- Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2
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The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210?nM and 170?nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
- Qiang, Hao,Gu, Weijie,Huang, DanDan,Shi, Wei,Qiu, Qianqian,Dai, Yuxuan,Huang, Wenlong,Qian, Hai
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Read Online
- Lead optimization to improve the antiviral potency of 2-aminobenzamide derivatives targeting HIV-1 Vif-A3G axis
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The viral infectivity factor (Vif)–apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) axis has been recognized as a valid target for developing novel small-molecule therapies for acquired immune deficiency syndrome (AIDS) or for enhancing innate immunity against viruses. Our previous work reported the novel Vif antagonist 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide (2) with strong antiviral activity. In this work, through optimizations of ring C of 2, we discovered the more potent compound 6m with an EC50 of 0.07 μM in non-permissive H9 cells, reflecting an approximately 5-fold enhancement of antiviral activity compared to that of 2. Western blotting indicated that 6m more strongly suppressed the defensive protein Vif than 2 at the same concentration. Furthermore, 6m suppressed the replication of various clinical drug-resistant HIV strains (FI, NRTI, NNRTI, IN and PI) with relatively high efficacy. These results suggested that compound 6m is a more potent candidate for treating AIDS.
- Zhong, Xinxin,Luo, Ronghua,Yan, Guoyi,Ran, Kai,Shan, Huifang,Yang, Jie,Liu, Yuanyuan,Yu, Su,Pu, Chunlan,Zheng, Yongtang,Li, Rui
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- Discovery and Evaluation of Pyrazolo[3,4-d]pyridazinone as a Potent and Orally Active Irreversible BTK Inhibitor
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The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.
- Zhang, Xuejun,Sheng, Xijun,Shen, Jie,Zhang, Shoubo,Sun, Wenjie,Shen, Chunli,Li, Yi,Wang, Jun,Lv, Huqiang,Cui, Minghui,Zhu, Yuchuan,Huang, Lei,Hao, Dongling,Qi, Zhibo,Sun, Guanglong,Mao, Weifeng,Pan, Yan,Shen, Liang,Li, Xin,Hu, Guoping,Gong, Zhen,Han, Shuhua,Li, Jian,Chen, Shuhui,Tu, Ronghua,Wang, Xuehai,Wu, Chengde
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supporting information
p. 1863 - 1868
(2020/01/02)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0125; 0127
(2019/08/22)
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- Preparation methods of JAK inhibitor and salt thereof
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The present invention relates to preparation methods of a JAK inhibitor and a salt thereof. The preparation method comprises: (1) carrying out a Suzuki coupling reaction on (R)-3-(4-boronic acid-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile and 6-halogen-5-(2-methoxyvinyl)pyrimidin-4-ylamine to generate (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile; and (2)carrying out a protection group removing and ring-closure reaction on the (3R)-cyclopentyl-3-[4-(5-(2-methoxyvinyl)pyrimidin-4-ylamine)pyrazol-1-yl]propionitrile to generate a JAK inhibitor ruxolitinib. According to the present invention, the new ruxolitinib preparation route is provided, wherein each reaction of the route has the high yield, the total yield of the route is high, the purity of theobtained product is good, the post-treatment of the reaction is simple, and column chromatography is not required; by adopting the route, the required raw materials or catalysts and other materials are relatively easy to obtain; and compared to the method in the prior art, the method of the present invention is economical and is suitable for industrial production.
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Paragraph 0106; 0110
(2018/03/24)
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- Intermediate of JAK inhibitor, and preparation method thereof
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The present invention relates to a novel key intermediate of a JAK inhibitor ruxolitinib, and a preparation method thereof, wherein the chemical name of the intermediate is (R)-3-(4-boric acid-1H-pyrazole-1-yl)-3-cyclopentylpropionitrile. According to the present invention, the new ruxolitinib preparation route is provided, wherein each reaction of the route has the high yield, the total yield ofthe route is high, the purity of the obtained product is good, the post-treatment of the reaction is simple, and column chromatography is not required; by adopting the route, the required raw materials or catalysts and other materials are relatively easy to obtain; and compared to the method in the prior art, the method of the present invention is economical and is suitable for industrial production.
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Paragraph 0111
(2018/03/24)
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- Substituted aminopyrimidine compounds and their method and use thereof
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The invention relates to a new aminopyrimidine compound and an application thereof as a drug for treating disorder or diseases related to PI3-kinase abnormity in a free form or a pharmaceutically acceptable salt and preparation form. The invention also relates to a pharmaceutical composition which contains the new aminopyrimidine compound and an application of the pharmaceutical composition in treating mammal disorder or diseases and especially treating human disorder or diseases related to the PI3-kinase abnormity, such as treatment of immunity and inflammatory diseases of PI3-kinase regulation which plays a leading role in a leucocyte function and treatment of proliferative diseases which are related to PI3-kinase activity and include but not limited to leukaemia and solid tumor.
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Paragraph 0588; 0589; 0590; 0591
(2017/12/28)
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- BTK INHIBITOR
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Provided are a series of BTK inhibitors, and specifically disclosed are a compound, pharmaceutically acceptable salt thereof, tautomer thereof or prodrug thereof represented by formula (I), (II), (III) or (IV).
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Paragraph 0227-0228
(2017/11/16)
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- Substituted pyrimidine derivatives with Akt inhibiting activity, and preparation method and application thereof
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The invention relates to novel substituted pyrimidine derivatives with Akt inhibiting activity and a preparation method thereof, a pharmaceutical composition comprising the substituted pyrimidine derivatives and salts thereof, and application of the substituted pyrimidine derivatives and salts thereof in preparing drugs for preventing and/or treating tumors. The structural formula of the compounds is disclosed as Formula (I) or Formula (II). The compounds have the advantages of novel structure, outstanding Akt inhibiting activity, high safety and low preparation cost, and have favorable application prospects in preparing antineoplastic drugs.
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Paragraph 0136; 0137; 0138
(2016/12/16)
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- PROCESSES AND INTERMEDIATES FOR MAKING A JAK INHIBITOR
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This invention relates to processes and intermediates for making {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, useful in the treatment of diseases related to the activity of Janus kinases (JAK) including inflammatory disorders, autoimmune disorders, cancer, and other diseases.
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Paragraph 0169
(2014/09/29)
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- PROCESSES FOR PREPARING JAK INHIBITORS AND RELATED INTERMEDIATE COMPOUNDS
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The present invention is related to processes for preparing chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines of Formula III, and related synthetic intermediate compounds. The chiral substituted pyrazolyl pyrrolo[2,3-d]pyrimidines are useful as inhibitors of the Janus Kinase family of protein tyrosine kinases (JAKs) for treatment of inflammatory diseases, myeloproliferative disorders, and other diseases.
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Page/Page column 101-102
(2010/08/07)
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- SUBSTITUTED PYRIMIDINE-5-CARBOXAMIDE AND 5-CARBOXYLIC ESTER KINASE INHIBITORS
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The present invention is directed to substituted pyrimidine-5-carboxamide and 5-carboxylic ester compounds of Formula (I): and forms thereof wherein R1, R2, R3, R4, R5, R6, R7 and L are as defined herein and their synthesis and use as kinase inhibitors for treating a chronic or acute protein kinase mediated disease.
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Page/Page column 16
(2009/05/29)
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- COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 39
(2009/03/07)
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- Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases
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We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC50 values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.
- Xu, Guozhang,Searle, Lily Lee,Hughes, Terry V.,Beck, Amanda K.,Connolly, Peter J.,Abad, Marta C.,Neeper, Michael P.,Struble, Geoffrey T.,Springer, Barry A.,Emanuel, Stuart L.,Gruninger, Robert H.,Pandey, Niranjan,Adams, Mary,Moreno-Mazza, Sandra,Fuentes-Pesquera, Angel R.,Middleton, Steven A.,Greenberger, Lee M.
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scheme or table
p. 3495 - 3499
(2009/04/11)
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- A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine having dual EGFR/HER2 kinase activity: Design, synthesis, and biological activity
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A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.
- Hughes, Terry V.,Xu, Guozhang,Wetter, Steven K.,Connolly, Peter J.,Emanuel, Stuart L.,Karnachi, Prabha,Pollack, Scott R.,Pandey, Niranjan,Adams, Mary,Moreno-Mazza, Sandra,Middleton, Steven A.,Greenberger, Lee M.
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scheme or table
p. 4896 - 4899
(2009/05/07)
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- SUBSTITUTED PYRIMIDINYL KINASE INHIBITORS
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The present invention is directed to substituted pyrimidine compounds of formula (I): and forms thereof, their synthesis and use for treating, preventing or ameliorating a chronic or acute protein kinase mediated disease, disorder or condition.
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Page/Page column 96-97
(2008/06/13)
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- SYNERGISTIC MODULATION OF FLT3 KINASE USING AMINOPYRIMIDINES KINASE MODULATORS
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The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from aminopyrimidine compounds of Formula I′: where R3, B, Z, Q, p, q and R1 are as defined herein. Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.
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Page/Page column 34
(2010/11/25)
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- SYNERGISTIC MODULATION OF FLT3 KINASE USING AMINOPYRIMIDINES KINASE MODULATORS
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The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from aminopyrimidine compounds of Formula I′: where R3, B, Z, r and R1 are as defined herein. Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.
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Page/Page column 40
(2010/11/25)
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- AMINOPYRIMIDINES AS KINASE MODULATORS
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The invention is directed to aminopyrimidine compounds of Formula I: where R3, B, Z, Q, p, q and R1 are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 25-26
(2010/11/25)
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- AMINOPYRIMIDINES AS KINASE MODULATORS
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Abstract The invention is directed to aminopyrimidine compounds of Formula I: where R3, B, Z, r and R1 are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of FLT3 and/or c-kit and/or TrkB, the use of such compounds to reduce or inhibit kinase activity of FLT3 and/or c-kit and/or TrkB in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to FLT3 and/or c-kit and/or TrkB . The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.
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Page/Page column 47
(2008/06/13)
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- PYRIDO PYRIMIDINONES, DIHYDRO PYRIMIDO PYRIMIDINONES AND PTERIDINONES USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds having the formula: (I) wherein A-B together represents one of the following structures; (II), (III), (IV) and n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
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Page/Page column 95
(2010/11/08)
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- Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors
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Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
- Gomtsyan, Arthur,Didomenico, Stanley,Lee, Chih-Hung,Matulenko, Mark A.,Kim, Ki,Kowaluk, Elizabeth A.,Wismer, Carol T.,Mikusa, Joe,Yu, Haixia,Kohlhaas, Kathy,Jarvis, Michael F.,Bhagwatt, Shripad S.
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p. 3639 - 3648
(2007/10/03)
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