- C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization
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Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in small-molecule discovery. In particular, 2-Aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2-N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C-H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C-H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.
- Ham, Won Seok,Choi, Hoonchul,Zhang, Jianbo,Kim, Dongwook,Chang, Sukbok
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p. 2885 - 2892
(2022/02/23)
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- Melanomas new drug reaches pulls phinney preparation method (by machine translation)
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The invention discloses melanomas new drug reaches pulls phinney preparation method, the black pigment the lump is new medicine reaches pulls phinney the chemical name is N - [3 - [5 - (2 - amino - 4 - pyrimidinyl) - 2 - (tert-butyl) - 4 - thiazolyl] - 2 - fluorophenyl] - 2, 6 - difluorobenzoic sulfonamide, its chemical formula is C23 H20 F3 N5 O2 S2 , Its structural formula is: ; The process of the invention has simple process, raw materials are easy, economic and environmental protection, quality is controllable, is beneficial for the industrialized, can promote the melanomas new drug reaches pulls phinney economic and technological development, and reduces the production cost, and is suitable for mass production. (by machine translation)
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- Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis
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Herein we report a highly efficient method for nickel-catalyzed C?N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C?N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.
- Kim, Taehoon,McCarver, Stefan J.,Lee, Chulbom,MacMillan, David W. C.
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p. 3488 - 3492
(2018/03/05)
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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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Page/Page column 34
(2017/03/21)
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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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Page/Page column 28; 32
(2017/03/21)
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- Novel Crystal Form of Dabrafenib Mesylate and Preparation Method Thereof
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Disclosed are a novel crystal form of Dabrafenib mesylate and preparation method thereof. The novel crystal form of the present invention is more stable in water or an aqueous system, and has greater solubility and dissolution in water, thus having better stability and bioavailability compared with the existing crystal forms.
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Paragraph 0111; 0112
(2016/03/13)
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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 7
(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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Page/Page column 24; 25
(2015/06/25)
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- Crystal Form of Dabrafenib and Preparation Method and Use Thereof
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The invention relates to a new crystal form of dabrafenib and preparation method thereof. With respect to known crystal forms, the new crystal form has the advantage of being more stable at room temperature or in aqueous systems, and has low hygroscopicity, and thus is more suitable for a wet granulation process or being prepared into a suspension. The present invention also relates to a pharmaceutical composition and formulations comprising the new crystal form, and their use in the treatment of Raf family kinase-related diseases.
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Paragraph 0227-0232
(2015/11/16)
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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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Page/Page column 20; 24
(2014/05/24)
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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 27; 31
(2015/01/06)
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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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Page/Page column 15-16
(2011/05/05)
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