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 formulae II or III:
 a)   
       
         
           
           
               
               
           
         
         wherein
 each R A1 , R A2 , R A3 , R A4 , R A5 , and R A6  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, optionally substituted heteroaryl, or a group having the structure —X A1 -G A1 -X A2 —C(═Y A1 )-G A2 -X A3 —R A7 , or R A1  and R A4  combine to form a carbon-carbon double bond; 
 each X A1 , X A2 , and X A3  is, independently, absent or selected from —O—, —S—, or —NR A8 —; 
 G A1  is absent or —(CR A9 R A10 ) m —; 
 G A2  is absent or —(CR A11 R A12 ) n —; 
 Y A1  is O, S, or NR A13 ; 
 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; 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof; or 
 
         (b) 
       
       
         
           
           
               
               
           
         
         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 , and 
 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; 
 where when each n, o, and p is 0, R B3  and R B4  combine to form a single bond, and 
 where 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—; 
 where 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 —; and 
 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; 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
       
     
     
         15 - 39 . (canceled) 
     
     
         40 . A compound having a structure according to formulae IV, V, or VI:
 (a)   
       
         
           
           
               
               
           
         
         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 
 where 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 
 where 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; or 
         (b) 
       
       
         
           
           
               
               
           
         
         where
 each X D1  and X D2  is selected, independently, from O, S, NR D5 , or CR D6 R D7 ; 
 Y D1  is selected from a covalent bond, —C(═O)—, —S(═O)—, or —S(═O) 2 —; 
 Y D2  is selected from a covalent bond, —C(═O)—, —OC(═O)—, —NR D8 C(═O)—, —S(═O)—, —S(═O) 2 —, —OS(═O)—, —OS(═O) 2 —, —NR D8 S(═O)—, —NR D8 S(═O) 2 —, or —C(═S)—; 
 A is selected from optionally substituted aryl or optionally substituted heteroaryl; 
 G D1  is selected from H, optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR D9 , or NR D9 R D10 ; 
 each R D1 , R D2 , R D3 , R D4 , R D6 , R D7 , is selected, independently, from H, halogen, CN, NC, N 3 , NO 2 , OR D11 , SR D11 , NR D11 R D12 , —COR D13 , —CO 2 R D13 , —CONR D13 R D14 , optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R D1  and R D4 , or R D1  and R D5 , or R D1  and R D6 , or R D3  and R D5 , or R D3  and R D6  combine to form a double bond; 
 each R D5 , R D8 , R D9 , R D10 , R D13 , R D14 , R D15 , and R D16  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 R D9  and R D10  combine to form a heterocyclyl; and 
 each R D11  and R D12  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 D15 , —CO 2 R D15 , —CONR D15 R D16 , —S(═O)R D15 , —S(═O)OR D15 , —S(═O)NR D15 R D16 , —S(═O) 2 R D15 , —S(═O) 2 OR D15 , —S(═O) 2 NR D15 R D16 ; 
 where Y D1  and Y D2  are each covalently bound to a carbon center in A; 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof; or 
 
         (c) 
       
       
         
           
           
               
               
           
         
         where
 each X E1  and X E3  is selected, independently, from N or CR E4 ; 
 each X E4  and X E5  is selected, independently, from O, S, or NR E5 ; 
 X E2  is selected from O, S, or N; 
 each Z E1 , R E2 , and Z E3  is selected, independently, from a single bond, —(CR E6 R E7 ) n —, —C(═O)—, —S(═O)—, or —S(═O) 2 —, or Z E1 —R E1  and Z E2 —R E2  combine to form a double bond; 
 each R E1 , R E2 , R E3 , R E4 , R E5 , R E6 , and R E7  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; 
 p is 0 or 1; and 
 n is an integer between 1-6; 
 
         where when X E2  is O or S, Z E2 —R E2  is not present;
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
       
     
     
         41 - 68 . (canceled) 
     
     
         69 . A compound having a structure according to formulae VII or VIII:
 (a)   
       
         
           
           
               
               
           
         
         wherein
 Z F1  is selected from a single bond, —(CR F10 R F11 ) n —, —C(═O)—, —S(═O)—, or —S(═O) 2 —; 
 each R F1 , R F2 , R F4 , R F10 , R F11 , R F12 , and R F13 , 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 R F2  and R F4  combine to form a carbon-carbon double bond; 
 each R F3  and R F5  is selected, independently, from H, halogen, CN, CO 2 R F12 , 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 F6 , R F7 , R F8 , and R F9  is selected, independently, from H, halogen, CN, NC, N 3 , NO 2 , OR F12 , SR F12 , NR F12 R F13 , —CO F12 , —CO 2 F12 , —CONR F12 R F13 , optionally substituted C 1-6  alkyl, optionally substituted C 3-10  cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and 
 where n is an integer between 1-6; 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof; or 
 
         (b) 
       
       
         
           
           
               
               
           
         
         where
 X G1  is selected from —O—, —N—, or —(CR G9 R G10 ) n —; 
 X G2  and X G3  are selected, independently, from N or CR G11 ; 
 each R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , R G7 , R G8 , R G9 , R G10 , and R G11  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 R G1  and R G2 , or R G3  and R G4 , or R G5  and R G6 , or R G7  and R G8  combine to form an optionally substituted cycloalkyl or heterocyclyl; and 
 n is 1 or 2; 
 or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
 
       
     
     
         70 - 92 . (canceled) 
     
     
         93 . The compound according to  claim 14 , having a structure according to formula II: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         94 . The compound according to  claim 14 , having a structure according to formula III: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         95 . The compound according to  claim 40 , having a structure according to formula IV: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         96 . The compound according to  claim 40 , having a structure according to formula V: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         97 . The compound according to  claim 40 , having a structure according to formula VI: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         98 . The compound according to  claim 69 , having a structure according to formula VII: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         99 . The compound according to  claim 69 , having a structure according to formula VIII: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         100 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 14 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         101 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 40 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         102 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 69 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         103 . 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 any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
     
     
         104 . 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 any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
     
     
         105 . A method of treating a condition in a subject, said method comprising the step of administering the compound of  claim 69 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, to said subject in a dosage sufficient to decrease necroptosis. 
     
     
         106 . A method of decreasing necroptosis comprising contacting a cell with a compound of  claim 14 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         107 . A method of decreasing necroptosis comprising contacting a cell with a compound of  claim 40 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof. 
     
     
         108 . A method of decreasing necroptosis comprising contacting a cell with a compound of  claim 69 , or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.