1268830-74-5Relevant articles and documents
COMPOUNDS FOR THE TREATMENT OF BRAF-ASSOCIATED DISEASES AND DISORDERS
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Paragraph 0738; 0739, (2021/01/20)
Provided herein are compounds of the Formula I: and pharmaceutically acceptable salts, solvates and polymorphs thereof, wherein L, X1, R1, R2, R3, R4, R5 and R6 are as defined herein, for the treatment of BRAF-associated diseases and disorders, including BRAF-associated tumors, including malignant and benign BRAF-associated tumors of the CNS and malignant extracranial BRAF-associated tumors.
KINASE MODULATING COMPOUNDS, COMPOSITIONS CONTAINING THE SAME AND USE THEREOF
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, (2013/06/05)
The invention provides a compound represented by formula (I) which may modulate a kinase, and a pharmaceutical composition thereof, as well as the method for preventing or treating a protein kinase mediated disease or condition.
Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties
Mathieu, Simon,Gradl, Stefan N.,Ren, Li,Wen, Zhaoyang,Aliagas, Ignacio,Gunzner-Toste, Janet,Lee, Wendy,Pulk, Rebecca,Zhao, Guiling,Alicke, Bruno,Boggs, Jason W.,Buckmelter, Alex J.,Choo, Edna F.,Dinkel, Victoria,Gloor, Susan L.,Gould, Stephen E.,Hansen, Joshua D.,Hastings, Gregg,Hatzivassiliou, Georgia,Laird, Ellen R.,Moreno, David,Ran, Yingqing,Voegtli, Walter C.,Wenglowsky, Steve,Grina, Jonas,Rudolph, Joachim
experimental part, p. 2869 - 2881 (2012/06/01)
Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-RafV600E mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-RafV600E mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.