Structure of 4331-28-6
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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. : | 4331-28-6 |
Formula : | C3H6ClN3 |
M.W : | 119.55 |
SMILES Code : | NC1=CNN=C1.[H]Cl |
MDL No. : | MFCD01693708 |
InChI Key : | KZDSLIPVDTVHLL-UHFFFAOYSA-N |
Pubchem ID : | 78034 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 29.96 |
TPSA ? Topological Polar Surface Area: Calculated from |
54.7 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.29 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.8 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.68 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.08 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.93 |
Solubility | 14.1 mg/ml ; 0.118 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.4 |
Solubility | 47.7 mg/ml ; 0.399 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.76 |
Solubility | 20.6 mg/ml ; 0.173 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 |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
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 |
-7.24 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 |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.3 |
* 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 |
---|---|---|
26.6 mg | With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; In tetrahydrofuran; tert-butyl alcohol; at 140.0℃; for 2h;Inert atmosphere; | A solution of 5-(2-chloropyridin-4-yl)-2-cyclopropylmethoxybenzonitrile (0.25 g, 0.0878 mmol) in t-butanol (5 ml) is degassed with nitrogen for 5 min. 1H-Pyrazol-4-ylamine hydrochloride (0.12 g, 1.08 mmol), Josiphos (24.3 mg, 0.00439 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40.0 mg, 0.00439 mmol) is then added. A solution of 1.6M lithium bis(trimethylsilyl)amide in THF (0.35 g, 2.1 mmol) is added dropwise. The mixture is irradiated in the microwave at 140 C. for 2 h. 30 ml of water are then added, and the mixture is filtered. The crude product is purified by chromatography, giving 26.6 mg of the desired product as brown solid; [0540] 1H NMR (400 MHz, DMSO-d6): delta [ppm] 12.47 (bs, 1H), 8.80 (s, 1H), 8.13 (d, J=5.36 Hz, 1H), 8.04 (d, J=2.16 Hz, 1H), 7.92 (dd, J=2.24, 8.82 Hz, 2H), 7.54 (bs, 1H), 7.34 (d, J=8.92 Hz, 1H), 6.92 (d, J=5.28 Hz, 1H), 6.86 (s, 1H), 4.06 (d, J=7.00 Hz, 2H), 1.23-1.30 (m, 1H), 0.59-0.63 (m, 2H), 0.31-0.39 (m, 2H); [0541] LCMS: (method A) 332 (M+H), RT. 3.25 min; [0542] HPLC: (method A) RT. 3.23 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylsilane; Pd/Al2O3; In ethanol; water; at 15.0℃; for 73h;Inert atmosphere; | A 1000-mL, multi-neck cylindrical jacketed reactor, fitted with a mechanical stirrer, temperature probe and nitrogen inlet, was charged with 4-nitropyrazole (50.0 g, 429 mmol) and palladium on alumina (5 wt %, 2.5 g). Ethanol (150 mL) was added, followed by a slow addition of concentrated hydrochloric acid (37 wt %, 180 mL). The reaction was cooled to 15 C., and triethylsilane (171 mL, 1072 mmol) was added slowly via addition funnel over 1 hour, while maintaining the internal temperature at 15 C. The reaction was stirred at 15 C. for 72 hours, after which the reaction mixture was filtered through a Celite pad and the pad was rinsed with warm ethanol (40 C., 2×100 mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to 100 mL. Acetonitrile (200 mL) was added and the resulting suspension was stirred at 20 C. for 1 hour and filtered. The filter cake was rinsed with acetonitrile (2×100 mL) and dried under vacuum at 20 C. to afford a white solid (10:1 mixture of 1a and 1H-pyrazol-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-d6) delta 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m/z 117 ([M]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In N,N-dimethyl-formamide; at 95℃; for 18h; | 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (22.1 g, 80 mmol) and 1H-pyrazol-4-aminehydrochloride (10.0 g, 84 mmol) were combined in DMF (398 mL). Triethylamine (33.3 mL, 239mmol) was added and the mixture was heated to 95 °C for 18 h. The reaction mixture was thencooled to ambient temperature and concentrated under reduced pressure. The residue was suspendedin water (300 mL) and sonicated and filtered. Trituration in ether provided 6-bromo-N-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (19.3 g, 68.9 mmol, 87percent); 1H NMR (400MHz, DMSO-d6) delta 12.67 (s, 1H), 10.65 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 2.75h; | To a mixture of (R)-2-(methylcarbamoyl)-6-(1-phenylethyl)isonicotinic acid (53.7 mg, 0.19 mmol),HATU (86.7 mg, 0.23 mmol) and 1H-pyrazol-4-amine, hydrochloride (28.9 mg, 0.24 mmol) in DMF (1mL) was added DIPEA (0.132 mL, 0.76 mmol). The resulting dark grey solution was stirred at rt for2.75 h. The reaction mixture was diluted with DMSO (2 mL) and directly purified by MDAP (3 mLinjection, high pH). The required fractions (fractions 1 and 2) were combined and evaporated in vacuoto give the desired product as a light yellow solid - (R)-N2-methyl-6-(1-phenylethyl)-N4-(1H-pyrazol-4-yl)pyridine-2,4-dicarboxamide (39.9 mg, 0.11 mmol, 61 % yield)LCMS (2 mm High pH): Rt = 0.92 mi [MH]+ = 350.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | 2-(Methoxy(phenyl)methyl)-6-(methylcarbamoyl)isonicotinic acid (150 mg, 0.50 mmol) was added to a dry flask. DMF (2 mL) was added, followed by HATU (228 mg, 0.60 mmol) and 1H-pyrazol-4-amine, hydrochloride (59.7 mg, 0.50 mmol). The reaction was stirred for 2 mm and then DIPEA (0.262 mL,1.498 mmol) was added. The reaction was stirred at rt for 30 mm. The reaction mixture was added directly to 3 x LCMS vials, diluting with DMS0/Me0H and purified by 3 x MDAP (High pH). Theappropriate fractions were concentrated in vacuoto afford the desired product as a yellow solid - (+1- )-6-(methoxy(phenyl)methyl)-N2-methyl-N4-( 1 H-pyrazol-4-yl)pyridine-2,4-dicarboxamide (100 mg, 0.27 mmol, 55 % yield)LCMS (2 mm Formic): Rt = 0.82 mi [MH]+ = 366.3.1H NMR (400 MHz, DMS0-d6) O ppm 12.69 (br. s., 1 H) 10.92 (5, 1 H), 8.67 (q, J=4.8 Hz, 1H), 8.45 (d, J=1.7 Hz, 1 H), 8.17 (d, J=1.5 Hz, 1 H), 8.04 (br. 5., 1 H), 7.72 (br. 5., 1 H), 7.51 (d, J=7.1 Hz, 2 H), 7.36 (t, J=7.5 Hz, 2 H), 7.24 - 7.31 (m, 1 H), 5.52 (5, 1 H), 3.39 (5, 3 H), 2.88 (d, J=4.9 Hz, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 3.5h; | To a mixture of 2-benzyl-6-(methylcarbamoyl)isonicotinic acid (251.8 mg, 0.93 mmol) and HATU(565.5 mg, 1.49 mmol) was added <strong>[4331-28-6]1H-pyrazol-4-amine hydrochloride</strong> (166.0 mg, 1.39 mmol) andDMF (4 mL). DIPEA (0.570 mL, 3.26 mmol) was added and the mixture was stirred at rt for 3.5 h.The mixture was concentrated under a stream of nitrogen and then diluted with acetonitrile to a totalvolume of 5 mL and directly purified by MDAP (5 x 1 mL injection; high pH) and the required fractions(fraction 1 from each run) were evaporated under a stream of nitrogen. The residues were eachredissolved in methanol ( 5 mL), combined into a tarred vial and the solvent evaporated under a stream of nitrogen to give a pale yellow solid - 6-benzyl-N2-methyl-N4-(1H-pyrazol-4-yl)pyridine-2,4- dicarboxamide (198.9 mg, 0.59 mmol, 64 % yield)LCMS (2 mm High pH): Rt = 0.85 mi [MH]+ = 336.1.1H NMR (400 MHz, DMSO-d6) O ppm 12.71 (br. 5., 1 H), 10.88 (s, 1 H), 8.78 (q, J=4.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1 H), 8.02 (br. 5., 1 H), 7.90 (d, J=1.5 Hz, 1 H), 7.70 (br. 5., 1 H), 7.36 - 7.41 (m, 2 H), 7.29 - 7.36 (m, 2 H), 7.19 - 7.26 (m, 1 H), 4.25 (s, 2 H), 2.88 (d, J=4.9 Hz, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate; In N,N-dimethyl-formamide; at 20.0℃; for 2h; | To a mixture of (S)-2-(methylcarbamoyl)-6-(1-phenylethyl)isonicotinic acid (80.5 mg, 0.28 mmol) and HATU (172.0 mg, 0.45 mmol) was added <strong>[4331-28-6]1H-pyrazol-4-amine hydrochloride</strong> (51.6 mg, 0.43 mmol) and DMF (1.8 mL). DIPEA (0.173 mL, 0.99 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was concentrated under a stream of nitrogen and diluted with acetonitrile to a total volume of 2 mL and directly purified by MDAP (2 x 1 mL injection; formic) and the required fractions (fraction 1 from both runs) were combined and evaporated in vacuo. The residue was redissolved inmethanol ( 6 mL) and transferred to a tarred vial, the solvent evaporated under a stream of nitrogen and the residue dried in vacuo to give the desired product as a yellow solid, (S)-N2-methyl-6-(1- phenylethyl)-N4-( 1 H-pyrazol-4-yl)pyridine-2,4-d icarboxamide (87.5 mg, 0.25 mmol, 88 % yield)LCMS (2 mm Formic): Rt = 0.91 mi [MH]+ = 350.3.1H NMR (400 MHz, DMSO-d6) O ppm 10.87 (5, 1 H) 8.80 (d, J=4.2 Hz, 1 H), 8.38 (5, 1 H) 7.80 - 7.96(m, 3 H), 7.43 (d, J=7.6 Hz, 2 H), 7.31 (t, J=7.2 Hz, 2 H), 7.13 - 7.25 (m, 1 H), 4.45 (q, J=6.6 Hz, 2 H), 2.91 (d, J=3.9 Hz, 3 H), 1.74 (d, J=6.8 Hz, 3 H) |
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