Therapeutic methods and compositions involving allosteric kinase inhibition

Abstract

The present invention is directed to methods and compositions for suppressing lymphangiogenesis, angiogenesis and/or tumor growth. The methods comprise contacting the tumor with a compound that (i) stabilizes a protein kinase in the inactive state and (ii) is not an ATP competitive inhibitor of the protein kinase in the active state.

1 . A compound has the structure 
       
         
           
           
               
               
           
         
       
       or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceutically acceptable salt thereof, wherein R 1  and R 2  are independently hydrogen, optional substituted alkyl, halogen, optional substituted amine, NH 2 , optional substituted alkyoxy, optional substituted thioalkyl, CF 3 S, optional substituted alkylsulfinyl or optional substituted alkylsulfonyl; Z′ is N or C; R m  is C 1-6  alkyl, or halogen substituted C 1-6  alkyl; and R 3  is independently a hydrogen, C 1-6  alkyl, halogen substituted C 1-6  alkyl, halogen substituted C 1-6  alkoxy, or C 3-10 cycloalkyl; or, optionally, R m  and R 3  are joined to form a five to seven membered carbocycle; and n is 0-4. 
     
     
         2 . The compound of  claim 1 , wherein R 1  is optional substituted alkyoxy, optional substituted thioalkyl, or CF 3 S. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is optional substituted amine or NH 2 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is optional substituted alkyoxy or optional substituted thioalkyl and R 2  is NH 2 . 
     
     
         5 . The compound of  claim 1 , wherein R m  is C 1-6  alkyl or CF 3 . 
     
     
         6 . The compound of  claim 1 , wherein R 3  is C 1-6  alkyl or halogen substituted C 1-6  alkyl. 
     
     
         7 . The compound of  claim 1 , wherein R m  and R 3  are joined to form a five to seven membered carbocycle. 
     
     
         8 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula II, 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (III), 
       
         
           
           
               
               
           
         
       
       in the presence of a base, wherein W is selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, triazine, 14uinolone, isoquinoline, cinnoline, quinazoline, quinoxaline, 1,2,4-benzotriazine and azaindole; X is O, S or NH; R 1  and R 2  are independently a hydrogen, optional substituted alkyl, halogen, optional substituted amine, —NH 2 , —OH, optional substituted alkoxy, optional substituted thioalkyl, —SCF 3 , optional substituted alkylsulfinyl or an optional substituted alkylsulfonyl; R 3  is independently a hydrogen, C 1-6  alkyl, halogen substituted C 1-6  alkyl, halogen substituted C 1-6  alkoxy, or C 3-10 cycloalkyl; or, optionally, two R3 are joined to form a 5 to 7 membered carbocycle; and m is 1-5. 
     
     
         10 . A process for preparing a compound of formula Ia: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula Iia, 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (IIIa), 
       
         
           
           
               
               
           
         
       
       in the presence of a base, wherein R 1  and R 2  are independently a hydrogen, optional substituted alkyl, halogen, optional substituted amine, —NH 2 , —OH, optional substituted alkoxy, optional substituted thioalkyl, —SCF 3 , optional substituted alkylsulfinyl or an optional substituted alkylsulfonyl and R 3  is a hydrogen, halogen substituted C 1-6  alkyl, or halogen substituted C 1-6  alkoxy. 
     
     
         11 . The process according to  claim 9 , wherein the molar ratio of said compound of formula II to said compound of formula III is in the range from 0.6:1 to 0.9:1. 
     
     
         12 . The process according to  claim 9 , wherein said base is an amine base. 
     
     
         13 . The process according to  claim 12 , wherein said amine base is 2,6-lutidine. 
     
     
         14 . The process according to  claim 9 , wherein R 1  is a hydrogen, —NH 2 , optional substituted alkoxy, optional substituted thioalkyl, CF 3 S, optional substituted alkylsulfinyl or an optional substituted alkylsulfonyl. 
     
     
         15 . The process according to  claim 9 , wherein R 2  is hydrogen, NH 2 , or optional substituted alkoxy. 
     
     
         16 . The process according to  claim 9 , wherein R 1  and R 2  are independently an optional substituted amine. 
     
     
         17 . The process according to  claim 9 , wherein R 1  is an optional substituted thioalkyl and R 2  is an optional substituted amine. 
     
     
         18 . The process according to  claim 17 , wherein R 1  is a MeS and R 2  is a NH 2 . 
     
     
         19 . The process according to  claim 18 , wherein R 3  is a hydrogen. 
     
     
         20 . A process for preparing a compound of formula IV: 
       
         
           
           
               
               
           
         
       
       comprising reacting a compound of formula V, 
       
         
           
           
               
               
           
         
       
       with a compound of formula (VI), 
       
         
           
           
               
               
           
         
       
       in the presence of a base wherein L is a leaving group; Y is —SH, —OH, or —NH 2 ; R 1  and R 2  are independently hydrogen, optional substituted alkyl, halogen, optional substituted protected amine, optional substituted alkoxy, optional substituted thioalkyl, CF 3 S, optional substituted alkylsulfinyl or optional substituted alkylsulfonyl and R 4  is a C 1-6  alkyl. 
     
     
         21 . The process according  claim 20 , wherein said compound of formula IV is a compound having the structure of formula IV: 
       
         
           
           
               
               
           
         
       
       said compound of formula V having the structure of Va, 
       
         
           
           
               
               
           
         
       
       said compound of formula VI is an alkyl hydroxybenzoate. 
     
     
         22 . The process according to  claim 20 , wherein R 1  and R 2  are independently an optional substituted protected amine. 
     
     
         23 . The process according to  claim 22 , wherein said optional substituted protected amine is protected by an acid labile protecting group. 
     
     
         24 . The process according to  claim 23 , wherein R 1  and R 2  are independently a —NHBoc or N(Boc) 2 . 
     
     
         25 . The process according to  claim 20 , wherein R 1  is an optional substituted thioalkyl and R 2  is an optional substituted protected amine. 
     
     
         26 . The process according to  claim 25 , wherein R 1  is an —Sme and R 2  is a —N(Boc) 2 . 
     
     
         27 . The process according to  claim 20 , where said base is 1,4-diazabicyclo[2.2.2]octane. 
     
     
         28 .- 63 . (canceled) 
     
     
         64 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         65 .- 71 . (canceled)