Braf inhibitors and use thereof for treatment of cutaneous reactions

Abstract

The present invention discloses novel BRaf inhibitors, compositions comprising these BRaf inhibitors and uses thereof for the treatment, amelioration and/or prevention of cutaneous reactions.

1 . A compound selected from
 (i) a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1-dimethylethyl)-1-methyl-TH-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         (ii) a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR 1 , wherein R 1  is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         (iii) a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR 1 , wherein R 1  is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptable salt or a solvate thereof, 
         or a combination thereof. 
       
     
     
         2 . The compound of formula I of  claim 1 , wherein R is 3-(trifluoromethoxy)phenyl. 
     
     
         3 . The compound of formula I, II or III of  claim 1 , wherein the compound inhibits the activity of BRaf. 
     
     
         4 . The compound of formula I, II or III of  claim 1 , wherein the compound increases the activity of Mitogen-Activated Protein Kinase (MAPK). 
     
     
         5 . The compound of formula I, II or III of  claim 1 , wherein the compound increases the activity of Mitogen-Activated Protein Kinase (MAPK) and wherein MAPK is an Extra-cellular Signal-Related Kinase (ERK). 
     
     
         6 . The compound of formula I, II or III of  claim 1 , wherein the compound has a photo-irritation factor (PIF) of less than 5. 
     
     
         7 . The compound of formula I, II or III of  claim 1 , wherein the compound has a mean photo effect (MPE) of less than 0.15. 
     
     
         8 . A pharmaceutical composition, comprising a compound selected from
 (i) a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or a solvate thereof, 
         (ii) a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR 1 , wherein R 1  is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         (iii) a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR1, wherein R1 is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         or a combination thereof; and a pharmaceutically acceptable carrier or excipient. 
       
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the compound is the compound of formula (I), and wherein R is 3-(trifluoromethoxy)phenyl. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the compound inhibits the activity of BRaf and increases the activity of Mitogen-Activated Protein Kinase (MAPK). 
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein the compound inhibits the activity of BRaf and increases the activity of Mitogen-Activated Protein Kinase (MAPK), and wherein the MAPK is an Extra-cellular Signal-Related Kinase (ERK). 
     
     
         12 . The pharmaceutical composition of  claim 8 , wherein the composition is formulated for systemic administration. 
     
     
         13 . The pharmaceutical composition of  claim 8 , wherein the composition is formulated for topical administration. 
     
     
         14 . The pharmaceutical composition of  claim 8 , wherein the composition is administered orally in the form of a tablet, a capsule, a liquid, a suspension or a powder. 
     
     
         15 . The pharmaceutical composition of  claim 8 , wherein the composition is in the form of a gel, a hydrogel, an ointment, a cream, a foam, a spray, a lotion, a liquid or a dermal patch. 
     
     
         16 . The pharmaceutical composition of  claim 8 , wherein the compound is present at a concentration of 1% w/w to 5% w/w of the total weight of the composition. 
     
     
         17 . The pharmaceutical composition of  claim 8 , wherein the compound is present at a concentration of 5% w/w to 10% w/w of the total weight of the composition. 
     
     
         18 . A method of treating, ameliorating, and/or preventing a cutaneous adverse reaction to EGFR inhibitors, PI3K inhibitors, MEK inhibitors or combinations thereof in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of a compound selected from
 (i) a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of p-chlorophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3-(1,1-dimethylethyl)-1-methyl-TH-pyrazol-5-yl, 3-(trifluoromethoxy)phenyl, 3,5-dihydroxyphenyl, phenyl-3-sulfonamide or 3-(trifluoromethyl)phenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         (ii) a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR 1 , wherein R 1  is 2-fluoro-4-iodophenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         (iii) a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein R is NHR 1 , wherein R 1  is 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 2-fluoro-4-iodophenyl, or 4-chloro-3-(trifluoromethyl) phenyl, or a pharmaceutically acceptable salt or a solvate thereof; 
         or a combination thereof, and a pharmaceutically acceptable carrier or excipient. 
       
     
     
         19 . The method of  claim 18 , wherein the compound is the compound of formula (I), and wherein R is 3-(trifluoromethoxy)phenyl. 
     
     
         20 . The method of  claim 18 , wherein the cutaneous adverse reaction is selected from acneiform rash, papulopustular rash, abnormal scalp hair growth, abnormal facial hair growth, abnormal hair growth, abnormal eyelash growth, paronychia with or without pyogenic granulomas and telangiectasia and combinations thereof.