Thiazolidinedione analogues

Abstract

The present invention relates to thiazolidinedione analogues that are useful for treating metabolic inflammation mediated diseases such as diabetes.

1 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic; 
 R 3  is hydrogen, halo, or optionally substituted aliphatic; and 
 Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1  at any chemically feasible position on ring A. 
 
   
   
       2 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula III: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; 
 R 3  is hydrogen, halo, or optionally substituted aliphatic; and 
 Ring A is a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S that is substituted with —CH 2 —R 1  at any chemically feasible position on ring A. 
 
   
   
       3 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula IV: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and 
 R 3  is hydrogen, halo, or optionally substituted aliphatic. 
 
   
   
       4 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula V: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and 
 R 3  is hydrogen, halo, or optionally substituted aliphatic. 
 
   
   
       5 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound of formula VI: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, hydroxyl, or aliphatic optionally substituted with hydroxy; and 
 R 3  is hydrogen, halo, or optionally substituted aliphatic. 
 
   
   
       6 . The method of  claim 1 , wherein R 1  is an optionally substituted straight or branched C 1-6  alkyl, an optionally substituted straight or branched C 2-6  alkenyl, or an optionally substituted straight or branched C 2-6  alkynyl. 
   
   
       7 . The method of  claim 1 , wherein R 1  is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted. 
   
   
       8 . The method of  claim 1 , wherein R 1  is a hydrogen or a halo. 
   
   
       9 . The method of  claim 1 , wherein R 2  is hydrogen, hydroxy, or oxo. 
   
   
       10 . The method of  claim 1 , wherein R 2  is an optionally substituted C 1-6  aliphatic. 
   
   
       11 . The method of  claim 1 , wherein R 2  is an optionally substituted straight or branched C 1-6  alkyl, an optionally substituted straight or branched C 1-6  alkenyl, or an optionally substituted straight or branched C 1-6  alkynyl. 
   
   
       12 . The method of  claim 1 , wherein R 2  is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy. 
   
   
       13 . The method of  claim 1 , wherein R 2  is methyl or ethyl, each of which is substituted with hydroxy. 
   
   
       14 . The method of  claim 1 , wherein R 3  is hydrogen or halo. 
   
   
       15 . The method of  claim 1 , wherein R 3  is an optionally substituted C 1-6  aliphatic. 
   
   
       16 . The method of  claim 1 , wherein R 3  is an optionally substituted straight or branched C 1-6  alkyl, an optionally substituted straight or branched C 1-6  alkenyl, or an optionally substituted straight or branched C 1-6  alkynyl. 
   
   
       17 . The method of  claim 1 , wherein R 3  is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is unsubstituted. 
   
   
       18 . The method of  claim 1 , wherein ring A is a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms selected from N, O, or S. 
   
   
       19 . The method of  claim 1 , wherein In other examples, ring A is a furan-yl, thiophene-yl, pyrrole-yl, pyridine-yl, pyrazole-yl, 1,3,4-thiadiaziole-yl, 1,3,5-triazine-yl, pyrazine-yl, pyrimidine-yl, pyridazine-yl, isoxazole-yl, or isothiazole-yl. 
   
   
       20 . The method of  claim 1 , wherein ring A is a pyridine-yl. 
   
   
       21 . The method of  claim 1 , wherein ring A is a pyridine-2-yl, pyridine-3-yl, or pyridine-4-yl. 
   
   
       22 . The method of  claim 1 , wherein ring A is a pyridine-2-yl or pyridine-3-yl. 
   
   
       23 . A method of treating a metabolic inflammation mediated disease comprising administering to a patient a pharmaceutical composition including a compound selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       24 . A method of treating or reducing the severity of inflammatory disease comprising administering metformin and a compound of formula I 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic; 
 R 3  is hydrogen, halo, or optionally substituted aliphatic; and 
 Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1  at any chemically feasible position on ring A. 
 
   
   
       25 . A method of treating or reducing the severity of a disease in a patient, wherein said disease is selected from dyslipidemia, central obesity, rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, multiple schlerosis, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), acute allergic reactions, transplant rejection, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, wherein said method comprises the step of contacting said patient with a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic; 
 R 3  is hydrogen, halo, or optionally substituted aliphatic; and 
 Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1  at any chemically feasible position on ring A. 
 
   
   
       26 . A pharmaceutical composition useful for treating metabolic mediated disease comprising metformin and a compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or an optionally substituted aliphatic; 
 R 2  is hydrogen, halo, hydroxy, oxo, or optionally substituted aliphatic; 
 R 3  is hydrogen, halo, or optionally substituted aliphatic; and 
 Ring A is a phenyl or a monocyclic heteroaryl having 1-3 heteroatoms selected from N, O, or S, either of which is substituted with —CH 2 —R 1  at any chemically feasible position on ring A.