Structure of 1421252-90-5
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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. : | 1421252-90-5 |
Formula : | C22H27BN2O4S |
M.W : | 426.34 |
SMILES Code : | O=S(N1N=C(C)C2=C1C=CC(C)=C2B3OC(C)(C)C(C)(C)O3)(C4=CC=C(C)C=C4)=O |
MDL No. : | MFCD28130306 |
InChI Key : | GSMMFVZBZKAEIG-UHFFFAOYSA-N |
Pubchem ID : | 71240658 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 30 |
Num. arom. heavy atoms | 15 |
Fraction Csp3 | 0.41 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 120.18 |
TPSA ? Topological Polar Surface Area: Calculated from |
78.8 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 |
4.91 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.58 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.47 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.77 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-5.75 |
Solubility | 0.000761 mg/ml ; 0.00000178 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-6.3 |
Solubility | 0.000213 mg/ml ; 0.0000005 mol/l |
Class? Solubility class: Log S scale |
Poorly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-7.19 |
Solubility | 0.0000277 mg/ml ; 0.000000065 mol/l |
Class? Solubility class: Log S scale |
Poorly 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) |
Yes |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.41 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 |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
4.12 |
* 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 |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 140.0℃; for 0.5h;Microwave irradiation; | 19-F. 2-(3,5-Dimethyl-lH-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-4-((3-e«A mixture of 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-((3-e«i o)-3-methoxy-8-azabicyclo[3.2.1]octan- 8-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (26 mg, 0.06 mmol), 3,5-dimethyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-indazole (25 mg, 0.06 mmol), Pd(PPh3)4 (7.0 mg, 0.006 mmol), and Na2C03 (2 M, 0.09 mL, 0.18 mmol) in DME (2 mL) was heated in a microwave reactor at 140 C for 30 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel chromatography (20-100%EtO Ac/heptane) to provide 2-(3 ,5-dimethyl- 1 -tosyl-1 H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-4- ((3-e« o)-3-methoxy-8-azabicyclo[3.2.1]octan-8-yl)-5,6,7,8-te1xahydropyrido[4,3-d]pyrimidine, which was used in the next step without further purification. MS (ESI+) m/z 705.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100.0℃; for 16.0h;Inert atmosphere; | 55-B. (l?)-6-Benzyl-2-(3,5-dimethyl-l-tosyl-l -indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-l- yl)-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidineTo a solution of (R)-6-benzyl-2-chloro-4-(4-methoxy-3,3-dimethylpiperidin-l-yl)-5, 6,7,8- tetrahydropyrido[4,3-d]pyrimidine (5.04 g, 12.6 mmol) in 1,4-dioxane (100 mL) was added 3,5-dimethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l//-indazole, Example 3, (6.16 g, 12.6 mmol), Pd(Ph3P)4 (2.18 g, 1.89 mmol) and a 2 M solution of sodium carbonate (18.9 mL, 37.7 mmol). The reaction mixture was heated at 100 C under a nitrogen atmosphere for 16 h. The reaction mixture was then allowed to cool to rt and was diluted with EtOAc and water. The layers were mixed and then separated. The organic layer was washed with water and then brine. The separated organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was then purified via FCC (0-70%> EtOAc/heptane) to give the title compound. MS (ESI+) m/z 665.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-tri-isopropyl-1,1?-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether; In dimethyl sulfoxide; at 110.0℃; for 1.16667h; | Example 33,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-indazole.A solution of l-(2-chloro-6-fluoro-3-methylphenyl)ethanone (10 g, 53.6 mmol) and hydrazine (5.05 mL, 161 mmol) in DMSO (50 mL) was heated at 80 C overnight. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04) and concentrated to provide crude 4-chloro-3, 5 -dimethyl- 1H- indazole as a white solid, which was used in the next step directly. MS (ESI+) m/z 180.9 (M+H)+.NaH (60% dispersion in mineral oil, 3.87 g, 97 mmol) was added portion wise to a solution of crude 4- chloro-3,5-dimethyl-lH-indazole (9.7 g, 53.7 mmol) in THF (200 mL) at -20 C. The mixture was allowed to warm to 0 C and stir for 20 min, then TsCl (14.33 g, 75 mmol) was added. The reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was cooled to -20 C and sat. NH4CI aqueous solution was added to quench excess base. The resulting mixture was extracted with CH2C12 (2X). The combined organics were washed with brine, dried (Na2S04) and concentrated. The residue was triturated with EtOAc and filtered to provide 4-chloro-3,5-dimethyl-l-tosyl-lH-indazole. LH NMR (400 MHz, CDC13) delta ppm 7.98 (d, J=8.34 Hz, 1 H) 7.84 (m, J=8.34 Hz, 2 H) 7.39 (d, J=8.59 Hz, 1 H) 7.25 (m, J=7.83 Hz, 2 H) 2.73 (s, 3 H) 2.46 (s, 3 H) 2.38 (s, 3 H); MS (ESI+) m/z 334.7 (M+H)+. A mixture of 4-chloro-3, 5 -dimethyl- 1-tosyl-lH-indazole (1.5 g, 4.48 mmol), dioxaborolane (3.41 g, 13.44 mmol), S-Phos palladacycle (CAS: 1028206-58-7, 0.151 g, 0.224 mmol), and K3P04 (2.85 g, 13.44 mmol) in DMSO (20 mL) was heated at 110 C for 70 min. The reaction mixture was then partitioned between DCM and water. The aqueous layer was extracted with DCM (2X). The combined organics were washed with brine, dried (Na2S04) and concentrated. The residue was purified by FCC (0-30%EtO Ac/heptanes) to provide 3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH- indazole. lU NMR (400 MHz, CDC13) delta ppm 8.09 (d, J=8.59 Hz, 1 H) 7.78 (m, J=8.34 Hz, 2 H) 7.35 (d,J=8.84 Hz, 1 H) 7.19 (m, J=8.08 Hz, 2 H) 2.59 (s, 3 H) 2.54 (s, 3 H) 2.35 (s, 3 H) 1.44 (s, 12 H); (ESI+) m/z 426.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 3-chloro-benzenecarboperoxoic acid; In ethanol; water; at 20.0℃; for 3.0h; | To a solution of <strong>[1421252-90-5]3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole</strong> (73) (450 mg, 1.1 mmol) in EtOH (12 mL) was added mCPBA (273 mg, 1.6 mmol) and water (6 mL). The reaction was stirred at 20 C. for 3 hours. LCMS analysis showed the reaction was finished. The crude reaction mixture was diluted with EtOAc (30 mL), washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified over silica gel which was eluted with 0-90% EtOAc/petroleum ether and gave 3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-ol (74) as a yellow solid (370 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6) delta 9.45 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.30 (d, J=8.4 Hz, 1H), 2.53 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H). LCMS (ESI) m/z 317 (M+H). |
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