Synthesis and Crystal Structure of 2-Benzylsulefnyl-3-cyano-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine

The title compound, C16H14N4S, has been synthesized by the reaction of pentane-2,4-dione with 5-amino-3-benzylthio-4-cyano-1-H-pyrazole in ethanol, and its crystal structure was determined by X-ray diffraction method. The crystal is of monoclinic, space group P21/n with a = 8.699(3), b = 23.139(9), c = 7.536(3) ? b = 92.400(8), V = 1515.5(10) 3, Z = 4, Mr = 294037, Dc = 1.290 g/cm3, = 0.71073 ? (MoKa) = 0.212 mm-1 and F(000) = 616. The structure was refined to R = 0.0533 and wR = 0.1141 for 2672 unique reflections with Rint = 0.06. The structure is a dimmer linked by intermolecular contact S(1)…HC(8) with the S(1)C(8) distance of 3.875 and the angle of 164.8.

Synthesis of 5,7-Dimethyl-2-(5-Substituted-1,3,4-Oxadiazole-2-yl)- Methylenethio-1,2,4-Triazolo[1,5-a]Pyrimidines as Potential Fungicides

A series of diheterocyclic compounds containing 1,2,4-triazolo [1,5-a]pyrimidine and 1, 3,4-oxadiazole were designed and synthesized starting from 2-mercapto-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine. The structure of all compounds prepared were confirmed by H-1 NMR spectroscopy and elemental analysis. The preliminary bioassay indicated that the title compounds displayed good fungicidal activity against Rhizoctonia solani.

Synthesis, Structure and Biological Activities of 2-Methylthio-3-cyano-7-(4-methoxyphenyl)-pyrazolo[1,5-a]pyrimidine

The crystal structure of 2-methylthio-3-cyano-7-（4-methoxyphenyl）-pyrazolo[1,5- a]-pyrimidine （C15H12N4OS, Mr = 296.35） has been determined by single-crystal X-ray diffraction analysis. The crystal belongs to monoclinic, space group P21/c with a = 9.200（3）, b = 15.570（5）, c = 11.125（4） A,β= 114.273（6）°, V= 1452.7（8） A^3, Z= 4, De= 1.355 g/cm^3, μ= 0.227 mm^-1, F（000） = 616, R = 0.0499 and wR = 0.0949 for 2947 unique reflections with 1633 observed ones （I 〉 2σ（I））. The results show that all ring atoms in the pyrazolopyrimidine moiety are almost coplanar with a strong tensile force, which might be an important active site. The preliminary biological test shows that the title compound has moderate herbicidal activities.

Design,synthesis and antiproliferative activity of novel 2,7-disubstituted triazolo[1,5-a]pyrimidines

In our efforts to identify novel potent anticancer agents, we synthesized a series of 2,7-disubstituted triazolo[1,5-a]pyrimidines （6-16）. Their antiproliferative activity against Bel-7402, HT- 1080 and WI-38 cell lines was tested by MTT assay in vitro. Four of the compounds （9-11 and 16） displayed promising antiproliferative activity superior to gefitinib, especially compound 9. A preliminary SAR study of these derivatives was performed.

Synthesis and Antiproliferative Activity of Novel [1,2,4]Triazolo[1,5-a]pyrimidine-7-amine Derivatives

A series of novel N-anilino-2-substituted-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-amine derivatives was prepared and evaluated for their in vitro antiproliferative activity against two cancer cell lines,Bel-7402 and HT-1080.Most of the compounds inhibited the cell proliferation at a low concentration.Seven compounds,VI5,VI7,VI10,and VI12―VI15,possessed marked antiproliferative activity superior to that of cisplatin.Of these seven initial hits,compound VI10 was the most active.

Facile Syntheses of New Pyrazolo[1,5-a]pyrimidines Derivatives via Reactions of Enaminones with Aminopyrazole

Ethyl 7-aryl-2-benzyhhiopyrazolo [ 1,5-a ] pyrimidine-3-carboxylates （3a-3f） were conveniently synthesized through the reactions of enaminones with 5-amino-3-benzyhhio4-ethoxycarbonyl-1 H-pyrazole in good yields and high regioselectivity. The structures of the new compounds were fully characterized by spectroscopic measurmehts, elemental analysis and X-ray diffraction analysis. A plausible reaction mechanism for the formation of the title compounds was also presented.

NH_(4)SCN-Promoted Formal[3+3]Annulation for the Synthesis of 5-Arylated Pyrazolo[1,5-a]pyrimidines

A formal[3+3]annulation of 3-aminopyrazoles with cinnamaldehydes or cinnamyl alcohols mediated by NH_(4)SCN has been developed.This protocol provides a practical route to construct 5-arylated pyrazolo[1,5-a]pyrimidines with high functional group tolerance.The use of NH_(4)SCN as the cyanide anion surrogate allows the transient generation of cyanohydrin,which shifts the reactive center within cinnamaldehydes from formyl group to alkene group to realize an opposite regiocontrol comparing with previous reports.

Crystal and Molecular Structure of 2-(2, 6-Dinitro-4-Trifluoromethyl) phenylthio-5, 7-Dimethyl-1,2,4-Triazolo [1, 5-a] Pyrimidine

The crystal structure of the title compound has been determined bysingle crystal X-ray diffraction analysis. C14H9F3N6O4S, Mr = 414. 32, monoclinic,space group P21/n, a=8. 287(3), b= 24. 972(4), c= 8. 617(3)A, β= 108. 36(3)°,V= 1693(2) A3, Z=4, Dx=1. 626 g. cm-3, μ=0. 2481 mm-1; F(000) =840, finalR = 0. 057 and Rw= 0. 057 for 1169 observed reflections [I≥3σ(I)]. The results showthat all ring atoms in the triazolopyrimidinyl moiety were coplanar with strong tensileforce, which might be an important active site.

Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent,specific and orally active P-glycoprotein(P-gp)inhibitor

Multidrug resistance(MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein(P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp,WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel(PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4(CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft(PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.

BrΦnsted acid-promoted ‘on-water’ C(sp^3)-H functionalization fot the synthesis of isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the SKP2-CKS1 interaction

The isoindolinone and biaryl scaffolds are prevalent in natural products and drug molecules,which have showed broad and interesting biological activities.The efficient construction of such hybridized molecules and biological evaluation are of great interest to medicinal chemistry community.In this communication,we report an efficient BrΦnsted acid-promoted C(sp^3)-H functionalization approach that enables the rapid construction of biologically important isoindolinone/[1,2,4]triazolo[1,5-a]pyrimidine hybrids from 5-methyl-7-(2,4,6-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine,2-formylbenzoic acid and various anilines.The title compounds were generated in high to excellent yields(up to 96%)regardless of the electronic nature and steric effects of the substituents.In this reaction,an isoindolinone scaffold,one C-C single bond,and two C-N bonds were formed simultaneously with high atom economy.In this work,we have envisioned that the methyl group linked to the electron-deficient Nheterocycles could be used as a new synthetic handle for late-state diversification and may have broad applications in the field of organic and medicinal chemistry.Besides,the title compounds have exhibited promising activity against the SKP2-CKS1 interaction.

Design, Synthesis, and Hypnotic Activity of Pyrazolo[1 ,5-a] pyrimidine Derivatives

On the basis of the Zaleplon structure, novel pyrazolo[l,5-a]pyrimidines were designed and prepared for studies on their hypnotic activity. This paper reported the synthesis of twelve new 5-methyl-7-substituted-pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives by using simple starting materials such as propane dinitrile and triethyl orthoformate. The structures of the derived target compounds were confirmed by their IR and 1H-NMR spectroscopic data. The preliminary pharmacological evaluations indicated that some compounds showed hypnotic activity, while derivative 1c was the most polent one.

Microwave Irradiation for Accelerating Synthesis of Diarylimidizo[1,5-a]pyrimidine Based on Isoflavones

Microwave irradiation was used to accelerate the cyclocondensation of i soflavones and 5-amino-1H-imidazole- 4-carboxamide in the presence of sodium hydroxide to produce 3,4-diphenyl-imidazo[ 1,5-a]pyrimidines in good to moderate yields.

Reaction of Enaminones with Aminopyrazoles： Synthesis,Structures and Bioactivities of 7-Aryl-3-cyano-2-substituted Pyrazolo[1,5-a]pyrimidines

The condensation reactions of 5-amino-4-cyano-3-substituted-1H-pyrazole 2 or 3 with enaminones 1 in the presence of glacial acetic acid gave twelve new 7-aryl-3-cyano-2-substituted pyrazolo[1,5-a]pyrimidines 4 and 5 at room temperature. Their structures were characterized by elemental analysis, IR and 1H NMR. The structure of 4a was further confirmed by X-ray crystallography analysis. A plausible reaction mechanism for the formation of the title compounds was also proposed. The bioassay tests showed that compounds 4a, 4e, 4e, 4f, 5a and 5d possessed moderate herbicidal activity.

Synthesis and Crystal Structure of Ethyl2-Methylthio-7-phenylpyrazolo[1,5-a] pyrimidine-3-carboxylate

The crystal structure of ethyl 2-methylthio-7-phenylpyrazolo[1,5-a]pyrimidine-3- carboxylate (C16H15N3O2S, Mr = 313.37) has been determined by single-crystal X-ray diffraction analysis. The crystal belongs to monoclinic, space group P21/n with a = 19.361(7), b = 7.595(3), c = 20.910(8) ?, β = 94.925(6)°, V = 3064(2) ?3, Z = 8, Dc = 1.359 g/cm3, μ = 0.222 mm-1, F(000) = 1312, R = 0.0546 and wR = 0.1082 for 5374 unique reflections with 3419 observed ones (I > 2σ(I)). The results show that all ring atoms in the pyrazolopyrimidine moiety are coplanar with strong tensile force. The structure analysis indicates that the single crystal contains strong nonclassical hydrogen bonds.

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 IC_(50) values less than 5 μmol/L.Besides,WS-722 inhibited growth of THP-1 cells with an IC_(50) 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.

Improved microwave-assisted catalyst-free synthesis of9-aryl-5,9-dihydropyrimido[4,5-d][1,2,4]triazolo[1,5-a]pyrimidine-6,8(4H,7H)-dione derivatives

Agreen regioselective synthesis of some new and known 9-aryl-5,9-dihydropyrimido[4,5-d][l,2,4]triazolo[1,5-a]pyrimidine-6,8（4H,7H）-diones has been described via the microwave-assisted one-pot reaction of 3-amino-1H-1,2,4-triazoles,aromatic aldehydes and barbituric acids under solvent- and catalyst-free conditions.This operationally simple procedure is less laborious and provides a better scope than previously reported procedures.

An efficient and green preparation of 5-aminophosphonate substituted pyrimidine nucleosides under solvent-free conditions

An environmentally benign and highly efficient one-pot preparation of α-aminophosphonates under solvent-free conditions was developed. By employing this method, 5-aminophosphonate substituted pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-forrnyl-2＇-deoxyuridine, aniline and dimethylphosphite.

Coupling Reaction of 4-Chloro-7-H-Pyrrolo[2,3-d]Pyrimidine with 2,3,5-Tri-O-Acetyl-b-D-Ribofuranosyl Chloride

Coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with 2,3,5-tri-O-acetyl -β-D-ribofuranosyl chloride under the basic condition was investigated. An abnormal coupling reaction, in which the heterocyclic base attacked at the carbon of 1,2-O-methylidene moiety instead of anomeric carbon of ribose was observed and the structure of products 5a, 5b were identified by NMR and X-Ray diffraction.

Design,Synthesis,and Biological Evaluation of 5H-Thiazolo[3,2-a]pyrimidine-6-carboxylic Acid Ethyl Ester Derivatives as a Novel Series of Acetylcholinesterase Inhibitors

Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer＇s drugs. A series of 5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester derivatives as the novel acetylcholinesterase inhibitors was designed based on virtual screening methods. The target compounds were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, ^1H NMR, and ^13C NMR. The biological evaluation against human acetylcholinesterase in vitro indicated all the target compounds show more than 50% inhibition at 10μmol/L by means of the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer＇s disease and lay the foundation of searching for improved acetylcholinesterase inhibitors with the novel scaffolds.

Crystal Structure and Herbicidal Activity of 5,7-Dimethoxy-(2,4-dichlorophenoxyacetyl- imino)-2H-1,2,4-thiadiazolo[2,3-a]pyrimidine

The title compound 5,7-dimethoxy-(2,4-dichlorophenoxyacetylimino)-2H-1,2,4- thiadiazolo[2,3-a]pyrimidine has been synthesized. In order to investigate the relationship between the structure and herbicidal activity of the target compound, we report its crystal structure and herbi- cidal behavior in the present paper. Crystallographic data: C15H12N4O4Cl2S, Mr = 415.25, mono- clinic, space group P21/n, a = 10.7361(8), b = 11.9610(9), c = 13.0990(10) ?, β = 96.988(2)o, Z = 4, V = 1669.6(2) ?3, Dc = 1.652 g/cm3, F(000) = 848, R = 0.0394, wR = 0.0797 and μ(MoKα) = 0.545 mm-1.