Prodrug modulators of the integrated stress pathway

Abstract

Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.

1 . A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from the group consisting of —C(O)—C 1-4 alkyl, —C(O)—O—C 1-4 alkyl, —C(O)—N(R a )—C 1-4 alkyl, —C(O)—C 1-4 alkylene-C 1-4 alkoxy, —C(O)—C 1-4 alkylene-O—C 1-4 alkylene-C 1-4 alkoxy, -methylene-O—P(O)(OH) 2 , —C(O)—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—O—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—N(R a )—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—C 1-5 alkylene-P(O)(OH) 2 , —C(O)—C 1-5 alkylene-phenylene-O—P(O)(OH) 2 , —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2 , —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 )(O—C 1-5 alkylene-P(O)(OH) 2 ), -methylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2  or -methylene-O—C(O)C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2 , —C(O)—O—C 1-5 alkylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2 , —C(O)—N(R a )-heteroarylene-C 1-2 alkylene-O—P(O)(OH) 2 , —P(O)(OH) 2 , —SO 3 H, —SO 2 NR a R b , —C(O)-heteroaryl, —C(O)—C 1-5 alkylene-O—C 1-5 alkylene-phenyl and methylene-C 1-5 alkoxide; 
 wherein —C(O)—C 1-4 alkyl is substituted by one or two substituents each independently selected from the group consisting of NR a R b  and —CO 2 H; and wherein —C(O)—O—C 1-4 alkyl, —C(O)—N(R a )—C 1-4 alkyl, —C(O)—C 1-4 alkylene-C 1-4 alkoxy, —C(O)—C 1-4 alkylene-O—C 1-4 alkylene-C 1-4 alkoxy, methylene-O—P(O)(OH) 2 , —C(O)—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—O—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—N(R a )—C 1-5 alkylene-O—P(O)(OH) 2 , —C(O)—C 1-5 alkylene-P(O)(OH) 2 , —C(O)—C 1-5 alkylene-phenylene-0-P(O)(OH) 2 , —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2 , —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 )(O—C 1-5 alkylene-P(O)(OH) 2 ), -methylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2  or -methylene-O—C(O)C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2 , —C(O)—O—C 1-5 alkylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2 , —C(O)-heteroaryl, —C(O)—C 1-5 alkylene-O—C 1-5 alkylene-phenyl and —C(O)—N(R a )-heteroarylene-C 1-2 alkylene-O—P(O)(OH) 2  may optionally be substituted by one, two, three or four substituents each independently selected from the group consisting of halogen, —CO 2 H, —NR a R b  and C 1-2 alkyl (optionally substituted by one, two or three fluorines) and aryl; and 
 R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl with the proviso that the compound is not 
 
       
         
           
           
               
               
           
         
          or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-4 alkyl, wherein —C(O)—C 1-4 alkyl is substituted by one or two substituents each independently selected from the group consisting of NR a R b  and —CO 2 H. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 1  is —C(O)—O—C 1-4 alkyl. 
     
     
         5 . The compound of  claim 4 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein R 1  is —C(O)—N(R a )—C 1-4 alkyl, wherein —C(O)—N(R a )—C 1-4 alkyl may optionally be substituted by one or two CO 2 H groups. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-4 alkylene-C 1-4 alkoxy. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-4 alkylene-O—C 1-4 alkylene-C 1-4 alkoxy. 
     
     
         11 . The compound of  claim 10 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-5 alkylene-O—P(O)(OH) 2 . 
     
     
         15 . The compound of  claim 14 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , wherein R 1  is —C(O)—O—C 1-5 alkylene-O—P(O)(OH) 2 . 
     
     
         17 . The compound of  claim 16 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , wherein R 1  is —C(O)—N(R a )—C 1-5 alkylene-O—P(O)(OH) 2 . 
     
     
         19 . The compound of  claim 18 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-5 alkylene-P(O)(OH) 2 . 
     
     
         21 . The compound of  claim 20 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-5 alkylene-phenylene-O—P(O)(OH) 2 —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2  or —C(O)—C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 )(O—C 1-5 alkylene-P(O)(OH) 2 ). 
     
     
         23 . The compound of  claim 22 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein R 1  is —C(O)—N(R a )-heteroarylene-C 1-2 alkylene-O—P(O)(OH) 2 . 
     
     
         25 . The compound of  claim 24 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 1 , wherein R 1  is —C(O)-heteroaryl. 
     
     
         27 . The compound of  claim 26 , wherein R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 1 , wherein R 1  is —C(O)—C 1-5 alkylene-O—C 1-5 alkylene-phenyl. 
     
     
         29 . The compound of  claim 28 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 1 , wherein R 1  is methylene-C 1-5 alkoxide. 
     
     
         31 . The compound of  claim 30 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 1 , wherein R 1  is —C(O)—O—C 1-5 alkylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2 , -methylene-O—C(O)C 1-5 alkylene-phenylene-O—P(O)(OH) 2  or -methylene-O—C(O)C 1-5 alkylene-phenylene-(O—P(O)(OH) 2 ) 2 . 
     
     
         33 . The compound of  claim 32 , wherein R 1  is represented by 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of —P(O)(OH) 2 , —SO 3 H, and —SO 2 NH 2 . 
     
     
         35 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A pharmaceutically acceptable composition comprising a compound of  claim 35  and a pharmaceutically acceptable carrier. 
     
     
         37 . (canceled) 
     
     
         38 . A method of treating a neurodegenerative disease, a leukodystrophy, a cancer, an inflammatory disease, an autoimmune disease, a viral infection, a skin disease, a fibrotic disease, a hemoglobin disease, a kidney disease, a hearing loss condition, an ocular disease, a musculoskeletal disease, a metabolic disease, or a mitochondrial disease, or a disease related to a modulation of eIF2B activity or levels, eIF2α activity or levels, or the activity or levels of a component of the eIF2 pathway or the ISR pathway, in a patient in need thereof, comprising administering to the patient an effective amount of a compound of  claim 35 . 
     
     
         39 .- 61 . (canceled)