- PYRIMIDINE AMIDE COMPOUNDS AND USE THEREOF
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Disclosed are compounds of formula (I) below or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: (I), in which each of variables each of variables R, R1, R2, X1, X2, X3 and n is defined herein. Also disclosed is a method for treating a cancer with a compound of formula (I) or a salt thereof and a pharmaceutical composition containing same.
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Page/Page column 52
(2021/04/30)
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- ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1 (ENPP1) MODULATORS AND USES THEREOF
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Provided herein are small molecule modulators of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
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Paragraph 00726
(2021/07/02)
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- DUAL KINASE-BROMODOMAIN INHIBITORS
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Provided herein are compounds of Formula (I) that are dual inhibitors of kinases and bromo-domain proteins. The disclosure also relates to pharmaceutical compositions containing such compounds, methods for using such compounds in the treatment of cancers, particularly, the treatment of multiple myeloma cancers, and to related uses.
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Page/Page column 97; 155
(2021/12/12)
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- Discovery of novel and potent PARP/PI3K dual inhibitors for the treatment of cancer
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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.
- Wu, Zhengyang,Bai, Ying,Jin, Jiaming,Jiang, Teng,Shen, Hui,Ju, Qiurong,Zhu, Qihua,Xu, Yungen
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- PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, preparation method and application thereof
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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.
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Paragraph 0157-0161
(2021/07/01)
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- Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool
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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.
- Zeng, Shaogao,Dou, Wenyuan,Li, Manna,Zhou, Yang,Guo, Jiehuang,Zhao, Nan,Huang, Hong,Zhou, Qiaoli,Hu, Wenhui,Ma, Yanfang,Zhao, Xin,Xie, Hui
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supporting information
p. 1608 - 1617
(2020/07/06)
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- Thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and preparation method and application thereof
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The invention provides a thienopyrimidinone compound or pharmaceutically-acceptable salt thereof and a preparation method and application thereof. The thienopyrimidinone compound or the pharmaceutically-acceptable salt thereof has a novel chemical structure, it is verified through in-vitro and in-vivo experiments that a very good selective inhibiting effect on DPP-IV is achieved, the activity of DPP-VIII and DPP-IX is barely affected while the activity of DPP-IV is effectively inhibited, meanwhile, the inhibition ratio of a potassium ion channel is low, and it can be predicted that the toxicity is low after the compound is developed into medicine. Compared with medicine trelagliptin orally taken once every week on the market, the thienopyrimidinone compound has fairly high or higher bioavailable efficiency, it can be predicted that after the compound is developed, the treatment effect that the compound is orally taken once for a long time, and the convenience and compliance of a patient are greatly improved. The preparation method is simple, the raw materials are easy to obtain, and the preparation method is suitable for industrial large-scale production.
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Paragraph 0130; 0131; 0163-0167
(2019/01/23)
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- Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti-metastatic drugs for cancer chemotherapy
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Axl tyrosine kinase has been shown to be involved in multiple pathways contributing to tumor development, angiogenesis, and metastasis. High Axl expression has been observed in many human tumors where it appears to confer aggressive tumor behavior. Here we present several series of dual Axl-VEGF-R2 kinase inhibitors based on extensive optimization of an acyl diaminotriazole. It was hypothesized that dual inhibition of these two receptor tyrosine kinases may have a synergistic affect in inhibiting tumor angiogenesis and metastasis. One of these molecules, R916562 showed comparable activity to Sunitinib in two mouse tumor xenograft models and a mouse corneal micropocket model.
- Goff, Dane,Zhang, Jing,Heckrodt, Thilo,Yu, Jiaxin,Ding, Pingyu,Singh, Raj,Holland, Sacha,Li, Weiqun,Irving, Mark
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p. 3766 - 3771
(2017/07/27)
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- PROCESS FOR MAKING THIENOPYRIMIDINE COMPOUNDS
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Process methods for making the dual mTOR/PI3K inhibitor GDC-0980, named as (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, having the structure: and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.
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Page/Page column
(2014/04/18)
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- THIENYL [3,2-D] PYRIMIDIN-4-ONE COMPOUNDS, PREPARATION METHOD, PHARMACEUTICAL COMPOSITIONS AND USE THEREOF
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Disclosed are new thienyl[3,2-d]pyrimidin-4-one compounds shown as the general formula (I), preparation method, pharmaceutical compositions and pharmacological use thereof. The compounds are strong DPPIV (dipeptide peptidase IV) inhibitors and can treat t
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Paragraph 0120-0121; 0161; 0163; 0188-0189
(2014/11/11)
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- PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
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Compounds of the formula I or II: wherein X, m, Ar, R1 and R2 are as defined herein. The subject compounds are useful for treatment of IRAK-mediated conditions.
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Page/Page column 108
(2012/02/01)
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- 4-CYANOPHENYLAMINO-SUBSTITUTED BICYCLIC HETEROCYCLIC COMPOUNDS AS HIV INHIBITORS
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This application concerns certain 4-cyanophenylamino-substituted bicyclic heterocycles of formula (I) where the dashed line represents a double bond that may be located either between A and C(V) or between C(V) and D, where A is S or C(Z); D is S or C(W); provided that one and only one of A and D is S; where T is NH, O, or S; and where other substituents are defined herein. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.
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Page/Page column 51
(2008/12/05)
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- PYRIMIDINE DERIVATIVES AS PI3K INHIBITORS
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Thienopyrimidines of formula (Ia) or (Ib): wherein R1, R2, R3, are as defined in the claims.
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Page/Page column 87-88
(2008/06/13)
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- Pyrimidine nucleus-containing compound and a medicament containing the same for a blood oxygen partial pressure amelioration, and a method for preparing the same
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A pyrimidine nucleus-containing compound represented by the formula (I): wherein ring A represents the ring of the formula (a): in which R1is a nitro group, an amino group, a substituted amino group or a halogen atom, or the ring of the formula (b): in which R1′is the group such as an alkyl group or an alkenyl group; R2to R5independently represent the group such as an alkyl group or an alkenyl group; with the proviso that at least one of R2to R5is an alkenyl group, or acid addition salts thereof.
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Referential example 16
(2010/01/30)
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- PYRIMIDINE NUCLEUS-CONTAINING COMPOUND AND A MEDICAMENT CONTAINING THE SAME FOR A BLOOD OXYGEN PARTIAL PRESSURE AMELIORATION, AND A METHOD FOR PREPARING THE SAME
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A pyrimidine nucleus-containing compound represented by the formula (I): wherein ring A represents the ring of the formula (a): in which R1 is a nitro group, an amino group, a substituted amino group or a halogen atom, or the ring of the formul
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- Synthesis of thieno[3,2-d]pyrimidine-2,4-diones cyclic and acyclic nucleosides as potential anti HIV agents
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Synthesis of cyclic and acyclic nucleosides was achieved by alkylation of 7-methyl or arylthieno[3,2-d]pyrimidine-2,4-diones following the Vorbruggen and Niedballa's method [1]. After a possible deprotection, potential anti HIV agents were obtained.
- Jourdan,Laduree,Robba
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p. 305 - 312
(2007/10/02)
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