Fluorinated tetrahydronaphthyridinyl nonanoic acid derivatives and uses thereof

Abstract

The present invention relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing the fluorinated compounds of the invention, and methods of treating fibrosis, macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is 
 
       
         
           
           
               
               
           
         
         Q is 
       
       
         
           
           
               
               
           
         
         X is CR 4  or N; 
         Y is CR 4  or N; 
         R 1  is H, F, Cl, C 1 -C 4  alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; 
         R 2  and R 3  are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2  and R 3  is not H; 
         each R 4  is independently H, CH 2 F, CHF 2 , or CF 3 ; and 
         R 51  and R 52  are each independently H, F, or Cl; 
         provided that the compound of formula I contains at least one fluorine atom, and provided that when R 1  is not H, F, or Cl, and R 51  and R 52  are each H, then at least one of X and Y is CR 4 , and R 4  is CH 2 F, CHF 2 , or CF 3 . 
       
     
     
         2 . The compound of  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein X is N and Y is CR 4 . 
     
     
         4 . The compound of  claim 2 , wherein X and Y are each CR 4 . 
     
     
         5 . The compound of  claim 2 , wherein X and Y are each N. 
     
     
         6 . The compound of  claim 2 , wherein R 1  is H. 
     
     
         7 . The compound of  claim 2 , wherein R 1  is F, Cl, C 1 -C 4  alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms. 
     
     
         8 . The compound of  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , having formula IVa or IVb: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 ′ is CH 2 F, CHF 2 , or CF 3 . 
     
     
         10 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         11 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         12 . A method of treating or preventing a disease or condition mediated by an αv integrin in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         13 . A method of treating or preventing a disease or condition mediated by an αv integrin in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Z is 
 
       
         
           
           
               
               
           
         
         Q is 
       
       
         
           
           
               
               
           
         
         X is CR 4  or N; 
         Y is CR 4  or N; 
         R 1  is H, F, Cl, C 1 -C 4  alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; 
         R 2  and R 3  are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2  and R 3  is not H; 
         each R 4  is independently H, CH 2 F, CHF 2 , or CF 3 ; and 
         R 51  and R 52  are each independently H, F, or Cl; 
       
       provided that the compound of formula Ia contains at least one fluorine atom. 
     
     
         14 . The method of  claim 13 , wherein the disease is a fibrosis. 
     
     
         15 . The method of  claim 13 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 15 , wherein X is N and Y is CR 4 . 
     
     
         17 . The method of  claim 15 , wherein X and Y are each CR 4 . 
     
     
         18 . The method of  claim 15 , wherein X and Y are each N. 
     
     
         19 . The method of  claim 15 , wherein R 1  is H. 
     
     
         20 . The method of  claim 15 , wherein R 1  is F, Cl, C 1 -C 4  alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms. 
     
     
         21 . The method of  claim 13 , wherein Q is