Structure of 663193-80-4
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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. : | 663193-80-4 |
Formula : | C4H3BrClN3 |
M.W : | 208.44 |
SMILES Code : | NC1=NC=NC(=C1Br)Cl |
MDL No. : | MFCD09999224 |
InChI Key : | DQSBRYJETNYGCI-UHFFFAOYSA-N |
Pubchem ID : | 45789713 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 39.15 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.8 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.45 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.51 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.48 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.78 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.67 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.58 |
Solubility | 0.552 mg/ml ; 0.00265 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.21 |
Solubility | 1.3 mg/ml ; 0.00622 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.77 |
Solubility | 0.356 mg/ml ; 0.00171 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 |
-6.5 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 |
1.0 |
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) |
1.76 |
* 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 potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃; | Intermediate (138.1 ): [1-(6-Amino-5-bromo^yrimidin-4-yl)-piperidin-4-yl]-(4-chloro- phenyl)-methanoneThe mixture of 5-bromo-6-chloro-pyrimidine-4-ylamine (2.0 g, 9.59 mmol, 1 .0 eq), 4- chlorophenyl-piperidin-4-yl-methanone (2.36 g, 10.55 mmol, 1 .10 eq) and potassium carbonate (6.63 g, 47.97 mmol, 5.0 eq) in DMF (5 ml_) was stirred at 50 C overnight. After pouring the reaction mixture to water, the precipitate was collected to give Intermediate (138.1 ). LC-MS (M+1 : 396, obsd: 396). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; | N-[3-Amino-1 -(6-amino-5-bromo-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl1-2,4-difluoro- benzamide ("195")A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (272.7 mg; 1 .24 mmol; 1 .02 eq.), N- [(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamide dihydrochloride (400.0 mg; 1 .22 mmol; 1 .0 eq.), potassium carbonate (336.8 mg; 2.44 mmol; 2.0 eq.) in DMSO (5.00 ml) was stirred at 60 C overnight. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, basic condition) to afford the title compound in 76% yield. LC-MS: (M+1 =427, obsd. = 427). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 8.0h; | A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (51 .6 mg; 0.24 mmol, 1 .0 eq.), intermediate (1 .1 ) (1 00.0 mg; 0.24 mmol, 1 .0 eq.) and potassium carbonate (97.5 mg; 0.7 mmol; 3.0 eq.) in DMSO (2.00 ml) was heated at 60 C for 8h. The reaction mixture was purified by pre-HPLC (Waters, basic condition) to afford the title compound as white solid in 70% yield. LC-MS: (M+1 =445, obsd. = 445). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 14.0h; | A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (317.78 mg; 1 .45 mmol; 1 .00 eq.), Intermediate (51 .2) (500.00 mg; 1 .45 mmol; 1 .00 eq.) and potassium carbonate (600.48 mg; 4.34 mmol; 3.00 eq.) in DMSO (5.00 m) was heated at 60 C for 14h. The reaction mixture was purified by pre-HPLC (Waters, basic condition) to afford the title compound. LC-MS: (M+1 =444, obsd. = 444). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80.0℃; | 6-(4-(1 -(2-(azetidin-1 -vnethvn-4-(2-(trifluoromethyl)Dyridin-4-yl)-1 H-imidazol-2- yl)piperidin-1 -yl)-5-bromopyrimidin-4-amine ("126")A reaction mixture of 5-Bromo-6-chloro-pyrimidin-4-ylamine (53.00 mg; 0.25 mmol; 1 .00 eq.), 4-[1 -(2-azetidin-1 -yl-ethyl)-2-piperidin-4-yl-1 H-imidazol-4-yl]-2- trifluoromethyl-pyridine hydrochloride (4) (133.56 mg; 0.25 mmol; 1 .00 eq.), and ethyl-diisopropyl-amine (0.23 ml; 1 .27 mmol; 5.00 eq.) in ACN 3ml was stirred at 80C for overnight. Purified by HPLC(basic), collected title compound, 30mg, yield, 21 %. LC-MS: (M+1 = 551 , obsd. = 551 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.9% | With caesium carbonate; In dimethyl sulfoxide; at 100.0℃; | Step 3: 2-(2-(1-(6-amino-5-bromopyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3- methylphenyl)- 1 H-imidazol- 1 -yl)ethanolA reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (370.00 mg; 1 .78 mmol; 1 .00 eq.), 2-[4-(4-fluoro-3-methyl-phenyl)-2-piperidin-4-yl-imidazol-1 -yl]-ethanol hydrochloride (3) (732.67 mg; 1 .78 mmol; 1 .00 eq.), and Cs2C03 (2313.40 mg; 7.1 0 mmol; 4.00 eq.) in DMSO 10ml, stirred at 1 00C for overnight, cooled, poured into water 60ml, stirred for 15mins, filtered, collected light yellow solid, which was washed with water, dried, got title compound , 750mg, 88.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; | 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1 -methyl-1 H-imidazol-2-yll-piperidin- 1 -yl)-pyrimidin-4-ylamine ("1 ")A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (357.2 mg; 1 .71 mmol; 1 .02 eq.), 4-[4- (4-fluoro-3-trifluoromethyl-phenyl)-1 -methyl-1 h-imidazol-2-yl]-piperidine (550.00 mg; 1 .68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36 mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60 C overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 86% yield. LC-MS: (M+1 =499, obsd. = 499). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; cesium fluoride; In tert-butyl alcohol; at 140.0℃; for 40.0h;Sealed tube; | (S)-2-(1 -Aminoethyl)-5-methyl-3-phenylpyrrolo[2, 1 -f{ ,2,4]triazin-4(3H)-one(300 mg, 1.12 mmol) was treated <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (373 mg, 1.79 mmol), cesium fluoride (340 mg, 2.24 mmol), Lambda/,/V-diisopropylethylamine (0.974 ml_, 5.59 mol) according to Preparation 13. The residue was purified using SP1Purification System (0% to 10%, dichloromethane-methanol) to give 0.26 g (60% yield) of the title compound as a solid. Purity 98%.LRMS (m/z): 440, 442 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; cesium fluoride; In tert-butyl alcohol; at 140.0℃; for 40.0h;Sealed tube; | (S)-2-(1 -Aminoethyl)-3-phenyl-5-(phenylthio)pyrrolo[2 -/][1 2 4]triazin-4(3H)-one (142 mg, 0.39 mmol) was treated with treated <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (245 mg, 1 .18 mmol), cesium fluoride (178 mg, 1 .17 mmol), /V,/V-diisopropylethylamine (341 muIota, 1 .96 mol) according to Preparation 13 to give 0.23 g (75% yield) of the title compound as a solid.LRMS (m/z): 534, 536 (M+1 )+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 120.0℃; | The reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (215.00 mg; 1.03 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine tetrahydrochloride (503.6 mg; 1.03 mmol; 1 eq.), and Cs2CO3 (1344.27 mg; 4.13 mmol; 4 eq.) in DMSO (1.5 ml) was stirred at 120 C. overnight. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration to yield the title compound as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 mg | With tris-(2-carboxyethyl)-phosphine hydrochloride; sodium hydroxide; In N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; | (0190) Compound 15. The disulfide, Intermediate 4, from above (111 mg, 0.169 mmol) was mixed with tris-2-carboxyethylphosphine hydrochloride (53 mg, 0.185 mmol) and DMF (2 mL), 1 M NaOH (0.88 mL, 0.88 mmol), and <strong>[663193-80-4]4-amino-5-bromo-6-chloro-pyrimidine</strong> (70 mg, 0.336 mmol) were added. The reaction was allowed to stir at RT overnight, whereupon it was flooded with 50 mL EtOAc, rinsed with 2x25 mL water, 25 mL brine, dried over sodium sulfate, filtered, evaporated to dryness, and purified by reverse phase HPLC to yield Compound 15 (31 mg) as a white solid. ES (+) MS m/e = 504 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.144 g | With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 144.0h;Reflux; | Example 48 5-bromo-4-N-{1-[3-(pyridin-2-yl)indolizin-2-yl]ethyl}pyrimidine-4,6-diamine Prepared similarly to Example 47, starting from 1-[3-(pyridin-2-yl)indolizin-2-yl]ethan-1-amine Q2 (0.171 g, 0.72 mmol) and <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (0.150 g, 0.72 mmol), heating to reflux for 6 days, and purified by flash chromatography on 28 g Biotage silica-NH SNAP cartridge (DCM to DCM:MeOH=99.5:0.5) followed by flash chromatography on Biotage silica-NH SNAP cartridge (cyclohexane:EtOAc=90:10 to 80:20) to afford title compound as a white solid (0.144 g). MS/ESI+ 408.9-410.9 [MH]+, Rt 0.63 min (Method A). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.73-7.77 (m, 1H), 8.67 (d, 1H), 7.92 (td, 1H), 7.82 (s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.32-7.37 (m, 1H), 6.77-6.86 (m, 2H), 6.68 (s, 1H), 6.57-6.64 (m, 1H), 6.43 (br. s., 2H), 5.58-5.68 (m, 1H), 1.40 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 135.0℃; for 2.0h;Microwave irradiation; | Example 14 4-Amino-5,7-dihydrofuro[3,4-d]pyrimidine To a mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (15 mg, 0.070 mmol), tributyl[tributylstannyl)methoxy]methyl}stannane according to Production Example 1-1 (53 mg, 0.084 mmol), tris(dibenzylideneacetone)dipalladium (6.4 mg, 0.0070 mmol), and X-Phos (13 mg, 0.028 mmol), 1,4-dioxane (0.7 mL) was added, and the resulting mixture was stirred at 135 C. for 2 hours under microwave irradiation. The resulting mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (2.4 mg, 25% yield). MS(ESI)m/z 138(MH)+ |
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