Nonanoic and decanoic acid derivatives and uses thereof

Abstract

The present disclosure relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present disclosure also relates to pharmaceutical compositions containing the fluorinated compounds of the disclosure, 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 4  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; 
         W is 
       
       
         
           
           
               
               
           
         
       
       NR 61 R 62 , NR 61 C(O)NR 61 R 62 , NR 61 C(O)OR 62 , NR 61 C(O)R 62 , or NR 61 C(S)NR 61 R 62 ,
 R 61  is H or C 1 -C 4  alkyl; 
 R 62  is C 1 -C 4  alkyl, C 6 -C 10  aryl, or heterocyclyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S wherein the aryl and heterocyclyl are optionally substituted with one or more halogen, amino, C 1 -C 3  alkylamino, or C 1 -C 3  dialkylamino; and 
 n is 1 or 2. 
 
     
     
         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 at least one R 4  is H. 
     
     
         7 . The compound of  claim 2 , wherein at least one R 4  is CF 3 . 
     
     
         8 . The compound of  claim 2 , wherein R 1  is H. 
     
     
         9 . 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 4  alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms. 
     
     
         10 . The compound of  claim 9 , wherein R 1  is CF 3 . 
     
     
         11 . The compound of  claim 9 , wherein R 1  is OCF 3  or OCHF 2 . 
     
     
         12 . The compound of  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein W is 
       
         
           
           
               
               
           
         
       
       and n is 1. 
     
     
         14 . The compound of  claim 1 , wherein W is NHR 62  and n is 2. 
     
     
         15 . The compound of  claim 1 , wherein R 62  is heterocyclyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S. 
     
     
         16 . The compound of  claim 1 , wherein W is NHC(O)NHR 62 , NHC(O)OR 62 , NHC(O)R 62 , or NHC(S)NHR 62  and n is 2. 
     
     
         17 . The compound of  claim 1 , having formula IIIa or IIIb: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein Z′ is 
       
         
           
           
               
               
           
         
       
     
     
         18 . 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 . 
     
     
         19 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         20 . 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 a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof.