1392429-91-2

Upstream product

• 535170-20-8 tert-butyl (3-amino-2,6-difluorophenyl)carbamate 
• 385-00-2 2,6-difluorobenzoic acid 
• 83141-10-0 2,6-difluoro-3-nitrobenzoic acid 
• 535170-17-3 tert-butyl (2,6-difluoro-3-nitrophenyl)carbamate 
• 260552-98-5 2,6-difluoro-3-nitrobenzoic acid chloride 
• 25892-08-4 N-(2,6-difluoro-3-nitrophenyl)acetamide 
• 3896-29-5 N-(2,6-difluorophenyl)acetamide 
• 5509-65-9 2,6-difluoroaniline 
• 946826-47-7 N-(3-amino-2,6-difluorophenyl)acetamide 

Downstream Products

• 1380228-32-9 N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)cyclopropanesulfonamide 
• 1380228-96-5 N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropansulfonamide 

Relevant academic research and scientific papers

Discovery of a highly specific and potent pan-RAF inhibitor

We describe the structure-based design and synthesis of N-(2,6-difluorophenyl)-3-(9H-purin-6-yl)pyridine-2-amine derivatives as a selective pan-RAF kinase inhibitor. The synthesized compounds showed highly potent and specific inhibition of the BRAFV600E mutant cell line. Among them, N-(3-((3-(9H-purin-6-yl) pyridine-2-yl)amino)-2,4-difluorophenyl)furan-3-sulfonamide (4b) exhibited the most potent inhibitory activities against protein kinase enzymes BRAFV600E, BRAFWT, and CRAF (IC50 of 2, 2, and 1 nM, respectively) and a mutant cell line bearing a BRAFV600E mutation, A375P (GI50 of 7 nM).

Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling

One of the challenges for targeting B-RafV600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-RafWT, as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-RafV600E. To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-RafV600E/B-RafWT biochemical (bS), cellular (cS) selectivity, and the phospho-ERK activation (pA). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-RafV600E selectivity.

NEW AZAINDOLYLPHENYL SULFONAMIDES AS SERINE/THREONINE KINASE INHIBITORS

The present invention encompasses compounds of general formula (I) wherein the groups R2 to R6, A, X, Y and m are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, pharmaceutical preparations which contain compounds of this kind and their use as medicaments.