Galactokinase inhibitors for the treatment and prevention of associated diseases and disorders

Abstract

Disclosed are inhibitors of human galactokinase of formula (1) that are useful in treating or preventing a galactokinase mediated disease or disorder, e.g., galactosemia. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal. Formula (I).

1 - 36 . (canceled) 
     
     
         37 . A method of inhibiting the enzymatic activity of galactokinase, the method comprising introducing a compound of formula (I) or a salt thereof to a galactosemic patient: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl or wherein R 1  and R 2 , taken together, along with the carbon atoms to which they are attached, form a 5- to 7-membered carbocyclic or heterocyclic ring, 
         wherein R 3  is selected from the group consisting of —NH-alkyl, —NH-cycloalkyl, —NH-aryl, —NH-alkylaryl, —NH-heteroaryl, and —NR 12 R 13  wherein R 12  and R 13  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, and heteroaryl, or wherein wherein R 12  and R 13  together form a heteroaryl or a heterocycloalkyl, 
         wherein R 4  is selected from the group consisting of hydrogen and alkyl, or 
         wherein R 3  and R 4  together form a group of the formula: 
       
       
         
           
           
               
               
           
         
         wherein R 6 , R 7 , R 8 , R 9 , R 10 , and R 11  are each independently selected from the group consisting of hydrogen, alkyl, aryl, and heteroaryl, 
         wherein m is 0 or 1, 
         wherein R 5  is heteroaryl, 
         wherein alkyl, aryl, heterocycloalkyl, carbocyclic ring, heterocyclic ring, arylalkyl, and heteroaryl groups are unsubstituted or optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halo, trifluoromethyl, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, 
         with the proviso that when R 5  is benzoxazol-2-yl, R 1  is hydrogen, R 2  is phenyl, R 3  and R 4  together form 
       
       
         
           
           
               
               
           
         
       
       and m is 1, R 10  and R 11  are not simultaneously methyl. 
     
     
         38 . The method of  claim 37 , wherein R 5  is selected from the group consisting of benzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 5-methyl-benzoxazol-2-yl, 6-methyl-benzoxazol-2-yl, 6-phenyl-benzoxazol-2-yl, benzoimidazol-2-yl, benzothiazol-2-yl, indol-1-yl, indol-2-yl, indol-3-yl, furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, imidazol-1-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl. 
     
     
         39 . The method of  claim 37 , wherein the R 5  is selected from the group consisting of benzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 5-methyl-benzoxazol-2-yl, 6-methyl benzoxazol-2-yl, and 6-phenyl-benzoxazol-2-yl. 
     
     
         40 . The method of  claim 37 , wherein R 5  is benzoxazol-2-yl. 
     
     
         41 . The method  claim 37 , wherein R 3  and R 4  together form 
       
         
           
           
               
               
           
         
         wherein m is 1, and wherein the compound has the formula (Ia): 
       
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 37 , wherein R 1  is hydrogen and R 2  is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, alkyl, alkoxy, aryloxy, and dialkylamino. 
     
     
         43 . The method of  claim 37 , wherein R 1  is hydrogen and R 2  is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, alkyl, alkoxy, aryloxy, and dialkylamino. 
     
     
         44 . The method of  claim 41 , wherein R 8  is hydrogen and R 9  is hydrogen or phenyl optionally substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, alkyl, alkoxy, aryloxy, amino, alkylamino, and dialkylamino, or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, alkyl, alkoxy, aryloxy, amino, alkylamino, and dialkylamino. 
     
     
         45 . The method of  claim 44 , wherein R 9  is phenyl substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, alkyl, alkoxy, and dialkylamino. 
     
     
         46 . The method of  claim 44 , wherein R 9  is heteroaryl selected from the group consisting of 5-methylthiophene-2-yl, pyridine-3-yl, pyridine-4-yl, 2-chloropyridin-4-yl, 3-trifluoropyridin-2-yl, 4-trifluoromethylpyridin-3-yl, 2-chloropyridin-3-yl, 2-bromopyridin-3-yl, 3-methylthiophene-2-yl, 3-bromopyridin-4-yl, 4-bromopyrazol-3-yl, 4-bromo-1-methylpyrazol-3-yl, 3-bromopyridin-4-yl, 4-chloro-1-methylpyrazol-3-yl, pyrazol-3-yl, 5-methylpyrazol-3-yl, and 4-chloro-1-methylpyrazol-3-yl. 
     
     
         47 . The method of  claim 37 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 37 , wherein the compound has the formula (Ib): 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of O, S, and SO 2 , 
         wherein R 14  is selected from the group consisting of hydrogen, alkyl, and aryl, and 
         wherein n is 0, 1, or 2. 
       
     
     
         49 . The method of  claim 48 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         50 . The method of  claim 37 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 37 , wherein R 3  is selected from the group consisting of —NH-alkyl, —NH-cycloalkyl, —NH-aryl, —NH-alkylaryl, —NH-heteroaryl, —N-heteroaryl, and —NR 12 R 13  wherein R 12  and R 13  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, and heteroaryl, or wherein R 12  and R 13  together form a heteroaryl or a heterocycloalkyl,
 wherein R 4  is selected from the group consisting of hydrogen and alkyl, 
 wherein R 5  is heteroaryl, and 
 wherein alkyl, aryl, heterocycloalkyl, carbocyclic ring, heterocyclic ring, arylalkyl, and heteroaryl groups are unsubstituted or optionally substituted with one or more substituents selected from the group consisting of alkyl, aryl, halo, trifluoromethyl, alkoxy, aryloxy, amino, alkylamino, and dialkylamino. 
 
     
     
         52 . The method of  claim 51 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         53 . The method of  claim 37 , wherein the compound has the formula (Ic): 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of —NH-alkyl, —NH-cycloalkyl, —NH-aryl, —NH-alkylaryl, —NH-heteroaryl, —N-heteroaryl, and —NR 12 R 13  wherein R 12  and R 13  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, and heteroaryl, or wherein R 12  and R 13  together form a heteroaryl or heterocycloalkyl, 
         wherein R 4  is selected from the group consisting of hydrogen and alkyl, 
         wherein Y is selected from the group consisting of CHR 10 , O, S, and SO 2 , 
         wherein R 10  and R 14  are each independently selected from the group consisting of hydrogen, alkyl, and aryl optionally substituted with one or more substituents selected from the group consisting of halo, trifluoromethyl, alkyl, alkoxy, aryloxy, and dialkylamino, and 
         wherein o is 0, 1, or 2. 
       
     
     
         54 . The method of  claim 53 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 37 , wherein the compound is delivered with a pharmaceutical carrier. 
     
     
         56 . The method of  claim 37 , wherein the patient is deficient in GALT.