- Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton's tyrosine kinase for treatment of Rheumatoid arthritis
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By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50 = 3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.
- Huang, Zhenhua,Zhang, Qian,Yan, Lianzhong,Zhong, Guizhen,Zhang, Linqi,Tan, Xiaojuan,Wang, Yanli
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Read Online
- Novel amino acid-substituted diphenylpyrimidine derivatives as potent BTK inhibitors against B cell lymphoma cell lines
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A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an L-proline substituent, was identified as the strongest BTK inhibitor, with an IC50/
- Wang, Changyuan,Li, Si,Meng, Qiang,Sun, Xiuli,Li, Hua,Shu, Xiaohong,Sun, Huijun,Liu, Kexin,Liu, Zhihao,Ma, Xiaodong
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Read Online
- Discovery of novel quinazoline derivatives as potent PI3Kδ inhibitors with high selectivity
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Inhibition of PI3Kδ has been proved to be an efficacious strategy for the treatment of hematological malignancies where the PI3K/Akt signaling pathway is hyperactive. Herein, a series of quinazoline derivatives bearing acrylamide fragment were prepared using skeleton-deconstruction strategy. The preliminary bioactivity evaluation resulted in the discovery of lead compound 15c. Compound 15c exhibited excellent enzyme activity against PI3Kδ (IC50 = 27.5 nM) compared with BEZ235 as well as the significant anti-proliferation activities. With the high selectivity over other PI3K isoforms and potent effects on PI3K/Akt pathway, 15c can be identified as a promising PI3Kδ inhibitor worthy of further profiling.
- Teng, Yu,Li, Xinyu,Ren, Shengnan,Cheng, Yu,Xi, Kun,Shen, Hongtao,Ma, Wenzhuo,Luo, Guoshun,Xiang, Hua
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Read Online
- Design, synthesis and antitumor activity evaluation of trifluoromethyl-substituted pyrimidine derivatives
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In order to find efficient new antitumor drugs, a series of novel trifluoromethyl-substituted pyrimidine derivatives were designed and synthesized, and the bioactivity against four human tumor cells (PC-3, MGC-803, MCF-7 and H1975) was evaluated by MTT assay. Compound 17v displayed potent anti-proliferative activity on H1975 (IC50 = 2.27 μΜ), which was better than the positive control 5-FU (IC50 = 9.37 μΜ). Further biological evaluation studies showed that compound 17v induced apoptosis of H1975 cells and arrested the cell cycle at G2/M phase. Furthermore, compound 17v induced H1975 cells apoptosis through increasing the expression of pro-apoptotic proteins Bax and p53 and down-regulating the anti-apoptotic protein Bcl-2. In addition, compound 17v was able to be tightly embedded in the active pocket of EGFR. In summary, these results demonstrated that compound 17v has a potential as a lead compound for further investigation.
- Dai, Honglin,Gao, Chao,Ke, Yu,Liu, Hongmin,Liu, Limin,Meng, Yaqi,Si, Xiaojie,Wang, Zhengjie,Zhang, Qiurong,Zhang, Yang,Zheng, Jiaxin
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- Synthesis and biological activity of imidazole group-substituted arylaminopyrimidines (IAAPs) as potent BTK inhibitors against B-cell lymphoma and AML
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Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family and plays a key role in the modulation of the B-cell receptor (BCR)-mediated signaling pathway. Inhibition of BTK has been proven to be an effective therapeutic approach for various hemat
- Li, Si,Wu, Bin,Zheng, Xu,Wang, Changyuan,Zhao, Jingyuan,Sun, Huijun,Sun, Xiuli,Tang, Zeyao,Yuan, Hong,Chen, Lixue,Ma, Xiaodong
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- Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
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In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.
- Chao, Gao,Dai, Honglin,Ke, Yu,Li, Erdong,Lihong, Shan,Liu, Hongmin,Liu, Limin,Si, Xiaojie,Wang, Zhengjie,Yang, Zhang,Zhang, Luye,Zhang, Qiurong,Zheng, Jiaxin
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- S-triazine compounds as well as preparation method and application thereof
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The invention discloses s-triazine compounds and pharmaceutically acceptable salts thereof; experiments prove that the compounds can be used for treating or preventing diseases related to protein kinase activity, such as leukemia and lymphoma, by inhibiti
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Paragraph 0069-0071
(2020/05/05)
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- Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
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A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small-molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N-(3-((5-chloro-2-(4-((1-morpholino)acetylamino)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6 a) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi-PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.
- Sun, Bo,Liu, Xiaowen,Zheng, Xu,Wang, Changyuan,Meng, Qiang,Sun, Huijun,Shu, Xiaohong,Liu, Kexin,Sun, Xiuli,Li, Yanxia,Ma, Xiaodong
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p. 182 - 187
(2019/12/03)
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- Synthesis and biological activity of thieno[3,2-d]pyrimidines as potent JAK3 inhibitors for the treatment of idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3–5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 μM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.
- Zhu, Yanming,Zheng, Xu,Wang, Changyuan,Sun, Xiuli,Sun, Huijun,Ma, Tengyue,Li, Yanxia,Liu, Kexin,Chen, Lixue,Ma, Xiaodong
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- Azolo pyrimidine derivative, pharmaceutical composition thereof and application of azolopyrimidine derivative in tumor resistance
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The invention discloses an azolopyrimidine derivative, a pharmaceutical composition thereof and an application of the azolopyrimidine derivative in tumor resistance, and relates to the field of medicines and chemical engineering. The azolopyrimidine deriv
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Paragraph 0028-0032; 0066; 0079-0080
(2020/05/01)
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- Benzopyrimidine compound, preparation method, and applications thereof
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The invention provides a benzopyrimidine compound, and a pharmaceutically acceptable salt and an isotope labeled product thereof, and applications of the benzopyrimidine compound and the derivatives of the benzopyrimidine compound in preparation of Btk or PI3K kinases inhibitors used in treatment or prevention of diseases related with the activity of protein kinase, for example, diseases such as tumor including leukemia and lymphoma can be treated through inhibiting Btk or PI3K.
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Paragraph 0066; 0069
(2019/11/04)
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- Antitumor compound and preparing method and use thereof
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The invention relates to an antitumor compound and a preparing method and use thereof. The compound has a structure shown as a formula I. The invention also relates to use of the compound shown as theformula I or pharmaceutically acceptable salts thereof
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Paragraph 0027; 0032-0034
(2019/06/12)
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- INHIBITORS OF MUTANT ISOCITRATE DEHYDROGENASES AND COMPOSITIONS AND METHODS THEREOF
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The invention provides novel chemical compounds useful for treating cancer, or a related disease or disorder thereof, and pharmaceutical composition and methods of preparation and use thereof.
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Paragraph 00153
(2018/04/27)
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- Structural optimization of diphenylpyrimidine scaffold as potent and selective epidermal growth factor receptor inhibitors against L858R/T790M resistance mutation in nonsmall cell lung cancer
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A new class of thiodiphenylpyrimidine analogs (Thio-DPPY) were synthesized as potent and selective EGFR T790M inhibitors to overcome gefitinib resistance in nonsmall cell lung cancer (NSCLC). This structural optimization led to the identification of two p
- Yi, Yuanyuan,Wang, Luhong,Zhao, Dan,Huang, Shanshan,Wang, Changyuan,Liu, Zhihao,Sun, Huijun,Liu, Kexin,Ma, Xiaodong,Li, Yanxia
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p. 1988 - 1997
(2018/09/06)
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- PYRAZOLOPYRIMIDINE DERIVATIVES AS KINASE INHIBITOR
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The present invention relates to a pyrazolopyrirmidine derivative, or a pharmaceutically acceptable salt thereof. The compound according to the present invention can be usefully used for the prevention or treatment of diseases which are associated with ki
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Page/Page column 49
(2018/02/03)
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- Identification of highly potent BTK and JAK3 dual inhibitors with improved activity for the treatment of B-cell lymphoma
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The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors.
- Ge, Yang,Wang, Changyuan,Song, Shijie,Huang, Jiaxin,Liu, Zhihao,Li, Yongming,Meng, Qiang,Zhang, Jianbin,Yao, Jihong,Liu, Kexin,Ma, Xiaodong,Sun, Xiuli
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p. 1847 - 1857
(2017/12/04)
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- NOVEL PYRROLOPYRIMIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and the compound according to the present invention can be usefully used for the prevention or treatment of diseases in which the
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Page/Page column 14; 15
(2018/05/27)
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- Tetrahydropyridine [4,3-d]miazines derivative and purpose thereof
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The invention relates to a tetrahydropyridine [4,3-d]miazines derivative and an optical isomer shown as a general formula I, pharmaceutically acceptable salt, a solvate or a prodrug, preparation methods thereof, and a pharmaceutical composition taking a compound shown as a general formula I as an active component, wherein substituent R1, R3, L, and P have meanings in the specification. The invention relates to the compound shown in the general formula I having strong ATX and EGFR kinases inhibition effect, the invention also relates to the compound and the optical isomer, and the application of the pharmaceutically acceptable salt for preparing a medicine for treating and/or preventing disease caused by ATX and EGFR abnormal expression, and especially relates to the purpose of the compoundin preparation of the medicine for treating and/or preventing fibration and cancer.
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Paragraph 0134; 0146; 0147
(2018/10/11)
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- Pyrimidine compound, composition, and applications thereof for treatment of lymphoma leukemia
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The invention relates to a pyrimidine compound, a composition and applications thereof for treatment of lymphoma leukemia, wherein the pyrimidine compound particularly is the compound represented as the general formula (I), substituent groups therein defi
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Paragraph 0028; 0034; 0036; 0037; 0038
(2018/10/19)
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- Diphenylaminopyrimidine compound, composition and application
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The invention relates to a diphenylaminopyrimidine compound, a composition and an application. Concretely, the diphenylaminopyrimidine compound is a compound as shown in a general formula (I) described in the specification, wherein substituents in the general formula (I) are as defined in the specification. The invention also relates to the compound as shown in the general formula (I) or pharmaceutically acceptable salts thereof, or the application of a pharmaceutical composition containing the compound in treatment of tumor diseases by inhibiting Bruton's tyrosine kinase BTK and/or Janus tyrosine kinase JAK3, especially in treatment of burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
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Paragraph 0074; 0076; 0077; 0078
(2017/08/28)
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- Synthesis and biological evaluation of morpholine-substituted diphenylpyrimidine derivatives (Mor-DPPYs) as potent EGFR T790M inhibitors with improved activity toward the gefitinib-resistant non-small cell lung cancers (NSCLC)
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Potential new EGFRT790M inhibitors comprised of structurally modified diphenylpyrimidine derivatives bearing a morpholine functionality (Mor-DPPYs) were used to improve the activity and selectivity of gefitinib-resistant non-small cell lung cancer (NSCLC) treatment. This led to the identification of inhibitor 10c, which displayed high activity against EGFRT790M/L858R kinase (IC50?=?0.71?nM) and repressed H1975?cell replication harboring EGFRT790M mutations at a concentration of 0.037?μM. Inhibitor 10c demonstrated high selectivity (SI?=?631.9) for T790M-containing EGFR mutants over wild type EGFR, suggesting that it will cause less side effects. Moreover, this compound also shows promising antitumor efficacy in a murine EGFRT790M/L858R-driven H1975 xenograft model without affecting body weight. This study provides new potential lead compounds for further development of anti-NSCLC drugs.
- Song, Zhendong,Huang, Shanshan,Yu, Haiqing,Jiang, Yu,Wang, Changyuan,Meng, Qiang,Shu, Xiaohong,Sun, Hunjun,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
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p. 329 - 339
(2017/04/11)
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- C-2 (E)-4-(Styryl)aniline substituted diphenylpyrimidine derivatives (Sty-DPPYs) as specific kinase inhibitors targeting clinical resistance related EGFRT790M mutant
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With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFRT790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFRT790M inhibitors. Among them, the compound 10e displayed strong potency against the EGFRT790M enzyme, with the IC50 of 11.0?nM. Compound 10e also showed a higher SI value (SI?=?49.0) than rociletinib (SI?=?21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFRT790M mutation, within the concentration of 2.91?μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50?=?22.48?μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFRT790M over wild-type (EGFRWT).
- Song, Anran,Zhang, Jianbin,Ge, Yang,Wang, Changyuan,Meng, Qiang,Tang, Zeyao,Peng, Jinyong,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
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p. 2724 - 2729
(2017/04/17)
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- Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia
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A new series of diphenylpyrimidine derivatives (SFA-DPPYs) were synthesized by introducing a functional sulfonamide into the C-2 aniline moiety of pyrimidine template, and then were biologically evaluated as potent Bruton's tyrosine kinase (BTK) inhibitors. Among these molecules, inhibitors 10c, 10i, 10j and 10k displayed high potency against the BTK enzyme, with IC50 values of 1.18?nM, 0.92?nM, 0.42?nM and 1.05?nM, respectively. In particular, compound 10c could remarkably inhibit the proliferation of the B lymphoma cell lines at concentrations of 6.49?μM (Ramos cells) and 13.2?μM (Raji cells), and was stronger than the novel agent spebrutinib. In addition, the inhibitory potency toward the normal PBMC cells showed that inhibitor 10c possesses low cell cytotoxicity. All these explorations indicated that molecule 10c could serve as a valuable inhibitor for B-cell lymphoblastic leukemia treatment.
- Liu, He,Qu, Menghua,Xu, Lina,Han, Xu,Wang, Changyuan,Shu, Xiaohong,Yao, Jihong,Liu, Kexin,Peng, Jinyong,Li, Yanxia,Ma, Xiaodong
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- Purine compounds, composition and application
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The invention belongs to the technical field of medicine and relates to purine compounds, composition and an application of the composition. The compounds represented as a general formula (I) as well as all possible isomers, pharmaceutical salts or hydrates or the composition of the compounds are used for treating diseases caused by BTK (Bruton tyrosine kinase) and particularly used for treating diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
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Paragraph 0066; 0069; 0070
(2017/07/04)
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- Structural optimization of diphenylpyrimidine derivatives (DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B leukemia cell lines
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A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib. Moreover, compound 7j is not sensitive to normal cells PBMC, indicating low cell cytotoxicity. In addition, flow cytometry analysis indicated that 7j significantly induced the apoptosis of Ramos cells, and arrested the cell cycle at the G0/G1 phase. These explorations provided new clues to discover pyrimidine scaffold as more effective BTK inhibitors.
- Zhao, Dan,Huang, Shanshan,Qu, Menghua,Wang, Changyuan,Liu, Zhihao,Li, Zhen,Peng, Jinyong,Liu, Kexin,Li, Yanxia,Ma, Xiaodong,Shu, Xiaohong
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p. 444 - 455
(2016/12/06)
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- Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines
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A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82?nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17?μM and 6.69?μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
- Ge, Yang,Yang, Haijun,Wang, Changyuan,Meng, Qiang,Li, Lei,Sun, Huijun,Zhen, Yuhong,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
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supporting information
p. 765 - 772
(2016/12/27)
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- Deuterated diphenylaminopyrimidine compound
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The invention belongs to the field of medicine, and relates to a deuterated diphenylaminopyrimidine compound or a pharmaceutically acceptable salt thereof, and more particularly to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, a preparation process thereof, a pharmaceutical composition thereof and application thereof in the treatment of a cell proliferative disease.
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Paragraph 0095; 0100; 0101; 0102; 0103
(2017/05/10)
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- Sulfamine pyrimidine compound, composition and purpose
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The invention relates to a sulfamine pyrimidine compound, a composition and a purpose. The sulfamine pyrimidine compound is concretely a compound shown by a general formula (I); each substituent group in the general formula (I) is defined as the descripti
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Paragraph 0079; 0080; 0085; 0086
(2017/07/23)
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- 2,4-dibasic miazines compound
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The invention belongs to the field of medical chemistry, relates to a 2,4-dibasic miazines compound and specifically relates to a compound shown as formula (I) or a pharmaceutically acceptable salt thereof, a drug compound thereof and an application thereof in treating EGFR or/and ALK mediated diseases.
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Paragraph 0144; 0149; 0150; 0151; 0152
(2017/08/29)
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- Phosphoryl pyrimidine compound, composition and use
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The invention relates to a phosphoryl pyrimidine compound, a composition and use. The phosphoryl pyrimidine compound is shown as the general formula (I) in the specification, and each substituent in the general formula (I) is defined as the specification.
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Paragraph 0067; 0068; 0069
(2017/08/28)
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- Diphenyl vinyl pyridine compound, composition and application thereof
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The invention relates to a diphenyl vinyl pyridine compound, a composition and application thereof. The diphenyl vinyl pyridine compound is specifically a compound shown by a general formula (I); and each substituent group of the general formula (I) is as shown by the definition in the specification. The invention also relates to application of the compound as shown in the general formula (I), pharmaceutically acceptable salts thereof or the pharmaceutical composition containing the same. The compound, the pharmaceutically acceptable salts thereof or the pharmaceutical composition containing the same is used for suppressing epidermal growth factor receptor (EGFR) protein tyrosine kinase to further treat tumor diseases, in particular, to treat non-small cell lung cancers, small cell lung cancers, squamous-cell carcinoma or pancreatic cancers.
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Paragraph 0085; 0086; 0087
(2017/08/28)
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- Pyrimidine derivative, preparation method and applications thereof
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The present invention provides a pyrimidine derivative represented by a formula (I), or a pharmaceutically acceptable salt, a preparation method and applications thereof. According to the present invention, the pyrimidine derivative represented by the formula (I), or the pharmaceutically acceptable salt thereof has JAK kinase inhibition activity, particularly provides selective and high inhibition activity on JAK3 kinase, can be used for preparation of JAK3 kinase inhibitors, and can be used for preparation of drugs for preventing or treatment of diseases associated with abnormal JAK3 kinase activity so as to prevent or treat diseases associated with abnormal JAK3 kinase activity. The formula (I) is defined in the specification.
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Paragraph 0084; 0085; 0086; 0096; 0097; 0098
(2016/10/08)
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- Pyrimidine derivative, preparation method and applications thereof
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The present invention provides a pyrimidine derivative represented by a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof, wherein the pyrimidine derivative represented by a formula (I), or pharmaceutically acceptable salt thereof has JAK kinase inhibition activity, particularly provides selective and high inhibition activity on JAK3 kinase, can be used for preparation of a JAK3 kinase inhibitor, and can be used for preparation of drugs for prevention or treatment of diseases associated with abnormal JAK3 kinase activity so as to prevent or treat diseases associated with abnormal JAK3 kinase activity. The formula (I) is defined in the specification.
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Paragraph 0085-0087; 0107-0110
(2016/11/17)
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- Compounds possessing kinase inhibition activity, preparation method and uses
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Compounds possessing kinase inhibition activity, a preparation method and uses are disclosed. The invention discloses the compounds shown as a general formula I, or pharmaceutically-acceptable salts thereof, or enantiomers, diastereomers, tautomerisms, solvates, polymorphic substances or prodrugs thereof, the preparation method of the above compounds, and application of the above compounds to medicines, and the groups in the general formula I are defined as the specification. The compounds possess relatively excellent kinase inhibition activity, and especially EGFR and ALK kinases and mutants thereof possessses relative good medicinal prospect.
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Paragraph 0063
(2016/10/10)
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- Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors
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A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790Minhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858Rkinase (IC50?=?3.3?nM), but also was able to repress the replication of H1975 cells harboring EGFRT790Mmutation at a concentration of 0.118?μmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI?=?299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects.
- Song, Zhendong,Jin, Yue,Ge, Yang,Wang, Changyuan,Zhang, Jianbin,Tang, Zeyao,Peng, Jinyong,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
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p. 5505 - 5512
(2016/10/24)
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- Pyrimidine derivative, preparation method therefor and application thereof in medicine
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The invention relates to a pyrimidine derivative, a preparation method therefor and an application thereof in medicine. Particularly, the invention relates to a compound as shown in general formula (M) or a stereisomer, an aquo-complex, a metabolic product, a solvate, a pharmaceutically acceptable salt, a co-crystallization or a prodrug thereof; the preparation method thereof; and the application of the medicine composition thereof and the compound medicine compound in the medicine, particularly the application as an EGFR target spot inhibitor, wherein the definition of each substituent group in the general formula (M) is the same as that of the specification.
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Paragraph 0179; 0185;0186; 0187; 0188; 0189
(2016/10/07)
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- PYRIMIDINE DERIVATIVES AS KINASE INHIBITORS AND THEIR THERAPEUTICAL APPLICATIONS
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The present invention provides kinase inhibitors with anti-proliferative activity comprising substituted pyrimidine derivatives and pharmaceutically-acceptable formulations thereof. In addition, the invention provides methods for making novel compounds and methods for using the compounds.
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Paragraph 00370
(2016/09/22)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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The disclosure includes compounds of Formula (I), wherein R0, R1, R2, R3, R4, R5, and L are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.
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Page/Page column 32
(2015/04/22)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column
(2015/03/31)
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- PROTEIN TYROSINE KINASE MODULATORS AND METHODS OF USE
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Heterocyclic pyrimidine compounds that modulate mutant-selective epidermal growth factor receptor (EGFR) and ALK kinase activity are disclosed. More specifically, the invention provides pyrimidines which inhibit, regulate and/or modulate kinase receptor, particularly in selectively modulation of various EGFR mutant activity and ALK kinase activity have been disclosed. Pharmaceutical compositions comprising the pyrimidine derivative,and methods of treatment for diseases associated with protein kinase enzymatic activity, particularly EGFR or ALK kinase activity including non-small cell lung cancer comprising administration of the pyrimidine derivative are disclosed.
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Page/Page column 43; 44
(2015/02/02)
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- MK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00867
(2014/10/03)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. Also disclosed are pharmaceutical compositions th
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Paragraph 00544; 00545
(2014/09/03)
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- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
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Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
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Page/Page column 74
(2013/07/31)
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