Structure of 53332-78-8
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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. : | 53332-78-8 |
Formula : | C4H8Cl2N2S |
M.W : | 187.09 |
SMILES Code : | Cl.Cl.NCC1=NC=CS1 |
MDL No. : | MFCD09817422 |
InChI Key : | SXOAJLQMTFZXKM-UHFFFAOYSA-N |
Pubchem ID : | 44890709 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 43.72 |
TPSA ? Topological Polar Surface Area: Calculated from |
67.15 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 |
1.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.05 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.09 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.77 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.04 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.26 |
Solubility | 1.03 mg/ml ; 0.00551 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.47 |
Solubility | 0.64 mg/ml ; 0.00342 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.28 |
Solubility | 9.75 mg/ml ; 0.0521 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 |
-6.41 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 |
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) |
2.26 |
* 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 |
---|---|---|
A mixture of 5-bromo-3-(pyrrolidin-l-ylsulfonyl)-lH-indole-2-carboxylic acid (37 mg,0.1 mmol), PS-DCC (170 mg, 0.20 mmol) and EtaOBt (14 mg, 0.1 mmol), (l,3-thiazol-2-ylmethyl)amine (dihydrochloride salt, 39 mg, 0.2 mmol), and DIEA (100 uL) in TEtaF/DCM (1:1, 2 mL) was shaken for 16 hours at room temperature. After this time, the resin was filtered and washed with DCM/MeOEta (1:1, 4 x 1.5 mL). The combined organic solution was concentrated and the residue was purified by LCMS to give the title product (TFA salt) as slightly yellow solidAnalytical LCMS: single peak (214 nm), 3.254 min, ES MS (M+l) = 469; lEta NuMR (500 MHz, d6-DMSO) delta 13.02 (br, IH), 9.61 (t, J= 6.1 Hz, IH),8.12 (d, J= 1.8 Hz, IH), 7.77 (d, J= 3.2 Hz, IH), 7.70 (d, J= 3.2 Hz, IH), 7.53 (d, J= 8.7 Hz, IH), 7.48 (dd, J= 8.7, 1.8 Hz, IH), 4.88 (d, J= 6.1 Hz, IH ), 3.16-3.12 (m, 4H), 1.67-1.63 (m, 4H); HRMS, calc'd for Ci7HisBrNu4theta3S2 (M+H), 468.9998; found 469.0015. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In NMP (1-methylpyrrolidin-2-one); at 180℃; for 1.5h; | Example 6 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide (Compound 6-1) N-Methyl-2-pyrrolidinone (13.3 ml) was added to N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide (627 mg, 1.33 mmol) and 2-aminomethylthiazole dichloride (1004 mg, 6.66 mmol) in a vial. Triethylamine (1.86 mL, 13.3 mmol) was added and the vial was sealed, the resulting solution was heated to 180 C. with stirring. After 1.5 h., the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was purified by preparative HPLC Reverse phase (C-18), eluding with Acetonitrile/Water+0.05% TFA, to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) delta 9.22 (d, 1H); 8.54 (d, 1H); 8.48 (s, 1H); 8.16 (m, 3H); 7.81 (d, 1H); 7.78 (dd, 1H); 7.71 (d, 1H); 7.63 (d, 1H); 7.41 (d, 1H); 7.33 (d, 1H); 4.67 (s, 2H); 4.43 (d, 2H); 3.88 (s, 3H). LRMS (APCI) calculated for C24H19N5O3S [M+H]+, 478.1; found 478.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With triethylamine; at 20℃; | To 2-thiazole methylamine dihydrochloride(1.0 g, 5.4 mmol) were added ethyl formate (5 mL) and Et3N (1.7 mL,11.2 mmol). The mixture was stirred at rt for overnight.The mixture was diluted by EA, washed by 10% citric acid, extracted by EA (5x25 mL), dried over Na2SO4,and concentrated under reduced pressure to get 2-(isocyanomethyl)thiazoleas dark oil (180 mg, 1.3 mmol, 24% yield), which was used directly for nextstep.2-(isocyanomethyl)thiazole (180 mg, 1.3mmol) in 2 mL of anhydrous DCM was added by NMM (343 muL, 3.1 mmol). Whenthe mixture was cooled to -45 oC, triphosgene (140 mg, 0.47 mmol) in2 mL of anhydrous DCM was added dropwise. Then the temperature was slowlywarmed up to rt over 1 h. The mixture was quenched carefully by adding it to 2M of Na2CO3 under 0 oC and organic layer wascollected, dried and purified by silica gel chromatography (PE/DCM = 1/1) togive the product as reddish oil (100 mg, 62% yield). |
24% | With triethylamine; at 22℃; | To 2-thiazole methylamine dihydrochloride (1.0 g, 5.4 mmol) were added ethyl formate (5 mL) and Et3N (1.7 mL, 11.2 mmol). The mixture was stirred at rt for overnight. The mixture was diluted by EA, washed by 10% citric acid, extracted by EA (5*25 mL), dried over Na2SO4, and concentrated under reduced pressure to get 2-(isocyanomethyl)thiazole as dark oil (180 mg, 1.3 mmol, 24% yield), which was used directly for next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In 1,4-dioxane; at 25℃;Inert atmosphere; | General procedure: Example 7. General Procedure G A mixture of the desired chlorotriazolopyrimidines i-G (1 equiv), desired aminomethyl heterocycle or benzylamine ii-G (1.2 equiv), and triethylamine (NEt3) (1.5- 3.5 equiv) in 1,4-dioxane (~0.2 M) was stirred at room temperature until the reaction was complete by LC-MS and/or TLC analysis. The crude reaction mixture was directly purified by silica gel chromatography (typical eluents included either a mixture of hexanes and EtOAc or a mixture of CH2Cl2 and MeOH or an 80:18:2 mixture of CH2Cl2/CH3OH/concentrated NH4OH) to afford the desired product iii-G. The product structures prepared according to General Procedure G were confirmed by 1H NMR and/or by mass analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine; In 1,4-dioxane; at 70℃;Inert atmosphere; | General procedure: Example 8. General Procedure H A mixture of the desired chloroimidazopyrimidines i-H (1 equiv), desired aminomethyl heterocycle or benzylamine ii-H (1.2 equiv), and triethylamine (NEt3) (1.5-3.5 equiv) in 1,4-dioxane (~0.1 M) was stirred at 70 C until the reaction was complete by LC-MS and/or TLC analysis. The crude reaction mixture was directly purified by silica gel chromatography (typical eluents included, for example, a mixture of hexanes and EtOAc, or a mixture of CH2Cl2 and MeOH, or an 80:18:2 mixture of CH2Cl2/CH3OH/concentrated NH4OH) to afford the desired product iii-H. The product structures prepared according to General Procedure H were confirmed by 1H NMR and/or by mass analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In 1,4-dioxane; at 75℃;Inert atmosphere; | Example 19.2-Chloro-7-methyl-N-(thiazol-2-ylmethyl)-7H-purin-6-amine A mixture of 2,6-dichloro-7-methyl-7H-purine (60 mg, 0.30 mmol), thiazol-2- ylmethanamine dihydrochloride (67 mg, 0.36 mmol) and triethylamine (0.15 mL, 1.05 mmol) in 1,4-dioxane (2 mL) was stirred at 75 C overnight. After this time the mixture was concentrated and the residue purified by column chromatography (silica gel, 0-6% MeOH in CH2Cl2) to afford the title compound as a white solid (48 mg, 58%): ESI MS (M+H) m/z 281; 1H NMR (300 MHz, DMSO-d6) G 8.27 (br s, 2H), 7.75 (d, J = 3.3 Hz, 1H), 7.63 (d, J = 3.3 Hz, 1H), 4.95 (d, J = 5.7 Hz, 2H), 4.03 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine; In dimethyl sulfoxide; at 60℃; for 2h;Inert atmosphere; | Example 24.2-Chloro-7-methyl-8-propoxy-N-(thiazol-2-ylmethyl)-7H-purin-6- amine A mixture of 2,6-dichloro-7-methyl-8-propoxy-7H-purine (28 mg, 0.11 mmol), <strong>[53332-78-8]thiazol-2-ylmethanamine dihydrochloride</strong> (70 mg, 0.37 mmol) and triethylamine (0.16 mL, 1.14 mmol) in DMSO (1.5 mL) was stirred at 60 C for 2 h. After this time the mixture was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layer was concentrated and the resulting residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to provide 2-chloro-7-methyl- 8-propoxy-N-(thiazol-2-ylmethyl)-7H-purin-6-amine (21 mg, 56%): ESI MS (M+H) 339; 1H NMR (500 MHz, DMSO-d6) G 7.93 (s, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.61 (d, J = 3.3 Hz, 1H), 4.90 (s, 2H), 4.44 (t, J = 6.5 Hz, 2H), 3.73 (s, 3H), 1.84-1.76 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 50℃; for 2h;Inert atmosphere; | Step 1.2-Bromo-5-chloro-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine A mixture of 2-bromo-5,7-dichlorothiazolo[5,4-d]pyrimidine (50 mg, 0.18 mmol), <strong>[53332-78-8]thiazol-2-ylmethanamine dihydrochloride</strong> (100 mg, 0.53 mmol) and triethylamine (0.23 mL, 1.65 mmol) in DMSO (3 mL) was stirred at 50 C for 2 h. After this time the mixture was cooled to room temperature, diluted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain 2-bromo-5-chloro-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine (69 mg), which was used in the next step without further purification: ESI MS (M+H) 362; 1H NMR (500 MHz, DMSO-d6) G 9.65 (t, J = 5.8 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.93 (d, J = 6.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; at 25℃;Alkaline conditions; Inert atmosphere; | Step 3a.8-bromo-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-N-(thiazol-2-ylmethyl)-9H- purin-6-amine 8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1 equiv), 2- (aminomethyl)thiazole dihydrochloride (1.1 equiv) and triethylamine or DIPEA (3 equiv) in 1,4-dioxane (~0.4 M) were stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography (EtOAc/hexanes) to afford the title compound (iv-D(a)) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) G 9.29 (s, 1H), 7.73 (d, J = 3.5 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H), 5.58 (dd, J = 11.0, 2.0 Hz, 1H), 4.89 (d, J = 6.0 Hz, 2H), 4.06 (s, 1H), 3.66 (td, J = 11.5, 3.5 Hz, 1H), 2.87-2.78 (m, 1H), 2.00 (s, 1H), 1.90-1.85 (m, 1H), 1.74-1.55 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 125℃; for 3h;Sealed tube; Inert atmosphere; | Example 16.6-Chloro-N-(thiazol-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine A mixture of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (53.6 mg, 0.284 mmol), <strong>[53332-78-8]2-(aminomethyl)thiazole dihydrochloride</strong> (75.4 mg, 0.403 mmol) and DIPEA (0.30 mL, 1.72 mmol) in 1,4-dioxane (1.2 mL) was heated in a sealed tube at 125 C for 3 h, then cooled to room temperature. The solvents were removed by rotary evaporation, and the crude residue was purified by chromatography on silica gel (gradient 0-10% MeOH in dichloromethane). The product isolated from chromatography was dissolved in acetonitrile/water, frozen and lyophilized, then dried under vacuum at 75 C for 16 h to afford the title compound (45.5 mg, 60%) as an off-white solid: ESI MS [M+H]+ m/z 267; 1H NMR (300 MHz, DMSO-d6) G 13.63 (br s, 1H), 9.52 (t, J = 5.9 Hz, 1H), 8.17 (s, 1H), 7.77 (d, J = 3.2 Hz, 1H), 7.66 (d, J = 3.3 Hz, 1H), 4.98 (d, J = 6.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22 mg | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 25℃; for 16.5h;Inert atmosphere; | Step 2.5-(methylthio)-N-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7- amine A mixture of crude 5-(methylthio)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl trifluoromethanesulfonate (130 mg, 0.43 mmol), <strong>[53332-78-8]2-(aminomethyl)thiazole dihydrochloride</strong> (99 mg, 0.529 mmol) and DIPEA (0.33 mL, 1.89 mmol) in 1,4-dioxane (2.0 mL) was stirred at room temperature 16.5 h. All volatiles were removed by rotary evaporation, and the crude residue was purified by chromatography on silica gel (gradient 0-20% methanol in DCM) to afford the title compound (22 mg, 18% over 2 steps) as an off-white solid: ESI MS m/z 280 [M + H]+; 1H NMR (500 MHz, DMSO-d6) G 9.99 (t, J = 6.0 Hz, 1H), 8.45 (s, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 3.3 Hz, 1H), 4.97 (d, J = 6.1 Hz, 2H), 2.50 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A mixture of the intermediate obtained from step 2 (1.00 g; 2.96 mmol), HATU (1.24 g; 3.25 mmol), DMF (2.50 mL) and DIPEA (0.56 mL; 3.25 mmol) is stirred at r.t. for 20 min. The amine 4-cyanobenzylamine (0.36 mL, 2.96 mmol) is added and the resulting mixture is stirred at r.t. for 2 h. A molar surplus of aq. NaHCOs solution is added with stirring and the precipitate is filtered off and dried at 50 C to yield the title compound. C20H19CI2N3O3S ESI pos.+neg. (Loop-Inj.): [M+H]+ 452 m/z (0129) HPLC (RT): 0.70 min (HPLC method A) |
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