Certain chemical entities, compositions, and methods

Abstract

Chemical entities based on quinoxaline that are kinase inhibitors are described. Specifically, quinoxaline derivatives of Formula I, containing a diarylamide or diarylurea substructure that inhibit Braf mutant kinase activity, pharmaceutical compositions containing the inhibitor compounds and methods of treatment of cancer comprising administering an effective amount of the Braf inhibitor compound are described.

1 .- 77 . (canceled) 
     
     
         78 . A process for preparing a compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
         contacting the compound having the structure of Formula A-7: 
       
       
         
           
           
               
               
           
         
         with a suitable isocyanate reagent under suitable reaction conditions to provide the compound having the structure of Formula I; 
         wherein:
 R 11  is —CONR 12 R 13 ;
 R 12  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 13  is hydrogen; 
 
 R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10  are each independently hydrogen or halo; and 
 R 9  is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
 
       
     
     
         79 . The process of  claim 78 , wherein:
 the suitable isocyanate reagent is an (optionally substituted aryl)-isocyanate.   
     
     
         80 . The process of  claim 79 , wherein:
 R 12  is optionally substituted aryl.   
     
     
         81 . The process of  claim 78 , wherein the compound having the structure of Formula A-7 is prepared from contacting a compound having the structure of Formula A-6: 
       
         
           
           
               
               
           
         
         with a suitable reagent under suitable reaction conditions to provide the compound having the structure of Formula A-7; 
         wherein PG is a suitable protecting group. 
       
     
     
         82 . The process of  claim 81 , wherein the suitable protecting group of step (i) is —C(═O)Ot-Bu or —C(═O)t-Bu. 
     
     
         83 . The process of  claim 82 , wherein the suitable reagent of step (i) is an acid selected from HCl, HBr, trifluoroacetic acid, and H 2 SO 4 , or a base selected from NaOH, KOH, or CsOH. 
     
     
         84 . The process of  claim 82 , wherein the suitable reagent is HCl. 
     
     
         85 . The process of  claim 81 , wherein the compound having the structure of Formula A-6 is prepared from contacting a compound having the structure of Formula A-5: 
       
         
           
           
               
               
           
         
         with a suitable oxidant under suitable reaction conditions to provide the compound having the structure of Formula A-5. 
       
     
     
         86 . The process of  claim 85 , wherein the compound having the structure of Formula A-5 is prepared from contacting a compound having the structure of Formula A-2: 
       
         
           
           
               
               
           
         
         with a metallated aryl compound compound having a structure of Formula A-4: 
       
       
         
           
           
               
               
           
         
         under suitable reaction conditions to provide the compound having the structure of Formula A-5 
         wherein:
 M is a metal ion selected from Li and Mg. 
 
       
     
     
         87 . The process of  claim 86 , wherein M is Li; and the metallated aryl compound having a structure of Formula A-4 is prepared by:
 (a) contacting a suitable aryl bromide compound with n-BuLi; or   (b) contacting a suitable aryl compound with LDA.   
     
     
         88 . The process of  claim 81 , wherein the compound having the structure of Formula A-6 is prepared from reacting a compound having the structure of Formula B-5: 
       
         
           
           
               
               
           
         
         under suitable reaction conditions to provide the compound having the structure of Formula A-5. 
       
     
     
         89 . The process of  claim 88 , wherein the suitable reaction conditions are nucleophilic displacement conditions. 
     
     
         90 . The process of  claim 88 , wherein the suitable reaction conditions are transition metal catalyzed cross-coupling conditions. 
     
     
         91 . The process of  claim 88 , wherein the compound having the structure of Formula B-5 is prepared from contacting a compound having the structure of Formula B-4: 
       
         
           
           
               
               
           
         
         with a suitable oxidant under suitable reaction conditions to provide the compound having the structure of Formula B-5. 
       
     
     
         92 . The process of  claim 91 , wherein the compound having the structure of Formula B-4 is prepared from contacting a compound having the structure of Formula B-3: 
       
         
           
           
               
               
           
         
         with a metallated aryl compound compound having a structure of Formula A-4: 
       
       
         
           
           
               
               
           
         
         under suitable reaction conditions to provide the compound having the structure of Formula B-4 
         wherein:
 M is a metal ion selected from Li and Mg. 
 
       
     
     
         93 . The process of  claim 92 , wherein M is Li; and the metallated aryl compound having a structure of Formula A-4 is prepared by:
 (a) contacting a suitable aryl bromide compound with n-BuLi; or   (b) contacting a suitable aryl compound with LDA.   
     
     
         94 . The process of  claim 78 , wherein:
 R 1  is hydrogen, optionally substituted amino, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;   R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 10  are each hydrogen;   R 6  is hydrogen or halo;   R 9  is hydrogen   R 12  is optionally substituted aryl; and   R 13  is hydrogen.   
     
     
         95 . The process of  claim 94 , wherein:
 R 1  is morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, imidazolyl, pyrazolyl, or pyridyl, each of which is optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted C 1 -C 6  alkyl, and —O—(C 1 -C 6  alkyl); and   R 12  is aryl substituted with one or more substituents independently selected from halo and optionally substituted C 1 -C 6  alkyl.   
     
     
         96 . A compound selected from the group consisting of:
 1-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-5-fluorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chlorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chlorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-dichlorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3,5-difluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chlorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-chlorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-dichlorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-5-fluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(5-fluoropyridin-3-yl)urea;   1-(5-chloropyridin-3-yl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea;   1-(4-fluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-methoxyquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-5-fluorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chlorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;   1-(3,4-difluorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-4-fluorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chlorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-dichlorophenyl)-3-(3-fluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chlorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3-chloro-4-fluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chlorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea;   1-(3,4-difluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-dichlorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-5-fluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3,5-difluorophenyl)-3-(3-fluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3,5-difluorophenyl)urea;   1-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea;   1-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3,4-difluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-difluoro-5-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluorophenyl)-3-(3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-chlorophenyl)-3-(3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(3-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(3-fluorophenyl)-3-(3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(3-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-chloro-4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3,5-difluorophenyl)-3-(4-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3,5-difluorophenyl)urea;   1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3,4-difluorophenyl)urea;   1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-fluorophenyl)urea;   1-(3,4-difluoro-5-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-fluorophenyl)urea;   1-(3-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-4-fluorophenyl)-3-(3-fluorophenyl)urea;   1-(3-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-4-fluorophenyl)-3-(4-fluorophenyl)urea;   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)urea;   1-(3-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-4-fluorophenyl)-3-(3,5-difluorophenyl)urea; and   1-(3-(3-((2-aminoethyl)amino)quinoxaline-6-carbonyl)-4-fluorophenyl)-3-(3,4-difluorophenyl)urea;   wherein the compound is prepared according to the process of  claim 78 .   
     
     
         97 . A compound selected from the group consisting of:
 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)urea;   1-(3-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea;   1-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea;   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)urea; and   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)urea;   wherein the compound is prepared according to the process of  claim 78 .