Small molecule 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)-(VIII) and by Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. 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 - 13 . (canceled) 
     
     
         14 . A compound having a structure according to the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 each R A1 , R A3 , and R A4  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R A1  and R A4  combine to form a carbon-carbon double bond; 
 G A2  is absent or —(CR A11 R A12 ) n —; 
 X A3  is absent or is O, S, or NR A8 ; 
 each R A8  and R A13  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —COR A14 , —CO 2 R A14 , or —CONR A14 R A15 ; 
 each R A9 , R A10 , R A11 , and R A12  is selected, independently, from H, halogen, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 3 -10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each R A7 , R A14  and R A15  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and 
 each m and n is, independently, 1, 2, or 3; and 
 wherein when one of R A1  and R A4  is H and the other is selected from H or CO 2 Et, and R A3  is unsubstituted phenyl, G A2 -X A3 —R A7  is not NHC 6 H 5 , NH(p-C 6 H 4 F), NH(p-C 6 H 4 OH), NH(p-C 6 H 4 OMe), NH(3-OH-4-C 1 -C 6 H 4 ), —CH 2 (O-p-C 6 H 4 Me), —CH 2 (4-ethylpiperazinyl), —CH 2 S(2-phenyltetrazolyl), —CH 2 S(4-chlorophenyl), —CH 2 S(2-benzothiazolyl), —CH 2 S(2-(N-methylimidazolyl)), —CH 2 S(4,6-dimethylquinazolinyl), adamantyl, or optionally substituted oxiranyl; and 
 wherein when R A1  and R A4  are each H and R A3  is 4-methoxyphenyl, G A2 -X A3 —R A7  is not optionally substituted oxiranyl; 
 
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         15 . The compound of  claim 14 , wherein R A1  and R A4  are H, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         16 . The compound of  claim 14 , wherein R A3  is unsubstituted phenyl, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         17 . The compound of  claim 14 , wherein R A3  is phenyl having 1, 2, 3, 4, or 5 substituents, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         18 . The compound of  claim 16 , wherein G A2  is absent, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         19 . The compound of  claim 18 , wherein X A3  is absent and R A7  is optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         20 . The compound of  claim 19 , wherein X A3  is NR A8  and R A7  is optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         21 . The compound of  claim 14 , wherein G A2  is CH 2 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         22 . The compound of  claim 21 , wherein X A3  is S and R A7  is optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         23 . The compound of  claim 20 , wherein X A3  is absent and R A7  is optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         24 - 79 . (canceled) 
     
     
         80 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 14 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         81 . The composition of  claim 80 , wherein said compound is selected from 
       
         
           
           
               
               
           
         
         or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
       
     
     
         82 . A method of treating a condition in a subject, said method comprising the step of administering the compound of  claim 14 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
     
     
         83 . (canceled) 
     
     
         84 . The method of  claim 82 , wherein said condition is a neurodegenerative disease of the central or peripheral nervous system, the result of retinal neuronal cell death, the result of cell death of cardiac muscle, the result of cell death of cells of the immune system; stroke, liver disease, pancreatic disease, the result of cell death associated with renal failure; heart, mesenteric, retinal, hepatic or brain ischemic injury, ischemic injury during organ storage, head trauma, septic shock, coronary heart disease, cardiomyopathy, myocardial infarction, bone avascular necrosis, sickle cell disease, muscle wasting, gastrointestinal disease, tuberculosis, diabetes, alteration of blood vessels, muscular dystrophy, graft-versus-host disease, viral infection, Crohn's disease, ulcerative colitis, asthma, or any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor. 
     
     
         85 . The method of  claim 84 , wherein said condition is a neurodegenerative disease of the central or peripheral nervous system. 
     
     
         86 . The method of  claim 84 , wherein said condition is hepatic or brain ischemic injury, or ischemic injury during organ storage, head trauma, septic shock, or coronary heart disease. 
     
     
         87 . The method of  claim 84 , wherein said condition is stroke. 
     
     
         88 . The method of  claim 84 , wherein said condition is myocardial infarction. 
     
     
         89 . A method of decreasing necroptosis comprising contacting a cell with the compound of  claim 14 , or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. 
     
     
         90 . (canceled) 
     
     
         91 . A kit comprising
 (a) a pharmaceutically acceptable composition comprising the compound of  claim 14 , 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.   
     
     
         92 . (canceled)