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.

1 . A compound having a structure according to Formula (I) 
     
       
         
         
             
             
         
       
     
     wherein
 X 1  and X 2  are, independently, N or CR 4 ; 
 X 3  is selected from O, S, NR 5 , or —(CR 5 ) 2 ; 
 Y is selected from C(O) or CH 2 ; and 
 Z is (CR 6 R 7 ) n , 
 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 3  is optionally substituted aryl; 
 each R 4  is selected from H, halogen, carboxamido, nitro, cyano, optionally substituted lower C 1-6  alkyl, or optionally substituted aryl; 
 R 5  is selected from H, halogen, optionally substituted lower C 1-6  alkyl, or optionally substituted aryl; 
 each R 6  and R 7  is, independently, selected from H or optionally substituted C 1-6  lower alkyl; and 
 n is 0, 1, 2, or 3; 
 wherein when X 1  and X 2  are N, X 3  is S, Y, is C(O), Z is CH 2 , R 2  is H, and R 3  is 2-chloro-6-fluoro-phenyl, R 1  is not methyl; 
 or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
 
   
   
       2 . The compound of  claim 1 , wherein both X 1  and X 2  are N or both X 1  and X 2  are CR 4  and X 3  is S or NR 5 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       3 . The compound of  claim 1 , wherein said compound has a structure according to Formula (I-a) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 6 , and R 7  are as defined for Formula (I), or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       4 . The compound of  claim 3 , wherein R 3  is a substituted phenyl group having the structure 
     
       
         
         
             
             
         
       
     
     wherein each R 8 , R 9 , R 10 , R 11 , and R 12  is selected, independently, from H, lower C 1-6  alkyl, halogen, amino, carboxamido, 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. 
   
   
       5 . The compound of  claim 4 , wherein R 1  is C 1-6  cycloalkyl or branched C 1-6  lower alkyl, R 8  and R 12  are halogens, and R 9 , R 10 , and R 11  are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       6 . The compound of  claim 5 , wherein R 1  is cyclopropyl, cyclobutyl, or isopropyl, R 8  is fluorine, and R 12  is chlorine, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       7 . The compound of  claim 1 , wherein R 2  is H, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       8 . The compound of  claim 1 , wherein R 6  and R 7  are both hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       9 . The compound of  claim 1 , wherein R 6  is hydrogen and R 7  is lower C 1-6  alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       10 . The compound of  claim 9 , wherein the carbon bearing R 6  and R 7  has the (S)-configuration, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       11 . The compound of  claim 1 , wherein said compound has a structure according to Formula (I-b) 
     
       
         
         
             
             
         
       
     
     wherein Y and Z are as defined for Formula (I) and R is selected from: hydrogen, halogen, azido, cyano, nitro, optionally substituted lower C 1-6  alkyl, aryl, alkoxy, aryloxy, amino, carboxylic group, ketone, carbonate, ester, carboxamide, or carbamate, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       12 . The compound of  claim 1 , wherein said compound is 
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound of  claim 1 , wherein said compound has a structure according to Formula (I-c) 
     
       
         
         
             
             
         
       
       wherein 
       R 1 , R 2 , and R 7  are as defined for Formula (I); 
       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; 
       each of R 8 , R 9 , R 10 , R 11 , and R 12  is selected, indepdently, 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. 
     
   
   
       14 . The compound of  claim 13 , 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. 
     
   
   
       15 . The compound of  claim 14 , wherein R 8  and R 12  are each halogen and R 9 , R 10 , and R 11  are hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       16 . The compound of  claim 13 , 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. 
   
   
       17 . The compound of  claim 16 , wherein said compound is 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 13 , wherein R 7  is hydrogen, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       19 . The compound of  claim 13 , wherein R 7  is optionally substituted lower C 1-6  alkyl, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       20 . The compound of  claim 13 , wherein the carbon bearing R 7  has the (S)-configuration, or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       21 . The compound of  claim 1 , selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       22 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 1 , or the compound having the formula: 
     
       
         
         
             
             
         
       
     
     or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       23 . A method of treating a condition in a subject, said method comprising the step of administering the compound of  claim 1 , or the compound having the formula: 
     
       
         
         
             
             
         
       
     
     or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
   
   
       24 . The method of  claim 23 , wherein said condition is a neurodegenerative disease or is caused by alteration in cell proliferation, differentiation, or intracellular signalling. 
   
   
       25 . A method of decreasing necroptosis comprising contacting a cell with the compound of  claim 1 , or the compound having the formula: 
     
       
         
         
             
             
         
       
     
     or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
   
   
       26 . A kit comprising
 (a) a pharmaceutically acceptable composition comprising the compound of  claim 1 , or the compound having the formula   
     
       
         
         
             
             
         
       
        or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, and 
       (b) instructions for the use of the pharmaceutical composition of (a) to treat a condition in a subject. 
     
   
   
       27 . The method of  claim 23 , wherein said condition is stroke, retinal or brain ischemic injury, head trauma, coronary heart disease, or the result of cell death of cardiac muscle.