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CAS No. : | 603288-22-8 | MDL No. : | MFCD20526532 |
Formula : | C28H25FN6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HRJWTAWVFDCTGO-UHFFFAOYSA-N |
M.W : | 512.53 | Pubchem ID : | 10029385 |
Synonyms : |
|
Num. heavy atoms : | 38 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 150.49 |
TPSA : | 91.95 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.67 cm/s |
Log Po/w (iLOGP) : | 3.05 |
Log Po/w (XLOGP3) : | 2.48 |
Log Po/w (WLOGP) : | 2.54 |
Log Po/w (MLOGP) : | 2.56 |
Log Po/w (SILICOS-IT) : | 2.32 |
Consensus Log Po/w : | 2.59 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.67 |
Solubility : | 0.011 mg/ml ; 0.0000215 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.06 |
Solubility : | 0.0451 mg/ml ; 0.000088 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.5 |
Solubility : | 0.000163 mg/ml ; 0.000000318 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.12 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-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 |
---|---|---|
60% | With triethylamine In methanol at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 50 percent Spectr. / acetonitrile / 6 h / 80 °C 2: 5.0 g / NH3 (gas) / methanol / 2 h / 100 °C 3: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 4: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 5: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 2: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 3: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: 95 percent / TsOH / toluene / 3 h / Heating 2.1: tetrahydrofuran / 0.67 h / -40 °C 2.2: 55 percent / 0.5 N aq. HCl / tetrahydrofuran / 1 h / 0 °C 3.1: 93 percent / H2 / Pd/c / methanol / 3 h / 20 °C / 760 Torr 4.1: 86 percent / aq. K2CO3 / tetrahydrofuran / 4 h / 0 °C 5.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 6.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 7.1: CH2Cl2 / 1 h / 0 °C 7.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 8.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 9.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 10.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 12 steps 1.1: 100 percent / BH3*THF / 72 h / 20 °C 2.1: 69 percent / PDC; 4 Angstroem molecular sieves / CH2Cl2 / 6 h / 20 °C 3.1: 95 percent / TsOH / toluene / 3 h / Heating 4.1: tetrahydrofuran / 0.67 h / -40 °C 4.2: 55 percent / 0.5 N aq. HCl / tetrahydrofuran / 1 h / 0 °C 5.1: 93 percent / H2 / Pd/c / methanol / 3 h / 20 °C / 760 Torr 6.1: 86 percent / aq. K2CO3 / tetrahydrofuran / 4 h / 0 °C 7.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 8.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 9.1: CH2Cl2 / 1 h / 0 °C 9.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 10.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 11.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 12.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 11 steps 1.1: 69 percent / PDC; 4 Angstroem molecular sieves / CH2Cl2 / 6 h / 20 °C 2.1: 95 percent / TsOH / toluene / 3 h / Heating 3.1: tetrahydrofuran / 0.67 h / -40 °C 3.2: 55 percent / 0.5 N aq. HCl / tetrahydrofuran / 1 h / 0 °C 4.1: 93 percent / H2 / Pd/c / methanol / 3 h / 20 °C / 760 Torr 5.1: 86 percent / aq. K2CO3 / tetrahydrofuran / 4 h / 0 °C 6.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 7.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 8.1: CH2Cl2 / 1 h / 0 °C 8.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 9.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 10.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 11.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: 86 percent / aq. K2CO3 / tetrahydrofuran / 4 h / 0 °C 2.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 3.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 4.1: CH2Cl2 / 1 h / 0 °C 4.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 5.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 6.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 7.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 0.67 h / -40 °C 1.2: 55 percent / 0.5 N aq. HCl / tetrahydrofuran / 1 h / 0 °C 2.1: 93 percent / H2 / Pd/c / methanol / 3 h / 20 °C / 760 Torr 3.1: 86 percent / aq. K2CO3 / tetrahydrofuran / 4 h / 0 °C 4.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 5.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 6.1: CH2Cl2 / 1 h / 0 °C 6.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 7.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 8.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 9.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: CH2Cl2 / 1 h / 0 °C 1.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 2.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 3.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 4.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: 100 percent / Et3N / tetrahydrofuran / 2 h / 0 °C 2.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 3.1: CH2Cl2 / 1 h / 0 °C 3.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 4.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 5.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 6.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 76 percent / NaH / dimethylformamide / 1 h / 0 °C 2.1: CH2Cl2 / 1 h / 0 °C 2.2: 98 percent / methanol; CH2Cl2 / -78 - 20 °C 3.1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 4.1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 5.1: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: KOt-Bu / tetrahydrofuran / 2 h / 20 °C 2: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 3: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.15 g / aq. HCl / CH2Cl2; dioxane / 1.5 h / 20 °C 2: 60 percent / Et3N / methanol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine In methanol; ethyl acetate | 1 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine EXAMPLE 1 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine Add piperidine-1-carbonyl chloride (0.5 mL, 4.0 mmol) to a solution of 3-(9-fluoro-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-imidazo[1,2-a]pyridin-3-yl-pyrrole-2,5-dione (1.42 g, 3.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) in methanol (80 mL). Stir at room temperature over night. Add triethylamine (1.04 mL, 7.5 mmol) and piperidine-1-carbonyl chloride (0.5 mL, 4.0 mmol). Stir at room temperature for 5 hours. Add ethyl acetate (500 mL) and wash sequentially with saturated aqueous sodium bicarbonate (300 mL*3) and saturated aqueous sodium chloride (200 mL). Dry the organic phase over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluding with 0% to 3% methanol in ethyl acetate to provide the title compound as a red solid (700 mg, 45%). m.p.=188-190° C. MS (APCI): m/z=513 [C28H25FN6O3+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With methanesulfonic acid In methanol; isopropyl alcohol | 2 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine methanesulfonate EXAMPLE 2 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine methanesulfonate Heat a slurry of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine (500 mg, 0.976 mmol) in methanol (2.5 mL) to 64° C. Add a solution of methanesulfonic acid (64 μL, 0.976 mmol) in methanol (1.0 mL) over 5 minutes. Stir the mixture at 64° C. for 15 minutes and then add isopropanol (5.0 mL) over 30 minutes. Allow the resulting slurry to cool to room temperature over 1 hour and then stir at room temperature for 4 hours. Filter the slurry, wash with isopropanol, and dry under reduced pressure at 42° C. to provide the title compound as an orange solid (478 mg, 88.5% (adjusted for 9.9% volatiles in starting material and 1.0% volatiles in product)). m.p.=282.3° C. (DSC) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 5 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine In methanol at 20℃; | 1 EXAMPLE 1 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine EXAMPLE 1 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine (0048) Add piperidine-1-carbonyl chloride (0.5 mL, 4.0 mmol) to a solution of 3-(9-fluoro-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-imidazo[1,2-a]pyridin-3-yl-pyrrole-2,5-dione (1.42 g, 3.0 mmol) and triethylamine (2.09 mL, 15.0 mmol) in methanol (80 mL). Stir at room temperature over night. Add triethylamine (1.04 mL, 7.5 mmol) and piperidine-1-carbonyl chloride (0.5 mL, 4.0 mmol). Stir at room temperature for 5 hours. Add ethyl acetate (500 mL) and wash sequentially with saturated aqueous sodium bicarbonate (300 mL×3) and saturated aqueous sodium chloride (200 mL). Dry the organic phase over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 0% to 3% methanol in ethyl acetate to provide the title compound as a red solid (700 mg, 45%). m.p. = 188-190°C. MS(APCI): m/z = 513 [C28H25FN6O3 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | In methanol at 64℃; for 0.333333h; | 2 EXAMPLE 2 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine methanesulfonate EXAMPLE 2 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine methanesulfonate (0049) Heat a slurry of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine (500 mg, 0.976 mmol) in methanol (2.5 mL) to 64°C. Add a solution of methanesulfonic acid (64 µL, 0.976 mmol) in methanol (1.0 mL) over 5 minutes. Stir the mixture at 64°C for 15 minutes and then add isopropanol (5.0 mL) over 30 minutes. Allow the resulting slurry to cool to room temperature over 1 hour and then stir at room temperature for 4 hours. Filter the slurry, wash with isopropanol, and dry under reduced pressure at 42°C to provide the title compound as an orange solid (478 mg, 88.5% (adjusted for 9.9% volatiles in starting material and 1.0% volatiles in product)). m.p. = 282.3°C (DSC) |