Compounds for the inhibition of cyclophilins and uses thereof

Abstract

The present invention relates to compounds, and pharmaceutically acceptable compositions thereof, useful as inhibitors of cyclophilins, and for the treatment of cyclophilin-related disorders.

1 - 17 . (canceled) 
     
     
         18 . A method for treating a cyclophilin-mediated disease or disorder in a subject in need thereof, comprising the step of administering to said subject a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is 
 
       
         
           
           
               
               
           
         
         each R′ is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, or —N(R) 2 ; 
         each R 1  is independently —H or C 1-6  aliphatic which is optionally substituted; 
         each R 1a  is independently —H or C 1-6  aliphatic which is optionally substituted; 
         or R 1  and R 1a  taken together with the atom to which they are attached form a 3-7 -membered carbocyclic ring optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted; 
         each R 2  is independently —H or C 1-6  aliphatic which is optionally substituted; 
         each R 2a  is independently —H or C 1-6  aliphatic which is optionally substituted; 
         X is CH 2  or O; or X and the bonds attached to X are absent; 
         each R is independently hydrogen, C 1-6  aliphatic, C 3-10  aryl, a 3-8 -membered saturated or partially unsaturated carbocyclic ring, a 3-7 -membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 -membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or 
         two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10  aryl, a 3-8 -membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 -membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; 
         m is 1 or 2; 
         n is 1 or 2; and 
         p is 1, 2, 3, 4, or 5. 
       
     
     
         19 . The method of  claim 18 , wherein the disease or disorder is selected from viral infections, inflammation, neurologic disorders, cardiac failure and cancer. 
     
     
         20 . The method of  claim 18 , wherein the disease or disorder is selected from Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Dementia, Multiple Sclerosis, and Huntington's disease. 
     
     
         21 . The method of  claim 18 , wherein each R′ is independently —R, —OR, or —N(R) 2 . 
     
     
         22 . The method of  claim 21 , wherein each R′ is independently H, -Me, -Et, —OH, or —NH 2 . 
     
     
         23 . The method of  claim 18 , wherein X is CH 2 . 
     
     
         24 . The method of  claim 18 , wherein X, and the bonds attached to X, are absent. 
     
     
         25 . The method of  claim 18 , wherein each R 1  is independently H, Me, or -Et. 
     
     
         26 . The method of  claim 25 , wherein each R 1  is independently —H or -Me. 
     
     
         27 . The method of  claim 18 , wherein R 1  and R 1a  taken together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted. 
     
     
         28 . The method of  claim 18 , of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 18 , of formula V: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The compound of  claim 18 , of formula VI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 . The method of  claim 18 , wherein the compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         32 . The method of  claim 18 , wherein the compound selected from