Synthesis and crystal structure of piperidinium 2-aryl[1,2,4]triazolo[1,5-a]pyridinides and their neutralization to 2-aryl[1,2,4]triazolo[1,5-a]pyridines

A one step synthesis of novel piperidinium 2-aryl[1,2,4]triazolo[1,5-a]pyridinides 6 from 2′-benzoyl-2-cyanoacetohydrazide (2) and α-substituted cinnamonitriles 3 is described. The reaction takes place by 6-exodig cyclization followed by an 5-exo-trig process to afford salts 6 . The X-ray diffraction of compound 6a reveal that the cation is strongly linked to the anion by hydrogen bonds and a characteristic partial stacking motive. 2-Aryl[1,2,4]triazolo[1,5-a]pyridines were obtained from salts 6 by treatment with hydrochloric acid.     

Synthesis of Substituted 5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines

A one-pot synthetic approach to the novel 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines by thermal cyclization of 4-acylhydrazino-2,3-dihydro-1H-1,5-benzodiazepines is described.     

A convenient synthesis of 2-aryl substituted benzo[f] [1,2,4]triazolo[1,5-a]azepine derivatives

A convenient synthetic pathway to 2-aryl-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[1,5-α]azepine derivatives 7 was developed. The synthesis was based on the cycloaddition of the 1,2,3,4-tetrahydronaphthalene a-acetoxy azo compounds 3 with Ar-CN in the presence of AlCl3 and the consecutive ring enlargement.     

Synthesis of Novel 2-Methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one and Derivatives

A novel 2-methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one was synthesized using dimethyl-n-cyanoimidodithiocarbonate and 2-hydrazinobenzoic acid as building blocks. Chemical transformation of the inherent lactam moiety in the targeted 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazolin-5-one offered access to a variety of derivatives.     

Thermolysis of [1,2,4]triazolo[1,5-a]pyrimidine n-ylides

5,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidinio-3-phenacylide ($\text{3}$) generated by the reaction of an iminium salt ($\text{2}$) with 1 eq. of triethylamine, underwent a new thermal ring cleavage of the triazole moiety to give the pyrimidine derivative. However reaction of $\text{2}$ with 2 eq. of triethylamine afforded the 2-iminooxazoline derivative. The iminooxazoline reacted with nucleophiles such as alcohols or amines to give imidazoles.     

1,2,4-Triazolo[1,5-a]benzimidazoles: Tautomerism and alkylation

The position of the tautomeric equilibrium in unsubstituted 1,2,4-triazolo[1,5-a] benzimidazole, as well as in its 2-methyl and 2-phenyl derivatives, was investigated by UV, IR, and PMR spectroscopy and by determination of the ionization constants. In all cases the amount of the 4H tautomer in the equilibrium mixture is two to three orders of magnitude greater than the amount of the 3H tautomer, while signs of the existence of the 1 H form are not observed. The synthesis of unsubstituted triazolo [1,5-a]-benzimidazole was accomplished for the first time. The alkylation of the indicated triazolo [1,5-a]benzimidazoles was studied and a relationship between the regiospecificity of this reaction and the position of the tautomeric equilibrium was established.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 209–220, February, 1989.     

Discovery of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new bromodomain-containing protein 4 (BRD4) inhibitors

Targeting bromodomain-containing protein 4(BRD4) has been proved to be an effective strategy for cancer therapy.To date,numerous BRD4 inhibitors and degraders have been identified,some of which have advanced into clinical trials.In this work,a focused library of new [1,2,4]triazolo [1,5-a]pyrimidine derivatives were discovered to be able to inhibit BRD4.WS-722 inactivated BRD4(BD1/BD2),BRD2(BD1/BD2) and BRD3(BD1/BD2) broadly with the IC₅₀ values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC₅₀ value of 3.86 μmol/L.Like(+)-JQ1,WS-722 inhibited BRD4 in a reversible manner and enhanced protein stability.Docking studies showed that WS-722 occupied the central acetyl-lysine(Kac) binding cavity and formed a hydrogen bond with Asn140.In THP-1 cells,WS-722 showed target engagement to BRD4.Cellular effects of WS-722 on THP-1 cells were also examined,showing that WS-722 could block c-MYC expression,induce G0/G1 phase arrest and p21 up-regulation,and promote differentiation of THP-1 cells.BRD4 inhibition by WS-722 resulted in cell apoptosis and upregulated expression of cleaved caspased-3/7 and PARP in THP-1 cell lines.The [1,2,4]triazolo[1,5-a]pyrimidine is a new template for the development of new BRD4 inhibitors.     

Synthesis of 4-alkylpyrazolo[1,5-a]benzimidazoles

2,4-Disubstituted pyrazole[1,5-a]benzimidazoles were obtained by the action of carboxylic acid anhydrides on 1-amino-2-methyl-3-alkylbenzimidazolium salts in the presence of potassium carbonate. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 814–817, June, 1980.     

Characterization of copper(II) coordination compounds of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine: the crystal structure of diaquatetrakis(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-N3)-copper(II) hexafluorophosphate

Copper(II) coordination compounds of several CuA₂ salts (A = PF₆, BF₄, ClO₄, CF₃SO₃ or NO₃) with 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine (dmtp) as a ligand have been studied. The crystal structure of [Cu(dmtp)₄(H₂O)₂](PF₆)₂ is described. This compound is monoclinic, space group P2₁/c, a = 11.826(2) Å, b = 9.463(2) Å, c = 17.673(3) Å, β = 97.50(1)°, Z = 2, d_calc. = 1.66 Mg m⁻³, and has been refined to a final discrepancy factor (R) of 0.0382 based on 2316 reflections. The structure consists of PF⁻₆ anions and centrosymmetric mononuclear [Cu(dmtp)₄(H₂O)₂]²⁺ cations, Cu₂₊ being coordinated by four equatorial N(3)-bonded dmtp molecules with CuN = 2.019 and 2.050 Å, and by two axial water molecules with CuO = 2.650 Å. The water molecules form intramolecular hydrogen bonds with the dmtp N(4) atoms.     

Synthesis and anti-tumor activities of novel [1,2,4]triazolo[1,5-a]pyrimidines

A series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives has been designed and synthesized in order to find novel anti-tumor compounds. The structures of all the compounds were confirmed by IR, 1H-NMR, MS and elemental analysis. Their anti-tumor activities against cancer cell lines (HT-1080 and Bel-7402) were tested by the MTT method in vitro. Among them, compound 19 displayed the best anti-tumor activity with IC50 values of 12.3 microM and 6.1 microM against Bel-7402 and HT-1080 cell lines respectively.     

A new series of 2-alkoxy(aralkoxy)-[1,2,4]triazolo[1,5-a]quinazolin-5-ones as adenosine receptor antagonists

This research was carried out to study the pharmacological activity of a newly synthesized series of 2-alkoxy-[1,2,4]triazolo[1,5-a]quinazolin-5-ones as adenosine receptor antagonists. These compounds have been tested in radioligand binding assays on cloned Chinese hamster ovary (CHO) cells transfected with A(1), A(2A), A(2B) and A(3) receptors. In particular, among the triazoloquinazolines (1-11), the dialkoxy derivative (7b) was found to have the highest affinity at A(1) subtype receptor, and its radioligand binding activity together with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) was studied. Finally, the structure-activity relationship (SAR) studies on the titled compounds provide some new insights about steric hindrance and lipophilic requirements for anchoring to the adenosine receptors recognition site.