Prodrugs of alpha-ketoglutarate, alpha-ketobutyrate, alpha-ketoisovalerate, and alpha-ketoisohexanoate, and uses thereof

Abstract

The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.

1 - 69 . (canceled) 
     
     
         70 . A compound of formula (VII), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —O(C═O)(alkyl); 
         R 2  is alkoxy; or
 R 1  and R 2 , together with the intervening atoms, form a fused 5-, 6-, or 7-membered heterocycle or cycloalkyl containing 0-3 N atoms and 0-3 O atoms in the ring, wherein the fused 5-, 6-, or 7-membered ring is substituted with halo, —CN, —OH, oxo, alkyl, haloalkyl, alkene, alkyne, alkoxy, heteroalkyl, monocyclic carbocycle, bicyclic carbocycle, monocyclic heterocycle, bicyclic heterocycle, or —CO 2 (alkyl); 
 
         R 3  is alkyl, heteroalkyl, alkoxy, or alkene; and 
         R 4  is alkyl, heteroalkyl, alkoxy, haloalkyl, alkene, or alkyne. 
       
     
     
         71 . The compound of  claim 70 , or a pharmaceutically acceptable salt thereof, wherein R 4  is alkyl. 
     
     
         72 . The compound of  claim 71 , or a pharmaceutically acceptable salt thereof, wherein R 4  is independently methyl, ethyl, or isopropyl. 
     
     
         73 . The compound of  claim 70 , or a pharmaceutically acceptable salt thereof, wherein R 3  is alkyl. 
     
     
         74 . The compound of  claim 73 , or a pharmaceutically acceptable salt thereof, wherein R 3  is methyl, ethyl, propyl, or isopropyl. 
     
     
         75 . The compound of  claim 70 , wherein R 2  is alkoxy. 
     
     
         76 . The compound of  claim 75 , wherein R 2  is ethoxy. 
     
     
         77 . The compound of  claim 70 , wherein R 3  is alkyl. 
     
     
         78 . The compound of  claim 77 , wherein R 3  is unsubstituted alkyl. 
     
     
         79 . The compound of  claim 78 , wherein R 3  is methyl, ethyl, or propyl. 
     
     
         80 . The compound of  claim 70 , wherein R 1  is —O(C═O)methyl; 
     
     
         81 . The compound of  claim 80 , wherein R 2  is ethoxy. 
     
     
         82 . The compound of  claim 81 , wherein R 3  is ethyl. 
     
     
         83 . The compound of  claim 70 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         84 . A pharmaceutical composition comprising a compound of  claim 70 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         85 . A method for treating an aging-related disease in a mammal, comprising administering to the mammal a compound, comprising administering to the mammal a compound of  claim 70 . 
     
     
         86 . The method of  claim 85 , wherein the disease or disorder is aging or an aging-related disease or disorder in a mammal. 
     
     
         87 . The method of  claim 86 , wherein the disease or disorder is cancer, neurodegenerative diseases or neurological disorder, sarcopenia, osteopenia, osteoporosis, arthritis, atherosclerosis, cardiovascular disease, hypertension, cataracts, presbyopia, glaucoma, type 2 diabetes, metabolic syndrome, alopecia, chronic inflammation, immunosenescence, age-related visual decline, age-related hair loss, thinning, or graying. 
     
     
         88 . The method of  claim 86 , wherein the age-related disease or disorder is a neurological disorder. 
     
     
         89 . The method of  claim 86 , wherein the age-related disease or disorder is an age-related heart condition.