichloride; N,N-dimethyl-formamide / N,N-dimethyl-formamide / 48 h / 20 °C 6.1: water; dimethyl sulfoxide / 16 h / 140 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 6-(4-aminophenyl)-2-(2-hydroxyethyl)-4,4-dimethyl-4,5-dihydropyridazin-3(2H)-one; 4-Nitrophenyl chloroformate In tetrahydrofuran at 20℃; for 14h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 14h; | 108 N-{4-[1 -(2-hydroxyethyl)-5, 5-dimethyl-6-oxo-1 ,4 ,5,6-tetrahydropyridazin-3-yl]phenyl}-5, 7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide To a solution of Intermediate 106 (520 mg, 1.99 minol) in THE (21 mL) was added at r.t. 4-nitrophenylchloroformate (0.40 g, 1.99 minol) and the mixture stirred for 14 h at thattemperature. After that the mixture was concentrated under reduced pressure and taken up in dichloromethane (56 mL). To this mixture N,N-diisopropylethylamine (1.1 mL, 6.2 minol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (384 mg, 1 .99 mol) were added at r.t. and the mixture was stirred for 14 h at that temperature. Then the reaction was quenched by additionof water and the phases were seprarated. The aqueous phase was extracted withdichioromethane and the combined organic phases were filtered through a silicone filter and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (550 mg, 1.27 mol, 64%).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, Prepcon5 software. Column: Chromatorex C18 10pM, 122x50 min. Eluent A: water + 0.1 Vol-% TEA; Eluent B: acetonitrile; gradient: 0-20 min 15-55% B. rate 250 mI/min, temperature 25°C.1H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 8.65 (s, IH), 8.62 (s, IH), 8.51 (d, IH), 7.75-7.64 (m,4H), 7.45 (d, I H), 4.83 (br d, 4H), 3.72 (t, 2H), 2.85 (s, 2H), 2.77 (t, 2H), 1.53 (br s, 2H), 1.09 (s,6H).LC-MS (Method 6): R = 0.79 min; MS (ESIpos): m/z = 407 [M÷H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-cyclopentyl-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran for 1h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran at 20℃; for 18h; | 8 N-[4-( I -cyclopentyl-4-methyl-6-oxo-1 4, 5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide To a solution of Intermediate 9, 60 mg (0.22 minol), and 4-dimethylaminopyridine, 32 mg (0.26 minol), in tetrahydrofuran, 25 mL, was added N,N-disuccinimidyl carbonate, 67.9 mg (0.26 minol). The reaction was stirred for 1 hour then triethylamine, 0.123 mL (0.88 minol), and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (147739-88-6), 50.9 mg (0.26 minol), was added and the reaction was left to stir at room temperature for 18 hours. Water was added and the mixture was extracted with dichloromethane. The combined organics were dried over solid sodium sulfate and concentrated under vacuum. Purification by flash chromatography on silica gel 60 (eluent: ethyl acetate-heptane 0:1, 1:1, 1:0 and methanol-ethyl acetate 1:9) gave thedesired product, 76.9 mg (81%).1H NMR (300 MHz, CDCI3): 6 [ppm] = 1.16 (d, 3H), 1.57-1.95 (m, 8H), 2.46 (d, IH), 2.65 (dd,IH), 3.27 (m, IH), 4.89 (d, 4H), 5.23 (m, IH), 6.42 (s, IH), 7.25 (t, IH), 7.53 (d, 2H), 7.65 (d,IH), 7.75 (d, 2H), 8.54 (d, IH).UPLC-MS (Method 4): R = 2.00 min., 98%. MS (ESIpos): mz (M+H)+ 418. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-cyclopropyl-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran for 2h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran at 20℃; for 18h; | 18 N-[4-( I -cyclopropyl-4-methyl-6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide To a solution of Intermediate 10, 60 mg (0.2 minol), and 4-dimethylaminopyridine, 29 mg (0.24 minol), in tetrahydrofuran, 25 mL, was added N,N-disuccinimidyl carbonate, 62 mg (0.24 minol). The reaction was stirred for 1 hour then triethylamine, 0.11 mL (0.80 minol), and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (147739-88-6), 62 mg (0.24 minol), were added and the reaction stirred at room temperature for 18 hours. Water was added and the mixture was extracted with dichloromethane. The combined organics were dried over solid sodium sulfate and concentrated. Purification by reverse phase chromatography (BIOTAGE SP4, 30 g Biotage cartridge, eluent: acetonitrile-water containing 10 min aminonium bicarbonate pH 10 buffer 3:97to 100:0) and flash chromatography on silica gel 60 (eluent: dichloromethane-methanol 1:0, 9:1) gave the desired product, 22 mg (28%).1H NMR (300 MHz, CDCI3): 6 [ppm] = 0.70-0.90 (m, 3H), 0.90-1.15 (m, IH), 1.13 (s, 3H), 2.48(dd, IH), 2.66 (dd, IH), 3.24 (m, IH), 3.56 (m, IH), 4.87 (d, 2H), 6.50 (s, IH), 7.28 (m, IH), 7.52(d, 2H), 7.45 (d, IH), 7.70 (d, 2H), 8.53 (s, IH).UPLC-MS (Method 3): R = 0.61 min., 100%. MS (ESIpos): mz [M÷H] 390. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-5-methyl-2-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyridazin-3(2H)-one With dmap In N,N-dimethyl-formamide at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; | 22 N-{4-[4-methyl-6-oxo-1 -(tetrahyd ro-2 H-pyran-4-yl)- 1,4,5, 6-tetrahyd ropyridazi n-3-yl]phenyl}-5, 7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide A solution of 110 mg of Intermediate 14 (0.38 minol, 1.00 eq) in DMF (10 mL) was treated with118 mg of N,N’-disuccinimidyl carbonate (0.46 minol, 1.20 eq) and 56.1 mg of 4- dimethylaminopyridine (0.46 minol, 1.20 eq). The mixture was left over night at room temperature. A suspension of 88.7 mg of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (0.46 minol, 1.20 eq) and 192 pL of triethylamine (1.38 minol, 3.60 eq) on DMF (3 mL) wasadded. The reaction mixture was stirred 3 days at room temperature. The mixture was poured into water and the aqueous phase was diluted with ethyl acetate. Insoluble material was collected by filtration and triturated with DMSO to yield 8.00 mg of the desired product Example 22(0.02 minol, 4%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.00-1.09 (m, 3H), 1.47-1.61 (m, 2H), 1.80-1.93 (m,IH), 2.03-2.15 (m, IH), 2.27-2.36 (m, IH), 2.64-2.74 (m, IH), 3.32-3.47 (m, 3H), 3.88-3.98(m, 2H), 4.69 - 4.76 (m, I H), 4.77 - 4.82 (m, 4H), 7.27 - 7.35 (m, I H), 7.64 - 7.70 (m, 2H), 7.74 -7.82 (m, 3H), 8.42 - 8.49 (m, I H), 8.57 - 8.62 (m, I H).U PLC-MS (Method 2): R 0.88 min; MS (ESipos): mz [M÷H] 434. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-(2-hydroxyethyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide | 23 N-{4-[1 -(2-hydroxyethyl)-4-methyl-6-oxo-1 ,4 ,5,6-tetrahydropyridazin-3-yI]phenyl}-5, 7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide solution of 160 mg of Intermediate 15 (0.65 minol, 1.00 eq) in THE (20 mL) was treated with199 mg of N,N’-disuccinimidyl carbonate (0.78 minol, 1.20 eq) and 94.9 mg of 4- dimethylaminopyridine (0.78 minol, 1.20 eq). The mixture was stirred over night at room temperature. A suspension of 150 mg 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (0.78 minol, 1.20 eq) and 4.00 mL of triethylamine (2.33 minol, 3.60 eq) in DMF (4 mL) wasadded. The resulting suspension was stirred over night. The THE was removed under reduced pressure. The remaining suspension was poured into water. The remaining slurry was taken to dryness, the residue was purified by preparative reverse phase HPLC to yield 58.0 mg of the desired product Example 23 (0.15 minol, 23%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.08 (d, 3H), 2.26-2.33 (m, IH), 2.65-2.75 (m, IH),3.35-3.42 (m, IH), 3.57-3.63 (m, 2H), 3.65-3.74 (m, IH), 3.93 (dt, IH), 4.65-4.70 (m, IH),4.80 (d, 4H), 7.33 (dd, I H), 7.67 - 7.71 (m, 2H), 7.72 - 7.76 (m, 2H), 7.81 (dd, I H), 8.48 (dd, I H),8.62 (s, IH).UPLC-MS (Method 2): R0.73 min; MS (ESIpos): mz [M÷H] 394. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-5-ethyl-2-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In N,N-dimethyl-formamide at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; | 25 N-[4-(4-ethyl-1 -methyl-6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6 H-pyrrolo[3,4-b]pyridine-6-carboxamide A solution of 100 mg of Intermediate 19 (0.43 minol, 1.00 eq) in DMF (6 mL) was treated with133 mg of N,N’-disuccinimidyl carbonate (0.52 minol, 1.20 eq) and 63.4 mg of 4-dimethylaminopyridine (0.52 minol, 1.20 eq). The mixt stirred over night at room temperature. Asuspension of 100 mg 6,7-dihydro-5H-pyrrolo[3,4-b] pyridine dihydrochloride (0.52 minol, 1.20eq) and 217 pL of triethylamine in DMF (3mL) was added and the reaction mixture was stirred 3days at room temperature. The mixture was poured into water and extracted three tomes withethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and thesolvent was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC to obtain 35.0mg of the desired product Example 25(0.09 minol, 21%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 0.86 (t, 3H), 1.32 - 1.56 (m, 2H), 2.44 (dd, IH), 2.67 (dd, I H), 3.22 - 3.28 (m, I H), 3.30 (s, 3H), 4.80 (d, 4H), 7.33 (dd, I H), 7.65 - 7.70 (m, 2H), 7.71 -7.76 (m, 2H), 7.78 - 7.85 (m, I H), 8.48 (dd, I H), 8.60 (s, I H).UPLC-MS (Method 1): R0.88 min; MS (ESIpos): mz [M÷H] 378. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.9% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-5-methyl-2-phenyl-4,5-dihydropyridazin-3(2H)-one With dmap In N,N-dimethyl-formamide at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In N,N-dimethyl-formamide | 37 N-[4-(4-methyl-6-oxo-I -phenyl-I 4, 5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6 Hpyrrolo[3,4-b]pyridine-6-carboxamide A solution of 100mg of Intermediate 23 (0.36 minol, 1.00 eq) in DMF (11 mL) was treated with110 mg of N,N’-disuccinimidyl carbonate (0.43 minol, 1.20 eq) and 70.1 mg of 4-dimethylaminopyrdine (0.43 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 82.9 mg of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (0.43minol, 1.20 eq) and 1.50 mL of triethylamine (10.74 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 6.0mg of the desired product (3.9%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.06 (d, 3H), 2.16 (s, 6H), 2.24 -2.36 (m, 2H), 2.61 -2.78 (m, 2H), 2.97 (s, 3H), 3.56 - 3.72 (m, I H), 3.91 - 4.08 (m, I H), 4.58 (s, 2H), 7.39 (dd, I H),7.59 (d, 2H), 7.64 - 7.80 (m, 3H), 8.44 - 8.60 (m, 2H), 8.66 (s, I H).UPLC-MS (Method 1): R0.96 min; MS (ESIpos): mz[M+H]426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-[2-(dimethylamino)ethyl]-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In N,N-dimethyl-formamide at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In N,N-dimethyl-formamide | 33 N-(4-{1 -[2-(dimethylamino)ethyl]-4-methyl-6-oxo-1 4, 5,6-tetrahydropyridazin-3-yl}phenyl)-5, 7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide A solution of 100 mg of Intermediate 24 (0.36 minol, 1.00 eq) in DMF (11 mL) was treated with112 mg of N,N’-disuccinimidyl carbonate (0.44 minol, 1.20 eq) and 53.4 mg of 4-dimethylaminopyrdine (0.44 minol, 1.20 eq). The mixture was stirred over night at roomtemperature. A solution of 84.4 mg of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (0.44minol, 1 .20 eq) and 3.05 mL of triethylamine (21.87 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 55.0mg of the desired product (35%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.08 (d, 3H), 2.18 - 2.35 (m, 7H), 2.69 - 2.61 (m, I H),2.71 (dd, I H), 3.38 (t, I H), 3.74 (dt, I H), 4.00 (dt, 2H), 4.73 - 4.85 (m, 4H), 7.33 (dd, I H), 7.66 -7.77 (m, 4H), 7.77-7.85 (m, IH), 8.19 (s, IH), 8.48 (dd, IH).UPLC-MS (Method 1): R0.66 min; MS (ESIpos): mz[M+H]421. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-methyl-5-phenyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran at 20℃; for 2h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran for 16h; | 30 N-[4-( I -methyl-6-oxo-4-phenyl-1 4, 5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6 Hpyrrolo[3,4-b]pyridine-6-carboxamide To a solution of Intermediate 31, 50 mg (0.18 minol) and 4-dimethylaminopyridine, 42mg (0.22 minol) in tetrahydrofuran, 30 mL, was added N,N-disuccinimidyl carbonate, 55 mg (0.22 minol)After 2h at room temperature, 6,7-dihydro-5H-pyrollo[3,4-b]pyridine dihydrochloride, 41 mg (147740-02-1,0.22 minol) and triethylamine, 0.12 mL (0.89 minol) were added and the reaction was stirred for a further 16 hours. Water and dichloromethane were added and the layers were separated. The aqueous was further extracted with dichloromethane and the combined organics were dried over solid sodium sulphate, filtered and concentrated under vacuum. The crudecompound was purified by reverse phase chromatography (BIOTAGE 5P4, 30 g Biotage cartridge) using acetonitrile and water containing 10min aminonium bicarbonate pH 10 buffer (3:97 to 100:0) to give Example 30, 35 mg (46%).1H NMR (400 MHz, CDCI3): 6 [ppm] = 2.81 (dd, 2H), 2.99 (dd, IH), 3.49 (s, 3H), 4.54 (d, IH),4.86 (d, 4H), 6.38 (s, IH), 7.14 (d, 2H), 7.20-7.30 (m, 4H), 7.47 (d, 2H), 7.62 (d, 2H), 7.70 (d,2H), 8.53 (d, IH).UPLC (Method 3): R = 0.66., 99%. MS (ESipos): mz [M÷H] 426. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-ethyl-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran for 1h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran at 20℃; for 18h; | 10 N-[4-( I -ethyl-4-methyl-6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6 H-pyrrolo[3,4- b]pyridine-6-carboxamide To a solution of Intermediate 8, 60 mg (0.26 minol), and 4-dimethylaminopyridine, 38 mg (0.31 minol), in tetrahydrofuran, 25 mL, was added N,N-disuccinimidyl carbonate, 79 mg (0.31 minol).The reaction was stirred for 1 hour then triethylamine, 0.15 mL (1 .04 minol), and 6,7-dihydro-5H- pyrrolo[3,4-b]pyridine dihydrochloride (147739-88-6), 59.7 mg (0.31 minol), was added and the reaction was left to stir at room temperature for 18 hours. Water was added and the mixture was extracted with dichloromethane. The combined organics were dried over solid sodium sulfate and concentrated under vacuum. Purification by flash chromatography on silica gel 60 (eluent:heptane-ethyl acetate 1:0, 1:1, 0:1 and methanol-ethyl acetate 1:9) gave the desired product, 84.5 mg (85%).1H NMR (300 MHz, CDCI3): 6 [ppm] = 1.19 (d, 3H), 1.27 (t, 3H), 2.45 (d, IH), 2.66 (dd, IH),3.27-3.31 (m, IH), 3.80-4.02 (m, 2H), 4.88 (d, 4H), 6.42 (s, IH), 7.25 (t, IH), 7.4 (d, 2H), 7.75 (d,IH), 7.76 (d, 2H), 8.54 (dd, IH).UPLC-MS (Method 4): R 1 .60 min., (99%) MS (ESIpos): mz [M÷H] 378. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazine-3(2H)-one With dmap In tetrahydrofuran at 20℃; for 72h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | 1 N-[4-( I ,4-dimethyl-6-oxo-1 ,4,5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-dihydro-6 H-pyrrolo[3,4-b]pyridine-6-carboxamide A solution of 4.10 g of Intermediate 4 (18.9 minol, 1.00 eq) in THE (60 mL) was treated with 5.80g of N,N’-disuccinimidyl carbonate (22.6 minol, 1.20 eq) and 2.77 g 4-dimethylaminopyridine(22.6 minol, 1.20 eq). The reaction mixture was stirred for 3 days at room temperature. Asuspension of 4.27 g 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (22.6 minol, 1 .20 eq)and 9.47 mL of triethylamine (67.9 minol, 3.60 eq) in DMF (40 mL) was added to the reaction mixture, additional DMF (100 mL) was added and the resulting suspension was stirred over night at room temperature. The precipitate was filtered off and discarded. The filtrate was evaporated under reduced pressure and purified by flash chromatography on silica gel (eluent:DCminethanol 100:0, 85:15). During the evaporation of the fractions a precipitate occurred which was collected by filtration and dried to obtain 4.24 g of the desired product Example 1. After complete evaporation of the solvent the remaining residue was triturated with ethyl acetate to yield additionally 1.86 g of the product (6.10 g, 89%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.07 (d, 3H), 2.30 (dd, IH), 2.71 (dd, IH), 3.32 (s, 3H),3.40 (s, I H), 4.79 (d, 4H), 7.33 (dd, I H), 7.66 - 7.71 (m, 2H), 7.72 - 7.77 (m, 2H), 7.78 - 7.83 (m, IH), 8.48 (dd, IH), 8.61 (s, IH).LC-MS (Method 2): R = 0.81 min; MS (ESIpos): mz = 364 [M÷H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Stage #1: di(succinimido) carbonate; (5R)-6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran at 20℃; for 72h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | 2B Preparation B: A solution of 500 mg of Intermediate 5 (2.30 minol, 1.00 eq) in THE (60 mL) was treated with 533 mg N,N’-disuccinimidyl carbonate (2.76 minol, 1.20 eq) and 337 mg 4- dimethylaminopyridine (2.76 minol, 12.0 eq). The mixture was stirred for 3 days at room temperature. A suspension of 533 mg of 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (2.76 minol, 12.0 eq) and 1.16 mL of triethylamine (8.29 minol, 3.60 eq) in THE (3 mL) wasadded. Additional DME (5 mL) were added to the mixture at it was stirred over night at room temperature. The precipitate was filtered off and discarded. The THE was removed from the filtrate and the remaining DME solution was poured into water. The aqueous phase was three times extracted with DCM. The combined organic layers were washed with brine, dried over Na2504 and the solvent was removed under reduced pressure. The residue was purified byflash chromatography on silica gel to provide the desired product which was resolved in DCM,insoluble material was filtered off, the filtrate was taken to dryness. 176 mg of the pure material Example 2 were obtained (21%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.07 (d, 3H), 2.30 (dd, IH), 2.71 (dd, IH), 3.32 (s, 3H),3.35 - 3.45 (m, I H), 4.80 (d, 4H), 7.33 (dd, I H), 7.65 - 7.71 (m, 2H), 7.71 - 7.76 (m, 2H), 7.81 (d,IH), 8.48 (d, IH), 8.61 (s, IH).Chiral HPLC (System: Agilent 1200, DAD 280 nm Column: Chiralpak IC 5 pm 100x4.6 min, Solvent: acetonitrile + 0.1% diethylamine ethanol 90:10 (vv)): R = 16.0 min, 96.6% enantiomeric excess.Optical rotation (Method 5): [a] = -291 •QO (c = 1.00, CHCI3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5% | Stage #1: di(succinimido) carbonate; (5S)-6-(4-aminophenyl)-2,5-dimethyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran at 20℃; for 72h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; | 3B Preparation B: A solution of 500 mg of Intermediate 6 (2.30 minol, 1.00 eq) in THE (60 mL) wastreated with 533 mg N,N’-disuccinimidyl carbonate (2.76 minol, 1.20 eq) and 337 mg 4-dimethylaminopyridine (2.76 minol, 12.0 eq). The mixture was stirred for 3 days at room temperature. A suspension of 533 mg of 6,7-dihydro 5H-pyrrolo[3,4-b]pyridine dihydrochloride (2.76 minol, 12.0 eq) and 1.16 mL of triethylamine (8.29 minol, 3.60 eq) in THE (3 mL) was added. Additional DME (5 mL) were added to the mixture at it was stirred over night at roomtemperature. The precipitate was filtered off and discarded. The THE was removed from the filtrate and the remaining DME solution was poured into water. The aqueous phase was three times extracted with DCM. The combined organic layers were washed with brine, dried over Na2504 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel and subsequent reverse phase, preparative HPLC to providethe desired product. 63 mg of the pure material Example 3 were obtained (7.5%).1H-NMR (500MHz, CDCI3-d): ö [ppm] = 1.21 (d, 3H), 2.48 (dd, IH), 2.68 (dd, IH), 3.26-3.35 (m, IH), 3.45-3.49 (m, 3H), 4.90 (d, 4H), 6.48 (s, IH), 7.24-7.30 (m, IH), 7.54-7.59 (m, 2H), 7.67 (d, I H), 7.74 - 7.78 (m, 2H), 8.55 (d, I H).LC-MS (Method 2): R = 0.82 min; MS (ESIpos): mz = 364 [M÷H].Chiral HPLC (System: Agilent 1200, DAD 280 nm Column: Chiralpak IC 5 pm 100x4.6 min, Solvent: acetonitrile + 0.1% diethylamine ethanol 90:10 (vv)): R = 12.6 min, 93% enantiomeric excess.Optical rotation (Method 5): [a] = + 359.8 ° (c = 1.00, DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-5-isopropyl-2-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In tetrahydrofuran at 20℃; for 2h; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In tetrahydrofuran for 16h; | 77 N-[4-(4-lsopropyl-1 -methyl-6-oxo-1 4, 5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-d ihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxamide To a solution of 6-(4-aminophenyl)-5-isopropyl-2-methyl-4, 5-dihydropyridazin-3(2H )-one Intermediate 91, 50 mg (0.20 minol) and 4-dimethylaminopyridine, 30 mg (0.25 minol) in tetrahydrofuran, 5 mL, N,N-disuccinimidyl carbonate, 63 mg (0.25 minol) was added. After 2 hours at room temperature, 6,7-dihydro-5H-pyrollo[3,4-b]pyridine dihydrochloride, 47 mg(147740-02-1, 0.25 minol) and triethylamine, 0.14 mL (1.02 minol) were added. The reaction was stirred for a further 16 hours. The reaction mixture was diluted with a saturated solution of aminonium chloride and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified by reverse phase chromatography (BIOTAGE SP4, 30 g Biotage cartridge) using acetonitrileand water containing 10min aminonium bicarbonate pH 10 buffer (3:97 to 100:0) to give Example 77, 33 mg, (40%) as a colourless solid.1H NMR (400 MHz, CDCI3): 6 [ppm] = 0.89 (m, 6H), 1.96 (m, IH), 2.56 (dd, IH), 2.66 (d, IH),3.04 (m, IH), 3.45 (s, 3H), 4.88 (d, 4H), 6.51 (s, IH), 7.25 (m, IH), 7.53 (d, 2H), 7.63 (d, IH),7.73 (d, 2H), 8.53 (d, IH).LCMS (Method 3, ii min runtime): R = 4.98 min., 98%. MS (ESIpos): mz = [M÷H] 392. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: di(succinimido) carbonate; 6-(4-aminophenyl)-2-isopropyl-5-methyl-4,5-dihydropyridazin-3(2H)-one With dmap In N,N-dimethyl-formamide at 20℃; Stage #2: 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride With triethylamine In N,N-dimethyl-formamide | 28 N-[4-( I -isopropyl-4-methyl-6-oxo-I 4, 5,6-tetrahydropyridazin-3-yl)phenyl]-5, 7-d ihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide A solution of 100 mg 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 6,7-dihydro-5H-pyrrolo[3,4-b]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 52.7mg of the desired product (33%).1H-NMR (400MHz, DMSO-d6): ö [ppm] = 1.04 (d, 3H), 1.16 (d, 3H), 1.25 (d, 3H), 2.23-2.34 (m,I H), 2.68 (dd, I H), 3.34 - 3.44 (m, I H), 4.70 - 4.84 (m, 4H), 4.90 (quin, I H), 7.33 (dd, I H), 7.63 -7.73 (m, 2H), 7.73-7.85 (m, 3H), 8.48 (dd, IH), 8.62 (s, IH).UPLC-MS (Method 1): R0.97 min; MS (ESIpos): mz [M÷H] 392. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.8 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.2 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.2 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.1 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.7 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.6 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.3 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.7 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.3 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.9 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.5 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.6 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; dichloromethane at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; HATU In tetrahydrofuran; dichloromethane at 20℃; | [00191] General procedure G: Amidation of acids 19. To a suspension of crude carboxylic acid 19 (1 equiv) and amine (1.5 equiv) in CThChiTHF (1 : 1 mixture, 0.08-0.09 M) was added triethylamine followed by HATU (1.2 equiv). The suspension was stirred overnight at room temperature and then diluted with CH2CI2. The reaction mixture was washed with saturated NaHCCb (aq.), brine and then dried with anhydrous Na2SO4. The salts were removed via gravity filtration and volatile materials were condensed in vacuo. The crude mixture was purified via automated flash chromatography. Crude acid 19a (31.7 mg, 69.3 mmol) was coupled with 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrochloride (20.1 mg, 104 mmol), and triethylamine (72 mL, 520 mmol) using General procedure G to give 21.8 mg of MOM-protected intermediate (56% yield) after purification via automated flash chromatography (10% to 50% acetone in CH2CI2). 'H NMR (400 MHz, CDCl3) d 8.56 - 8.42 (m, 1H), 7.67 - 7.43 (m, 1H), 7.21 (ddd, J = 13.1, 7.7, 4.9 Hz, 1H), 7.06 (ddd, J = 9.9, 6.0, 2.6 Hz, 2H), 6.70 - 6.57 (m, 2H), 6.45 (d, J = 2.5 Hz, 1H), 6.39 (dd, J = 7.5, 2.1 Hz, 1H), 6.23 (dd, J = 13.2, 2.1 Hz, 1H), 5.84 (s, 1H), 5.30 -4.72 (m, 9H), 4.61 -4.41 (m, 1H), 3.68 (d, J= 2.8 Hz, 3H), 3.44 (dd, J = 4.3, 2.0 Hz, 6H), 2.23 (d, J = 3.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 167.2, 167.2, 159.9, 159.0, 158.9, 157.6, 157.2, 155.4, 155.4, 149.4, 149.3, 147.6, 147.6, 143.9, 143.8, 139.4, 139.2, 131.0, 130.6, 130.3, 129.9, 128.8, 128.6, 128.5, 122.5, 122.4, 113.9, 113.8, 107.1, 98.5, 98.5, 96.5, 95.4, 95.3, 95.1, 95.1, 94.3, 94.2, 56.6, 56.5, 56.3,56.2, 55.2, 55.1, 53.8, 53.4, 52.6, 51.4, 51.3,51.3,50.5, 29.3, 14.2, 14.2. LC/MS (m/z): 560.225 [M+H+]; UPLC tR 1.41 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.9% | With benzotriazol-1-ol; trimethylamine In tetrahydrofuran; dichloromethane at 20℃; | [00395] 5-((1-(2-methylpropyl)-1H-pyrazol-5-yl)amino)-4-(5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl)benzene-1,3-diol (63). [00194] H2: Identical to General procedure HI, except using 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine instead of isoindoline hydrochloride. Carboxylic acid 19j (46 mg, 120 mmol) was subjected to General procedure H2 to afford 4.7 mg of 63 (9.9% yield) after purification using mass-guided preparative HPLC. 1H NMR (400 MHz, CD3OD) d 8.44 (dd, J = 5.2, 1.5 Hz, 1H), 7.80 (d, J= 7.7 Hz, 1H), 7.40 (d, J= 2.0 Hz, 1H), 7.35 (dd, J= 7.8, 5.0 Hz, 1H), 6.06 (d, J= 2.0 Hz, 1H), 5.92 (d, J= 2.1 Hz, 1H), 5.75 (d, J= 2.1 Hz, 1H), 5.04 -4.57 (m, 4H), 3.77 (d, J= 7.5 Hz, 2H), 2.12 (hept, J = 7.0 Hz, 1H), 0.81 (d, J = 6.7 Hz, 6H). LC/MS (m/z): 394.341 [M+H+]; UPLC tR 1.08 min. |
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