16234-14-3

Usage

Uses

Used in Pharmaceutical Industry:
2,4-Dichlorothieno[3,2-d]pyrimidine is used as a key intermediate in the synthesis of PI3K inhibitors, which are important for the development of targeted cancer therapies. These inhibitors modulate the PI3K/AKT/mTOR signaling pathway, a crucial regulator of cell growth, survival, and metabolism, often dysregulated in various cancers. The compound's role in the synthesis process is to facilitate the creation of PI3K inhibitors under noncryogenic conditions, making the production process more efficient and cost-effective.

Upstream product

• 16233-51-5 1H-thieno[3,2-d]pyrimidine-2,4-dione 
• 22288-78-4 Methyl 3-aminothiophene-2-carboxylate 
• 57-13-6 urea 
• 51322-68-0 methyl 3-[(aminocarbonyl)amino]-2-thiophenecarboxylate 
• 16233-51-5 2,4-dihydroxythieno[3,2-d]pyrimidine 
• 16233-51-5 thienoyleneurea 

Downstream Products

• 147972-18-7 4'-[[[2-chlorothieno-[3,2-d]pyrimidin-4-yL]amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester 
• 152943-20-9 2-(3,4-Dimethoxyphenethylamino)-4-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl)thieno[3,2-d]pyrimidine hydrochloride 
• 1024603-85-7 4-((2-chlorothiophene[3,2-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 
• 1024603-87-9 2-chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine 
• 1024603-84-6 2-chloro-4-(mesityloxy)thieno[3,2-d]pyrimidine 
• 1197192-85-0 C₁₄H₉ClN₂OS 
• 319440-72-7 2-chlorothieno[3,2-d]pyrimidin-4-yl phenylmethanone 
• 1197192-86-1 C₁₄H₉ClN₂O₂S 
• 1002726-48-8 C₁₃H₁₀ClN₃OS 
• 1235451-09-8 2-chloro-N-phenylthieno[3,2-d]pyrimidine-4-amine 
• 1245811-20-4 2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one 
• 1259978-29-4 2-methoxythieno[3,2-d]pyrimidine 
• 885698-98-6 4-(6-(bromomethyl)-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 
• 885675-66-1 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]-pyrimidin-4-yl)morpholine 

Relevant academic research and scientific papers

Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer

PARP inhibitors have achieved great success in cancers with BRCA mutations, but only a small portion of patients carry BRCA mutations, which results in their narrow indication spectrum. Recently, emerging evidence has demonstrated that combinations of PARP and PI3K inhibitors could evoke unanticipated synergistic effects in various cancers, even including BRCA-proficient ones. In this work, a series of PARP/PI3K dual inhibitors were designed, synthesized, and evaluated for their biological activities. It was found that compounds 9a and 23a exhibited excellent inhibitory activities against PARP-1 (9a: IC50 = 1.57 nM, 23a: IC50 = 0.91 nM) and PI3Kα (9a: IC50 = 2.0 nM, 23a: IC50 = 1.5 nM), and showed promising antiproliferative activities against both BRCA-deficient (HCT-116, HCC-1937) and BRCA-proficient (SW620, MDA-MB-231/468) tumor cells. 9a and 23a also exhibited considerable in vivo antitumor efficacy in an MDA-MB-468 xenograft mouse model, with TGI values of 56.39% and 48.77%, respectively. Additionally, 23a possessed promising profiles including high kinase selectivity and low cardiotoxicity. Overall, this work indicates 9a and 23a might be potential PARP/PI3K dual inhibitors for cancer therapy and deserve further research.

PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof

The invention discloses a PARP-1/PI3K double-target inhibitor or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. According to the invention, the single active component can play a dual inhibition role on PARP-1 and PI3K, so that the dosage is reduced, the treatment effect is improved, and the toxic and side effects are reduced; and the dual inhibition effect on PARP-1 and PI3K is significant, the IC50 value of each target does not exceed 1.0 [mu]M, and the drug using the PARP-1/PI3K double-target inhibitor as the active component can be used for treating a variety of cancers or tumors related to PARP-1 and/or PI3K.

Design, synthesis and biological evaluation of novel 2,4-bismorpholinothieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives as potent antitumor agents

To develop novel therapeutic agents with anticancer activities, two series of novel 2,4-bismorpholinyl-thieno[3,2-d]pyrimidine and 2-morpholinothieno[3,2-d]pyrimidinone derivatives were designed, synthesized and evaluated for their biological activities. Among them, compound A12 showed the most potent antitumor activities against HCT116, PC-3, MCF-7, A549 and MDA-MB-231 cell lines with IC50 values of 3.24 μM, 14.37 μM, 7.39 μM, 7.10 μM, and 16.85 μM, respectively. Further explorations in bioactivity were conducted to clarify the anticancer mechanism of compound A12. The results showed that compound A12 obviously inhibited the proliferation of A549 cell lines and decreased mitochondrial membrane potential, which led to the apoptosis of cancer cells and suppressed the migration of tumor cells.

COMBINATION THERAPY WITH A PHOSPHOINOSITIDE 3-KINASE INHIBITOR WITH A ZINC BINDING MOIETY

The invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject: (a) a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or an acyl group; and (b) a PD-1 signaling inhibitor; wherein the compound of Formula I or pharmaceutically acceptable salt thereof and the PD-1 signaling inhibitor are administered in amounts which in combination are therapeutically effective. The invention further provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, a PD-1 signaling inhibitor and a pharmaceutically acceptable carrier or excipient.

Preparation method of thienopyrimidine compounds and application thereof

The invention relates to thienopyrimidine derivatives as shown in a general formula I, pharmaceutically acceptable salts or prodrugs and a preparation method thereof, which belong to the technical field of medicinal chemistry. In the general formula I, substituent groups L and R2 have meanings given in the specification. The invention also relates to a compound shown in the general formula I, which has a strong effect of inhibiting PI3K. The invention also relates to an application of the compounds and pharmaceutically acceptable salts, solvates or prodrugs thereof in preparation of drugs fortreating and/or preventing diseases caused by abnormal high expression of PI3K, especially the application in preparation of drugs for treating and/or preventing cancers.

Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.

Design, synthesis and antitumor activity of novel thiophene-pyrimidine derivatives as EGFR inhibitors overcoming T790M and L858R/T790M mutations

Five series of novel thiophene-pyrimidine derivatives (9a-h, 10a-f, 11a-f, 12a-f, 13a-f) have been synthesized and tested for their anti-proliferative activity against several cancer cell lines in which EGF is highly expressed. Most of the target compounds showed excellent activity against one or more cancer cell lines. The most promising compound 13a, of which IC50 values on of cell lines A549 and A431 (4.34 ± 0.60 μM and 3.79 ± 0.57 μM) were similar to the lead compound Olmutinib, showed strong activity and selectivity to EGFRT790M and EGFRT790M/L858R. Inhibition data of human normal hepatoma cell line LO2 indicated that most target compounds were less toxic to normal cells and had selective inhibitory effects on cancer cells. In addition, the structure-activity relationship was analyzed and the mechanism of apoptosis induced by the 13a was studied. The results showed that compound 13a induced late apoptosis of A431 cancer cells in a dose-dependent manner.

N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide: design, synthesis, crystal structure, antiproliferative activity, DFT, Hirshfeld surface analysis and molecular docking study

The compound N-{2-[(2-chlorothieno[3,2-d]pyrimidin-4-yl)amino]ethyl}-3-methoxybenzamide (8) was synthesized by the condensation of 3-methoxybenzoic acid (7) with N 1-(2-chlorothieno[3,2-d]pyrimidin-4-yl)ethane-1,2-diamine (6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate (1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with ethane-1,2-diamine. The crystal structure of the title compound was determined and the crystal of the title compound belongs to the tetragonal system, space group P4(3) with a = 9.4694(10) ?, b = 9.4694(10) ?, c = 18.886(3) ?, α = 90°, β = 90°, γ = 90°. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. The calculated HOMO and LUMO energies showed the character of the title compound. The molecular electrostatic potential (MEP) surface map of the related molecule was investigated with theoretical calculations at the B3LYP/6-311 + G(d,p) levels. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. In addition, the title compound possesses marked inhibition against the proliferation of human colon cancer cell line HT-29 (IC50 = 1.76 μM), human lung adenocarcinoma cell line A549 (IC50 = 1.98 μM) and human gastric cancer cell line MKN45 (IC50 = 2.32 μM), displaying promising anticancer activitiy. The molecular docking studies revealed that the title compound may exhibit activity inhibiting PDB:3D15. Communicated by Ramaswamy H. Sarma.

Design, synthesis and biological evaluation of thieno[3,2-d]pyrimidine derivatives containing aroyl hydrazone or aryl hydrazide moieties for PI3K and mTOR dual inhibition

Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.

Follow on-based optimization of the biphenyl-DAPYs as HIV-1 nonnucleoside reverse transcriptase inhibitors against the wild-type and mutant strains

The present work follows our preliminary discovery of biphenyl diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors. Further structural optimization of biphenyl-DAPYs led to the identification of a new series of biphenyl-substituted thiophene[3,2-d]pyrimidine analogues by a scaffold-hopping strategy. Biological evaluation of this series showed that these compounds possessed up to single-digit nanomolar potency (EC50 = 7.8–526.2 nM) and prominently low toxicity (CC50 = 18.5–280.8 μM) against wild-type (WT) HIV-1-infected cells. Furthermore, the results also demonstrated that compounds 29–32 exhibited high, broad-spectrum antiviral effects against clinically observed HIV-1 mutants. Specifically, compound 30, which had the highest selectivity index (SI = 16094) and the best anti-reverse transcriptase ability (IC50 = 39 nM), displayed marked inhibitory activity (EC50 = 13.5, 9.4, 17.0, 52.0, and 58.2 nM) against WT, K103N, E138K, L100I, Y181C mutants and moderate activity against double mutants. This study provides important avenues for the further design of HIV-1 inhibitors.