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 (I)-(I), (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.

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-Cl—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 .- 30 . (canceled) 
     
     
         31 . A compound having a structure according to the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 R B1  is selected from H, optionally substituted C 1-6  alkyl, —C(═O)R B18 , —C(═O)OR B18 , or —C(═O)NR B18 R B19 ; 
 R B2  is selected from H, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, or optionally substituted C 2-6  alkynyl; 
 each R B3  and R B4  is selected, independently from H, optionally substituted C 1-6  alkyl, or R B3  and R B4  combine to form a bridging group having the structure —(CH 2 ) n —(CR B13 ═CR B14 ) o —(CH 2 ) p —; 
 each n, o, and p is, independently, 0 or 1; 
 each R B5 , R B6 , R B7 , R B8 , R B9 , R B10 , R B11 , and R B12  is selected, independently, from H, halogen, —CN, —NO 2 , —N 3 , —R B13 , —OR B13 , —SR B13 , —NR B13 R B14 , —C(═O)R B15 , —C(═O)OR B15 , —C(═O)NR B15 R B16 , —OC(═O)R B15 , —OC(═O)OR B15 , —OC(═O)NR B15 R B16 , —NR B15 C(═O)R B15 , —NR B15 C(═O)OR B16 , —NR B15 C(═O)NR B16 R B17 , —C(═S)R B15 , —C(═S)NR B15 R B16 , —NR B15 C(═S)R B16 , —NR B15 C(═S)NR B16 R B17 , —C(═NR B13 )NR B15 R B16 , —NR B15 C(═NR B13 )R B16 , —NR B15 C(═NR B13 )NR B16 R B17 ; 
 each R B13  and R B14  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R B18 , —C(═O)OR B18 , or —C(═O)NR B18 R B19 , 
 each R B15 , R B16 , R B17 , R B18 , and R B19  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 wherein when each n, o, and p is 0, R B3  and R B4  combine to form a single bond, and 
 wherein R B1  is not H or CH 3  when R B5 , R B6 , R B7 , R B8 , R B9 , R B10 , R B11 , and R B12  are each H, R B2  is ethyl, ethenyl, 2-haloethenyl, ethynyl, haloethynyl, propynyl, or —C≡C—C(OH)(CH 3 ) 2 , and when R B3  and R B4  are each H or combine to form a bond, —CH 2 CH 2 — or —CH═CH—; 
 wherein R B1  is not H when R B5 , R B6 , R B7 , R B8 , R B10 , and R B11  are each H, at least one of R B9  or R B12  is fluoro, R B2  is ethynyl, and when R B3  and R B4  combine to form —CH 2 CH 2 —; 
 wherein R B1  is not H when R B5 , R B7 , R B9 , and R B11  are H and one or two of R B6 , R B8 , R B10 , and R B12  is halogen, nitro, or methyl; and 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         32 .- 39 . (canceled) 
     
     
         40 . A compound having a structure according to the following formula 
       
         
           
           
               
               
           
         
       
       wherein
 each R C1 , R C2 , and R C3  is selected, independently, from H, optionally substituted C 1-6  alkyl, —Y—R C7 , or R C1  and R C2  combine to form a (═O) or a (═S) group, or R C1  and R C3  combine to form a carbon-nitrogen double bond; 
 R C4  is selected from H, halogen, —CN, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —C(═O)ZR C8 , 
 each R C5  and R C6  is selected, independently, from H, optionally substituted C 1-6  alkyl, or R C5  and R C6  combine to form an optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each R C7 , R C8 , R C9 , R C10 , R C11 , and R C12  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 X is —CR C11 —CR C12 —, O, S, or NR C9 ; 
 Y is, independently, a single bond, (CR C8 R C9 ) n , O, S, or NR C10 ; and 
 Z is a single bond, O, S, or NR C10 ; 
 n is an integer between 0-4; and 
 wherein when X is S, R C1  and R C2  combine to form a (═O) group, R C4  is H, and R C5  and R C6  combine to form unsubstituted cyclopentyl, R C3  is not —CH 2 —R C7 , where R C7  is unsubstituted phenyl, unsubstituted naphthyl, unsubstituted 8-quinolyl, unsubstituted 2-oxoquinolyl, or phenyl having 1 or 2 substituents selected from F, OMe, Me, CN, or Cl; 
 wherein when X is S, R C1  and R C2  combine to form a (═O) group, R C4  is H, and R C5  and R C6  are each CH 3 , R C3  is not —CH 2 —R C7 , where R C7  is unsubstituted phenyl; and 
 wherein when X is CH═CH, R C1  and R C2  combine to form a (═O) group, R C4  is H, and R C5  and R C6  are H, R C3  is not —CH 2 (4-halophenyl); 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         41 . (canceled) 
     
     
         42 . The compound of  claim 40 , wherein said compound has a structure according to the following formula 
       
         
           
           
               
               
           
         
       
       wherein X, R C1 , R C2 , R C3 , and R C4  are as defined for Formula (IV) and n is an integer between 0-3,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         43 . The compound of  claim 42 , wherein R C1  and R C2  combine to form a (═O) group,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         44 . The compound of  claim 42 , wherein X is S,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         45 . The compound of  claim 42 , wherein n is 1,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         46 . The compound of  claim 45 , wherein R C3  is —Y—R C7 ,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         47 . The compound of  claim 46 , wherein R C3  is —(CH 2 )-(optionally substituted aryl),
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         48 .- 54 . (canceled) 
     
     
         55 . A compound having a structure according to one of the following formulas 
       
         
           
           
               
               
           
         
       
       wherein
 each Z E2  and Z E3  is selected, independently, from a single bond, —(CR E6 R E7 ) n —, —C(═O)—, or R E1  and Z E2 —R E2  combine to form a double bond; 
 each R E1 , R E2 , and R E4  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R E3  is selected from optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each R E6  and R E7  is selected, independently, from H or optionally substituted C 1-6  alkyl; and 
 each n is an integer between 1-6; and 
 wherein when R E1  and R E4  are H, Z E2  and Z E3  are each CH 2 , and R E2  is unsubstituted 3-indolyl, R E3  is not 4-chlorophenyl or CH 2 CH 2 O(p-C 6 H 4 F); or 
 
       
         
           
           
               
               
           
         
       
       wherein
 each Z E2  and Z E3  is selected, independently, from a single bond, —(CR E6 R E7 ) n —, —C(═O)—, or E E1  and Z E2 —R E2  combine to form a double bond; 
 each R E1 , R E2 , and R E4  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R E3  is selected from optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 each R E6  and R E7  is selected, independently, from H or optionally substituted C 1-6  alkyl; and 
 each n is an integer between 1-6; and 
 wherein when R E1  and R E4  are H, Z E2  is CH 2 , and Z E3  is CH 2 CH 2 , R E2  is unsubstituted 3-indolyl, R E3  is not 4-morpholine, 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
     
     
         56 . The compound of  claim 55 , wherein said compound has a structure according to one of the following formulas: 
       
         
           
           
               
               
           
         
       
       wherein
 R E3  is optionally substituted aryl or optionally substituted heteroaryl; and 
 R 9  is H, halogen, CN, NO 2 , OR 13 , NR 13 R 14 , COR 15 , CO 2 R 15 , or optionally substituted C 1-6  alkyl; 
 each R 13  and R 14  is selected, independently, from H, COR 16 , CO 2 R 16 , optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and, 
 each R 15  and R 16  is selected, independently, from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or 
 
       
         
           
           
               
               
           
         
       
       wherein
 R E3  is optionally substituted aryl or optionally substituted heteroaryl; and 
 R 9  is H, halogen, CN, NO 2 , OR 13 , NR 13 R 14 , COR 15 , CO 2 R 15  or optionally substituted C 1-6  alkyl; 
 each R 13  and R 14  is selected, independently, from H, COR 16 , CO 2 R 16  optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and, 
 each R 15  and R 16  is selected, independently, from H, optionally substituted C 1-6  alkyl, 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. 
 
     
     
         57 .- 58 . (canceled) 
     
     
         59 . The compound of  claim 55 , wherein R E3  is unsubstituted C 3-10  cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         60 . (canceled) 
     
     
         61 . The compound of  claim 55 , wherein R E3  is substituted C 3-10  cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl;
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         62 .- 63 . (canceled) 
     
     
         64 . The compound of  claim 61 , wherein R E3  is substituted phenyl,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         65 .- 66 . (canceled) 
     
     
         67 . The compound of  claim 55 , wherein the stereocenter marked by the asterisk has the (R)-configuration,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         68 . The compound of  claim 55 , wherein the stereocenter marked by the asterisk has the (S)-configuration,
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.   
     
     
         69 .- 79 . (canceled) 
     
     
         80 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 40 ,
 or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.   
     
     
         81 . (canceled) 
     
     
         82 . A method of treating a condition in a subject, said method comprising the step of administering the compound of  claim 40 ,
 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 .- 88 . (canceled) 
     
     
         89 . A method of decreasing necroptosis comprising contacting a cell with the compound of  claim 40 ,
 or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.   
     
     
         90 .- 92 . (canceled)