Heterocyclic Flavone Derivatives, Compositions, and Methods Related Thereto

Abstract

In certain embodiments, the disclosure relates to heterocyclic flavone derivatives, such as those described by formula provided herein, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to methods of treating or preventing diseases or conditions related to BDNF and TrkB activity, such as depression, stroke, Rett syndrome, Parkinson's disease, and Alzheimer's disease by administering effective amounts of pharmaceutical compositions comprising compounds disclosed herein.

1 . A method of treating Alzheimer's disease comprising the administering to a subject in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or salt thereof wherein, 
         X is O; 
         A is pyrrolidinyl; 
         R 1  and R 2  and attached atoms form a 5 membered heterocyclic ring optionally substituted with R 15 ; 
         R 3 , R 4 , R 5 , R 6 , and R 8 , are hydrogen; 
         R 7  and R 9  are halogen; 
         R 15  is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         R 16  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula I is administered in combination with memantine. 
     
     
         3 . The method of  claim 1 , wherein the compound of formula I is administered in combination with donepezil. 
     
     
         4 . The method of  claim 1 , wherein the compound of formula I is administered in combination with galantamine. 
     
     
         5 . The method of  claim 1 , wherein the compound of formula I is administered in combination with rivastigmine. 
     
     
         6 . The method of  claim 1 , wherein the compound is selected from:
 8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one,   2-chloro-8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(3H)-one, and   8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazole-2,6(1H,3H)-dione, or salts thereof.   
     
     
         7 . A method of treating dementia comprising the administering to a subject in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or salt thereof wherein, 
         X is O; 
         A is pyrrolidinyl; 
         R 1  and R 2  and attached atoms form a 5 membered heterocyclic ring optionally substituted with R 15 ; 
         R 3 , R 4 , R 5 , R 6 , and R 8 , are hydrogen; 
         R 7  and R 9  are halogen; 
         R 15  is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         R 16  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethyl sulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         8 . The method of  claim 7 , wherein the compound of formula I is administered in combination with memantine. 
     
     
         9 . The method of  claim 7 , wherein compound of formula I is administered in combination with donepezil. 
     
     
         10 . The method of  claim 7 , wherein the compound of formula I is administered in combination with galantamine. 
     
     
         11 . The method of  claim 7 , wherein the compound of formula I is administered in combination with rivastigmine. 
     
     
         12 . The method of  claim 7 , wherein the compound is selected from:
 8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one,   2-chloro-8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(3H)-one, and   8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazole-2,6(1H,3H)-dione, or salts thereof.   
     
     
         13 . The method of  claim 7 , wherein the subject is diagnosed with Alzheimer's disease.