1402746-99-9

Upstream product

• 1780-26-3 2,4-dichloro-2-methylpyrimidine 
• 1402747-70-9 6-chloro-2-methyl-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride 
• 1402747-81-2 N¹-(2-methyl-6-morpholinopyrimidin-4-yl)benzene-1,3-diamine 
• 1402747-80-1 2-methyl-6-morpholinyl-N-(3-nitrophenyl)pyrimidin-4-amine 
• 367-21-5 3-chloro-4-fluorophenylamine 
• 1402747-82-3 3-(2-methyl-6-morpholinopyrimidin-4-ylamino)phenyl carbamate (4-nitrobenzene) hydrochloride 

Relevant academic research and scientific papers

A urea compound, preparation method thereof, wherein the intermediate and its application

Disclosed are urea compounds represented by formula I or pharmaceutically acceptable salts, polymorphic forms, solvates or stereoisomers thereof; as well as preparation methods, intermediates and uses thereof. The urea compounds according to the present invention show various degrees of inhibitory activity against a variety of protein kinases in biological tests, and showed various degrees of activity against tumor cell growth and against angiogenesis in in vitro tests on resistance to the proliferation of human tumor cell line and human umbilical vein endothelial cells (HUVECs) respectively, and also exhibit good antitumor activity in vivo in animals.

Identification of type II inhibitors targeting BRAF using privileged pharmacophores

V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4-phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non-small-cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG-out conformation of BRAF. A novel pharmacophore, 4-phenylaminopyrimidine urea (4-PAPU) was hybrid-designed to successfully identify selective inhibitors of BRAF. Docking suggested that they might be type II kinase inhibitors binding to the DFG-out conformation of BRAF.