Heterocyclic inhibitors of necroptosis

Abstract

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

What is claimed is: 
     
         1 - 19 . (canceled) 
     
     
         20 . A compound having a structure according to Formula (I-c) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from H, halogen, optionally substituted C 1-6  lower alkyl, or optionally substituted C 1-6  cycloalkyl, or optionally substituted aryl; 
         R 2  is selected from H or optionally substituted C 1-6  lower alkyl; 
         R 4A  and R 4B  are selected, independently, from hydrogen, halogen, carboxamido, nitro, and cyano; 
         R 5  is H or optionally substituted C 1-6  lower alkyl; 
         R 7  is H or optionally substituted C 1-6  lower alkyl; 
         each of R 8 , R 9 , R 10 , R 11 , and R 12  is selected, independently, from H, lower C 1-6  alkyl, halogen, amino, amido, alkoxy, nitro, and cyano, wherein at least one of R 8 , R 9 , R 10 , R 11 , and R 12  is not hydrogen; 
         or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         21 . The compound of  claim 20 , wherein R 1  is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         22 . The compound of  claim 20 , wherein R 2  is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         23 . The compound of  claim 20 , wherein R 4A  is H and R 4B  is CN, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         24 . The compound of  claim 20 , wherein R 4A  is CN and R 4B  is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         25 . The compound of  claim 20 , wherein R 5  is unsubstituted C 1-6  lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         26 . The compound of  claim 20 , wherein R 7  is C 1-6  lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         27 . The compound of  claim 20 , wherein R 8  and R 12  are each, independently, halogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         28 . The compound of  claim 20 , wherein R 9 , R 10 , and R 11  are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         29 . The compound of  claim 20 , wherein said compound has a structure according to Formula (I-d) 
       
         
           
           
               
               
           
         
         wherein R 4B , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         30 . The compound of  claim 29 , wherein R 5  is unsubstituted C 1-6  lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         31 . The compound of  claim 29 , wherein R 7  is C 1-6  lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         32 . The compound of  claim 20 , wherein said compound has a structure according to Formula (I-e) 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 4A , R 4B , R 5 , and R 7  are as defined in Formula (I-c), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         33 . The compound of  claim 32 , wherein R 1  is H or unsubstituted C 1-6  lower alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         34 . The compound of  claim 32 , wherein R 7  is hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         35 . The compound of  claim 20 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         36 . The compound of  claim 20 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         37 . A pharmaceutical composition, comprising a pharmaceutically acceptable excipient and the compound of  claim 20 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         38 . A method of treating a condition in a subject, said method comprising the step of administering the compound of  claim 20 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
     
     
         39 . The method of  claim 38 , wherein the condition is a neurodegenerative disease selected from the group consisting of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, HIV-associated dementia, cerebral ischemia, amyotropic lateral sclerosis, multiple sclerosis, Lewy body disease, Menke's disease, Wilson's disease, Creutzfeldt-Jakob disease, and Fahr disease.