- Deaminative chlorination of aminoheterocycles
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Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)?NH2 can be converted into C(sp2)?Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents. [Figure not available: see fulltext.]
- Ghiazza, Clément,Faber, Teresa,Gómez-Palomino, Alejandro,Cornella, Josep
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- C-TERMINAL SRC KINASE INHIBITORS
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Provided herein are novel C-terminal Srk Kinase (CSK) inhibitors, e.g., having Formula G, I, II, or III. Also provided are methods of preparing the novel CSK inhibitors and method of using the novel CSK inhibitors for treating diseases or disorder such as cancer or for promoting immune response in a subject in need thereof. (G)
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- LIM KINASE INHIBITORS, PHARMACEUTICAL COMPOSITION AND METHOD OF USE IN LIMK-MEDIATED DISEASES
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The present invention relates to LIM Kinase inhibitors of Formula (I) and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, R3, R4, X1, X2, X3, Y1, Y2 and Z are as defined in the claims, and their use for the treatment and/or prevention of LIMK-mediated diseases.
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- COMBINATION OF RIBOCICLIB AND DABRAFENIB FOR TREATING OR PREVENTING CANCER
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The present disclosure relates to pharmaceutical combinations comprising a cyclin dependent kinase 4/6 (CDK4/6) inhibitor compound, (b) a B-Raf inhibitor compound, and optionally (c) an alpha-isoform specific phosphatidylinositol 3 -kinase (PI3K) inhibitor compound, for the treatment or prevention of cancer, as well as related pharmaceutical compositions, uses, and methods of treatment or prevention of cancer.
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- PHARMACEUTICAL COMBINATION COMPRISING THE PI3K INHIBITOR ALPELISIB AND THE B-RAF INHIBITOR DABRAFENIB; THE USE OF SUCH COMBINATION IN THE TREATMENT OR PREVENTION OF CANCER
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The present disclosure pertains to a pharmaceutical combination comprising (a) alpha- isoform specific PI3K inhibitor and (b) a B-RAF inhibitor; combined preparations and pharmaceutical compositions thereof; the uses of such combination in the treatment or prevention of cancer; and methods of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of such combination.
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- PROCESSES FOR THE PREPARATION OF DABRAFENIB
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A process for the preparation of dabrafenib and pharmaceutically acceptable salts thereof comprising the step of reacting formula-Ill (wherein X is a leaving group) with formamide in the presence of a base to get formula-ll
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Page/Page column 8-9
(2016/05/24)
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- COMBINATIONS OF TRAMETINIB, PANITUMUMAB AND DABRAFENIB FOR THE TREATMENT OF CANCER
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A novel combination comprising a B-Raf inhibitor, particularly N-{3-[5-(2- Amino-4-pyrimidinyl)-2-(1, 1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and/or the MEK inhibitor N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl;- 2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, and panitumumab (Vectibix); pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf and/or EGFR is beneficial, eg. cancer.
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- COMBINATIONS OF AN ANTI-PD-L1 ANTIBODY AND A MEK INHIBITOR AND/OR A BRAF INHIBITOR
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A novel combination comprising the MEK inhibitor N-{3-[3-cyclopropyl-5-(2-fluoro- 4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3- d]pyrimidin-1 -yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, and/or a B-Raf inhibitor, particularly N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1 - dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody; pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf and/or neutralizing or inhibiting the interaction between PD-L1 and its receptor, e.g. PD-1, is beneficial, eg. cancer.
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Page/Page column 30
(2015/01/06)
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- COMBINATION
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A novel combination comprising a B-Raf inhibitor, particularly N-{3-[5-(2-Amino- 4-pyrimidinyl)-2-(l, 1 -dimethylethyl)- 1,3-thiazol-4-yl]-2-fluorophenyl} -2,6- difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, and/or the MEK inhibitor N- {3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl;-2,4,7- trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-l-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, and an EGFR inhibitor suitably cetuximab (Erbitux) or erlotinib; pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf and/or EGFR is beneficial, eg. cancer.
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- Discovery of dabrafenib: A selective inhibitor of Raf Kinases with antitumor activity against B-Raf-driven tumors
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Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-RafV600E mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-RafV600E human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
- Rheault, Tara R.,Stellwagen, John C.,Adjabeng, George M.,Hornberger, Keith R.,Petrov, Kimberly G.,Waterson, Alex G.,Dickerson, Scott H.,Mook, Robert A.,Laquerre, Sylvie G.,King, Alastair J.,Rossanese, Olivia W.,Arnone, Marc R.,Smitheman, Kimberly N.,Kane-Carson, Laurie S.,Han, Chao,Moorthy, Ganesh S.,Moss, Katherine G.,Uehling, David E.
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supporting information
p. 358 - 362
(2013/05/09)
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- COMBINATION
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A novel combination comprising the MEK inhibitor N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl;-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, with a B-Raf inhibitor, particularly N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf is beneficial, eg. cancer.
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- Benzene Sulfonamide Thiazole and Oxazole Compounds
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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