- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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- Denitrified purine compound and pharmaceutical composition, preparation method and application thereof
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The invention relates to denitrified purine compound which has a structure as a following general formula 1, a preparation method of the denitrified purine compound, a pharmaceutical composition containing the denitrified compound and application of the denitrified compound. The compound has selective B-Raf V600E mutation cancer cell inhibition activity, so that the denitrified purine compound disclosed by the invention and the pharmaceutical composition of the denitrified purine compound can be applied to preparing medicine for treating tumor or cancer.
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- SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS
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The present invention relates to a process for the preparation substantially pure propane-1-sulfonicacid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide or Vemurafenib of Formula (I). The present invention further relates to a process for the preparation substantially pure propane-1-sulfonic acid-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3 -b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII)
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Paragraph 0123
(2018/12/04)
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- Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf V600E inhibitors
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The mutation of B-Raf V600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf V600E is an ideal drug target. This study focused on developing novel B-Raf V600E inhibitors as drug leads against various cancers with B-Raf V600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf V600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf V600E inhibitors. A highly potent fragment binding to the hinge area of B-Raf V600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf V600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf V600E inhibitor with an IC 50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-Raf WT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf V600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.
- Wang, Gui-Min,Wang, Xiang,Zhu, Jian-Ming,Guo, Bin-Bin,Yang, Zhuo,Xu, Zhi-Jian,Li, Bo,Wang, He-Yao,Meng, Ling-Hua,Zhu, Wei-Liang,Ding, Jian
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p. 1059 - 1068
(2017/07/11)
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- SUBSTANTIALLY PURE VEMURAFENIB AND ITS SALTS
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The present Invention relates to a process for the preparation substantially pure propane- 1 -sulfonicacid- { 3 -[5 -(4-chiorophenyI)-1 H-pyrrolo [2,3-b]pyridine-3 -carbonyl]-2,4-difluoro-phenyl} -amide or Vemurafenib of Formula (1), The present invention further relates to a process for the preparation substantially pure propane- 1 -sulfonic acid- { 3 - [5-(4-chlorophenyi)-1H-pyrrolo [2,3-b]pyridine-3 -carbonyl] -2,4-difluoro-phenyl} -amide trifluoro methane sulfonic acid salt or Vemurafenib triflate of Formula (VII).
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Page/Page column 23
(2016/06/14)
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- NOVEL PROCESSES FOR THE MANUFACTURE OF PROPANE-1-SULFONIC ACID {3-[5-(4-CHLORO-PHENYL)-1H-PYRROLO[2,3-B]PYRIDINE-3-CARBONYL]-2,4-DIFLUORO-PHENYL}-AMIDE
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According to the present invention there are provided novel processes for the manufacture of the compound of formula (1) as well as novel synthesis routes for key intermediates used in those processes.
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Page/Page column 26-27
(2012/02/05)
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- PROCESS FOR THE MANUFACTURE OF PHARMACEUTICALLY ACTIVE COMPOUNDS
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According to the present invention there are provided novel processes for the manufacture of the compound of formula 1 as well as novel synthesis routes for key intermediates used in those processes.
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Page/Page column 8-9
(2011/02/25)
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- PYRROLO [2, 3. B] PYRIDINES WHICH INHIBIT RAF PROTEIN KINASE
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Compounds (I) and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on each of BRaf and c-Raf -1 protein kinase, and may also be active on either or both of A-Raf and B-Raf V600E protein kinase. Also described are methods of use thereof to treat diseases and conditions, including melanoma, colorectal cancer, thyroid cancer, ovarian cancer, and biliary tract cancer.
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- PYRROLO [2, 3-B] PYRIDINE DERIVATIVES FOR THE INHIBITION OF RAF KINASES
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Propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide, propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, propane-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide, N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide, N-[3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide, pyrrolidine-1-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, N,N-dimethylamino-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on at least one Raf protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Raf protein kinases, including melanoma, glioma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, and biliary tract cancer.
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Page/Page column 34
(2010/10/03)
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- N- (6-AMINOPYRIDIN-3-YL) -3- (SULFONAMIDO) BENZAMIDE DERIVATIVES AS B-RAF INHIBITORS FOR THE TREATMENT OF CANCER
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Compounds of Formula (I) are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.
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- PYRROLO[2,3-B] PYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Compounds of formula III which are active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Page/Page column 75
(2010/11/25)
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