1190380-49-4Relevant articles and documents
JAK1 SELECTIVE KINASE INHIBITOR
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Page/Page column 78-79, (2020/10/28)
Disclosed herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, that are useful as JAK kinase inhibitors. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula (I), and methods of using such compounds or compositions to treat respiratory conditions (e.g., asthma or COPD).
TGF-betaR1 inhibitor and application thereof
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Paragraph 0351; 0356-0358, (2020/06/09)
The invention belongs to the field of medical chemistry, and particularly relates to a compound serving as a TGF-betaR1 inhibitor and application of the compound. Specifically, the invention providesa compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition to treatment and/or prevention of TGF-betaR1 related diseases, such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compound provided by the invention shows significant inhibitory activity on TGF-betaR1 kinase, and is very expected to become a therapeutic agent for TGF-betaR1 related diseases.
Design, synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-β (TGF-β) type I receptor inhibitors
Li, Bo,Li, Wei,Li, Xue,Quan, Xu,Tan, Bin,Zhang, Xiaomeng,Zhao, Liwen,Zheng, Guochuang
supporting information, (2020/06/22)
TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6percent. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-βR1 inhibitor.
Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study
Wang, Ruifeng,Zhao, Xiangxin,Yu, Sijia,Chen, Yixuan,Cui, Hengxian,Wu, Tianxiao,Hao, Chenzhou,Zhao, Dongmei,Cheng, Maosheng
, (2020/07/23)
Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery.
Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents
Wang, Ruifeng,Chen, Yixuan,Zhao, Xiangxin,Yu, Sijia,Yang, Bowen,Wu, Tianxiao,Guo, Jing,Hao, Chenzhou,Zhao, Dongmei,Cheng, Maosheng
, (2019/09/30)
A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymatic activities of FAK, with IC50 values in the 10?8–10?9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 μM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors.
2-substituted parazoleamino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
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Paragraph 0097; 0098; 0101, (2019/04/10)
The invention relates to a series of new compounds as a JAK inhibitor, as well as compositions and applications thereof, and particularly provides a series of compounds (I) that have a strong JAK inhibiting activity, or stereisomers, geometrical isomers, tautomers, pharmaceutically acceptable salts, prodrugs, metabolites, isotope derivatives, and solvates, as well as medicine compositions comprising such compounds. The invention also discloses applications of the compounds or the medicine compositions in preparation of a medicine, which is used for treatment of autoimmune diseases or cancer.
FUSED RING PYRIMIDINE COMPOUND, INTERMEDIATE, AND PREPARATION METHOD, COMPOSITION AND USE THEREOF
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Paragraph 0453-0454, (2018/08/12)
Disclosed area fused ring pyrimidine compound, and an intermediate, a preparation method, a composition and a use thereof. The fused ring pyrimidine compound is a compound as shown in formula I, a tautomer, an enantiomer, a diastereoisomer, a pharmaceutically acceptable salt, a metabolite, a metabolic precursor or a prodrug thereof, wherein the above-mentioned compound is used for the preparation of a medicine for preventing, remitting or treating one or more of immune system diseases, autoimmune diseases, cell proliferative diseases, allergic disorders and cardiovascular diseases, and the compound has a strong inhibitory effect on the Janues kinase, FGFR kinase, FLT3 kinase and Src family kinase.
HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
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Page/Page column 117, (2017/01/09)
Disclosed are compounds of Formula (I) Formula(I) or salts thereof, wherein HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[l,2-b]pyridazin-3-yl, and pyrazolo[l,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; and R1, R3, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
Five-And-Six-Membered Heterocyclic Compound, And Preparation Method, Pharmaceutical Composition And Use Thereof
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Paragraph 0285; 0287, (2015/12/07)
A five-and-six-membered heterocyclic compound as represented by general formula I, pharmaceutically acceptable salt, metabolite, metabolic precursors or drug precursors thereof, preparation method, pharmaceutical composition, and use thereof; the five-and-six-membered heterocyclic compound has activity as a Janus kinase (JAK) inhibitor, and can be used to prepare drugs for treating diseases caused by the abnormal activity of kinase, such as cell proliferation diseases like cancer.
BIARYL COMPOUNDS USEFUL FOR THE TREATMENT OF HUMAN DISEASES IN ONCOLOGY, NEUROLOGY AND IMMUNOLOGY
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Paragraph 0211; 0220, (2015/06/25)
The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.
