Structure of 1209646-17-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 1209646-17-2 |
Formula : | C14H20N4O4 |
M.W : | 308.33 |
SMILES Code : | O=C(C1=NC=C(N2CCN(C(OC(C)(C)C)=O)CC2)N=C1)O |
MDL No. : | MFCD12923092 |
InChI Key : | ANDWAJHNYJXSJC-UHFFFAOYSA-N |
Pubchem ID : | 45789761 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 22 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.57 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 86.19 |
TPSA ? Topological Polar Surface Area: Calculated from |
95.86 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.08 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.47 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.11 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.03 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.69 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.1 |
Solubility | 2.44 mg/ml ; 0.0079 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.35 |
Solubility | 1.37 mg/ml ; 0.00444 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.69 |
Solubility | 6.25 mg/ml ; 0.0203 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.64 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.01 |
* 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 |
---|---|---|
To a stirred suspension of 1-76 (8.60 g, 26.68 mmol) in ethanol (250 ml) is added 5M NaOH (26.68 ml, 133.39 mmol) at room temperature. The mixture becomes homogenous before a persisting precipitate forms and becomes a solid mass. Water (200 ml) is added and the mixture is stirred for 4 h after which time the reaction appears complete. The light brown sludge is poured into a beaker and treated with water. AcOH is added to reach acidic pH and the product is extracted into DCM (2x). The combined organics are dried over anhydrous MgS04, filtered and concentrated to give the product as a solid which is suspended in heptanes. The solid is collected via filtration and washed with heptanes to give 1-77 (7.90 g); m/z 309.4 [M+H]. | ||
With water; sodium hydroxide; In ethanol; at 20℃; for 4h; | Step 2: Synthesis of 2,3,5,6-Tetrahydro-ri,2'lbipyrazinyl-4,5'-dicarboxylic acid 4-tert- butyl esterR8 (5.0 g, 15.51 mmol) is treated with ethanol (150 ml) and 5N NaOH at room temperature. The mixture becomes homogenous before a persisting precipitate forms. At this time water is added (200 ml) and the resulting solid mass is broken up using a spatula. The reaction is stirred for 4 h and treated with water. The mixture is acidified using acetic acid (AcOH) and the product is extracted into DCM (2x). The combined organics are dried (MgS04), filtered and concentrated to give the title compound. (4.3 g) | |
With water; sodium hydroxide; In ethanol; for 24h; | Step 2: synthesis of 2,3,5,6-Tetrahydro-[l,2']bipyrazinyl-4,5'-dicarboxylic acid 4-tert- butyl ester (R50).R49 (890 mg, 2.76 mmol) is treated with ethanol (25 mL) and 5N NaOH (2.76 mL, 13.8 mmol). The mixture is stirred for several minutes at which time water (approximately 10 mL) is added and the reaction is stirred for 24 hours. The resulting mixture is diluted with water, acidified with acetic acid., and extracted twice with CH2CI2. The combined organic phases are washed with brine, dried over MgS04, filtered, and the solvent is removed in vacuo to afford R50 (690 mg); m/z 309.4 [M+H]. |
7.90 g | With water; sodium hydroxide; In ethanol; for 4h; | To a stirred suspension of I-76 (8.60 g, 26.68 mmol) in ethanol (250 ml) is added 5M NaOH (26.68 ml, 133.39 mmol) at room temperature. The mixture becomes homogenous before a persisting precipitate forms and becomes a solid mass. Water (200 ml) is added and the mixture is stirred for 4 h after which time the reaction appears complete. The light brown sludge is poured into a beaker and treated with water. AcOH is added to reach acidic pH and the product is extracted into DCM (2×). The combined organics are dried over anhydrous MgSO4, filtered and concentrated to give the product as a solid which is suspended in heptanes. The solid is collected via filtration and washed with heptanes to give I-77 (7.90 g); m/z 309.4 [M+H]. |
300 mg | With ethanol; sodium hydroxide; In tetrahydrofuran; at 60℃; for 2h; | Methyl 5-(4-(tert-butoxycarbonyl) piperazin- 1 -yl) pyrazine-2-carboxylate (2 g, crude) was added into a solution of EtOH (5 ml), THF (5 ml) and NaOH (2 N, 5 ml). The mixture was stirred at 60 C. for 2 h. When the reaction finished, the pH was adjusted to 1 and it was extracted by EA, concentrated to afford the pink solid. (300 mg, 15% yield, 2 steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 1-77 (3.0 g, 9.71 mmol) in THF (40 ml) is added 1,1'- carbonyldiimidazole (1.6 g, 9.71 mmol) at room temperature. The mixture is stirred at 50 C for 30 minutes. After this time 1-16 (2.5 g, 8.83 mmol) is added and the resulting mixture is heated at 80C for 3 hours. The mixture is cooled down and treated with AcOH (8ml). The mixture is warmed to 80C and stirred over night. Upon cooling toroom temperature, the reaction is concentrated and diluted with water. The product is extracted into DCM (2x). The combined organics are washed with brine and dried over anhydrous MgS04. The mixture is filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford 1-78 (2.2 g). | ||
2.2 g | To a suspension of I-77 (3.0 g, 9.71 mmol) in THF (40 ml) is added 1,1?-carbonyldiimidazole (1.6 g, 9.71 mmol) at room temperature. The mixture is stirred at 50 C. for 30 minutes. After this time I-16 (2.5 g, 8.83 mmol) is added and the resulting mixture is heated at 80 C. for 3 hours. The mixture is cooled down and treated with AcOH (8 ml). The mixture is warmed to 80 C. and stirred over night. Upon cooling to room temperature, the reaction is concentrated and diluted with water. The product is extracted into DCM (2×). The combined organics are washed with brine and dried over anhydrous MgSO4. The mixture is filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford I-78 (2.2 g). In a microwave reaction vessel is added I-78 (0.50 g, 0.90 mmol) in 15 ml of DMF, followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (0.30 g, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.09 mmol) and aq. Na2CO3 (2.0M, 1.8 ml). The reaction mixture is stirred at 85 C. for 16 hours. After this time the reaction mixture is poured into brine and extracted with EtOAc (3×). The combined organic fractions are dried over anhydrous MgSO4, filtered, then concentrated in vacuo to give the crude material. Purification via flash chromatography (silica gel, 0-5% MeOH/DCM) affords the title intermediate (150 mg); m/z 570.4 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of 1-77 (1.0 g, 3.53 mmol) in THF (20 ml) is added 1,1'- carbonyldiimidazole (0.63 g, 3.88 mmol) at room temperature. The mixture is stirred at 50 C for 30 minutes. After this time 1-19 (1.2 g, 3.88 mmol) is added as a THF solution (15 ml) and the resulting mixture is heated at 80C for 3 hours. The mixture is cooled and treated with AcOH (8 ml) then warmed to 80C and stirred over night. After this time the reaction is cooled to room temperature, concentrated and diluted with water.Extracted the product into DCM (2x). The combined organics are washed with brine and dried (MgS04). Filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford 1-84 (1.2 g). | ||
1.2 g | To a suspension of I-77 (1.0 g, 3.53 mmol) in THF (20 ml) is added 1,1?-carbonyldiimidazole (0.63 g, 3.88 mmol) at room temperature. The mixture is stirred at 50 C. for 30 minutes. After this time I-19 (1.2 g, 3.88 mmol) is added as a THF solution (15 ml) and the resulting mixture is heated at 80 C. for 3 hours. The mixture is cooled and treated with AcOH (8 ml) then warmed to 80 C. and stirred over night. After this time the reaction is cooled to room temperature, concentrated and diluted with water. Extracted the product into DCM (2×). The combined organics are washed with brine and dried (MgSO4). Filtered and concentrated. The remaining crude is purified via flash chromatography (silica gel, 0-5% MeOH/DCM) to afford I-84 (1.2 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 214Step 1: Synthesis of 5'-(3-{ l-r4-(2-Amino-pyrimidin-5-yl)-phenyll-cyclobutyl|- r i,2,41oxadiazol-5-yl)-2,3,5,6-tetrahydro-r i,2'lbipyrazinyl-4-carboxylic acid tert-butyl ester (R81)To a suspension of R80 (490 mg, 1.59 mmol) in dioxane (10 ml) is added CDI (260 mg, 1.59 mmol) at room temperature. The mixture is stirred at 50 C for 30 minutes. After this time 1-2.5 (300 mg, 1.06 mmol) is added and the resulting mixture is heated at 80 C for 18 hours. After this time the reaction appears complete and is cooled and poured into NaHCC"3 (sat.) and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc (2x). The combined organics are dried (MgS04), filtered and concentrated to give the crude product which is purified via flash chromatography (25g silica gel, 0-8% MeOH/DCM). Product-containing fractions are combined and concentrated to give R81. (210 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Method 19: Synthesis of 5-(5-{(R)-l-Cvclopropyl-l-r5-(3,4,5,6-tetrahvdro-2H- ri,2nbipyrazinyl-5'-yl)-ri,2,41oxadiazol-3-yll-ethyl}-pyridin-2-yl)-pyrimidin-2- ylamine (Example 134) Step 1: Synthesis of 1-25A suspension of 1- 18.3 (209 mg, 0.657 mmol) and CDI (102 mgs, 06328 mmol) in 1,4- dioxane (3 mL) in a sealed tube is stirred at 55 C for one hour. A solution of 1-8.10 (225 mg, 0.598 mmol) in dioxane (3ml) is added and the reaction mixture is stirred at 120 C for 18 hours. After cooling to room temperature, the reaction mixture is poured into brine and extracted with EtOAc (4x20ml). The combined organic fractions are dried with sodium sulfate, filtered, and is concentrated in vacuo. The resdiue is purified by flash chromatography (Si02, Biotage SNAP lOOg, 0-5 MeOH/DCM) to yield 1-25 (298 mg), m/z 649 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 4: synthesis of 5-[5-(l-{5-[5-(piperazin-l-yl)pyrazin-2-yl]-l,2,4-oxadiazol-3- yl}cyclobutyl)pyridin-2-yl]pyrimidin-2-amine (Example 60).Methanol (10.0 mL) is cooled to -5 C and treated with acetyl chloride (1.00 mL). To this mixture is added R51 (0.50 g, 0.90 mmol) and the resulting mixture is stirred for 16 hours. The resulting mixture is treated with 7N ammonia in methanol until basic by pH paper and concentrated in vacuo. The resulting solid is treated with acetonitrile and diluted with water. The mixture is filtered and the filtrate is treated with saturated NaHC03 (3 mL) and the solid is collected by filtration to afford the title compound (90.00 mg). m/z 457.3 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; | 5-(4-(tert-butoxycarbonyl) piperazin-1 -yl) pyrazine-2-carboxylic acid (200 mg, 0.65 mmol), tert-butyl 2-amino-4-(thiophen-2-yl) phenylcarbamate (157 mg, 0.54 mmol) and EDCI (311 mg, 1.62 mmol) were added into Py (5 ml). The mixture was stirred at room temperature for overnight. When the reaction finished, it was concentrated and washed with Et20. The yellow solid was collected as product (310 mg, 65% yield). |
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