New [g]-fused [1,2,4]triazolo[1,5-c]pyrimidines: Synthesis of pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine,pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-c]pteridine derivatives

A number of 2-aryl-substituted pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-c]pteridines 11,12a,b,e , their corresponding 5-carbonyl derivatives 7,8a,b,e and some pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ones 7,8c,d have been synthesized, according to different pathways. The new tricyclic heterocycles were prepared with the aim of studying their possible benzodiazepine receptors affinity.     

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.     

5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶双杂环衍生物的合成与生物活性

以2-巯基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶为原料, 设计合成了17种含5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶环和1,2,4-三唑环的新型双杂环化合物, 结构经元素分析, MS, 1H NMR及13C NMR进行表征. 初步的生物活性测试表明, 部分化合物表现出较好的杀菌、除草活性.     

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.     

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.     

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.     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

On triazoles XXIV . Synthesis of cycloalka[1,2,4]triazolo[1,5-a]pyrimidinones

The uv and nmr spectral data of some 6,7,8,9,10,11-hexahydrocyclohepta[d][1,2,4]triazolo[1,5-a]pyrimidin-5-one, 5,6,7,8,9,11-hexahydrocyclohepta[e][1,2,4]triazolo[1,5-a]pyrimidin-10-one, 6,7,8,9,10,11-hexahydrocycloocta[d][1,2,4]triazolo[1,5-a]pyrimidin-5(12H)-one, 5,6,7,8,9,10-hexahydrocycloocta[e][1,2,4]triazolo[1,5-a]-pyrimidin-11(12H)-one, 6,7,8,9,10,11,12,13,14,15-decahydrocyclododeca[d][1,2,4]triazolo[1,5-a]pyrimidin-5(16H)-one and 5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[e][1,2,4]triazolo[1,5-a]pyrimidin-15(16H)-one as well as their N-benzylated derivatives representing six novel ring systems were compared to prove their structure. The N-benzylation of the highly insoluble cyclic amides to yield the isomeric N-benzyl derivatives 3/1, 3/2 and 3/3 distinguished by INAPT was performed through their readily soluble tetrabutylammonium salts.     

Cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydroxylamine and hydrazine

The cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (3) with hydroxylamine or hydrazine leads to 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenylisoxazolo-[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4a ) and 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4b ), respectively. In the presence of methanolic hydrogen chloride, 4b undergoes a cleavage of the pyrimidine ring to yield (5-amino-1,2,4-triazol-1-yl)(3,5-dimethylpyrazol-4-yl)phenylmethane ( 5 ). The structure determination of the compounds obtained is based on ¹H and ¹³C nmr spectra including NOE measurements.     

Synthesis and cytotoxicity studies of novel [1,2,4]triazolo[1,5-a]pyrimidine-7-amines

A series of novel N-anilino-5-methyl-2-(3-(5-(alkylaminomethyl)furan-2-yl-methylthio)propyl)-[1,2,4]triazolo-[1,5-a]pyrimidine-7-amine derivatives were synthesized and evaluated for their in vitro cytotoxicity against two cancer cell lines, Bel-7402 and HT-1080. Compounds 9, 14, 19 and 23 possessed marked cytotoxicity, especially 23 (with IC(50) values of 15.0 microM and 7.8 microM against Bel-7402 and HT-1080 cell lines, respectively), which had emerged as lead compound. The activity was found to depend strongly on substitution pattern of the side chains at C-2 position, and 4-triflouromethylanilino substituent at C-7 position was an option for anticancer potency.     

New Facile Route to Synthesize Furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine and Furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives

A new facile route for synthesis of 3-(aryl)-8,9-diphenylfuro[3,2-e][1,2,4]triazolo pyrimidines derivative from the same starting material, 2-amino-4,5-diphenylfuran-3-carbonitrile, has been developed through heterocyclization of the corresponding arylidene-hydrazono-5,6-diphenylfuro[2,3-d]pyrimidine and N-(arylmethylene)-4-imino-5,6-diphenylfuro[2,3-d]pyrimidin-3(4H)-amine under refluxing condition with acetic anhydride followed by air oxidation. The products were obtained in good yield with an easy workup along with the purification of products by a nonchromatographic method. This general synthetic procedure can be extended to the preparation of a wide range of isomeric triazoles using 2-amino 3-carbonitrile bifunctional derivatives.     

2-aryl(hetaryl)-4H-[1,2,4]triazolo[1,5-a]benzimidazoles

2-(4-Methylphenyl)-4H-[1,2,4]triazolo[1,5-a]benzimidazole and its previously unknown 2-(2-furyl)- and 2-(2-thienyl)-substituted analogs were synthesized by cyclization of benzimidazole-1,2-diamine with the corresponding carboxylic acid chlorides. The IR, ¹H, ¹³C, and ¹⁵N NMR, and mass spectra of the cyclization products in combination with the results of quantum-chemical calculations of NMR chemical shifts showed radical differences of [1,2,4]triazolo[1,5-a]benzimidazoles having no substituent on N⁴ from the recently reported low-melting products of oxidation of 2-amino-1-arylmethylideneaminobenzimidazoles with (diacetoxy-λ³-iodanyl)benzene, which, as we believe, were erroneously assigned analogous structure.     

Facile one-pot synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives by ultrasonic irradiation

Herein, we report an ultrasonic promoted facile and convenient “one-pot” procedure for the synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives 3, 4 and 5, using Amberlite IRA-400, in short reaction times and high yields and its comparison with classical reaction conditions. The structures of new compounds were assigned with the help of analytical ¹H, ¹³C NMR, and mass spectral studies.