SMALL MOLECULE INHIBITORS OF NECROPTOSIS

20190135718 · 2019-05-09

Inventors

Cpc classification

International classification

Abstract

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-) 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- 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.

Claims

1-13. (canceled)

14. A compound having a structure according to formulae II or III: a) ##STR00190## wherein each R.sub.A1, R.sub.A2, R.sub.A3, R.sub.A4, R.sub.A5, and R.sub.A6 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a group having the structure X.sub.A1-G.sub.A1-X.sub.A2C(Y.sub.A1)-G.sub.A2-X.sub.A3R.sub.A7, or R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond; each X.sub.A1, X.sub.A2, and X.sub.A3 is, independently, absent or selected from O, S, or NR.sub.A8; G.sub.A1 is absent or (CR.sub.A9R.sub.A10).sub.m; G.sub.A2 is absent or (CR.sub.A11R.sub.A12).sub.n; Y.sub.A1 is O, S, or NR.sub.A13; each R.sub.A8 and R.sub.A13 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, COR.sub.A14, CO.sub.2R.sub.A14, or CONR.sub.A14R.sub.A15; each R.sub.A9, R.sub.A10, R.sub.A11, and R.sub.A12 is selected, independently, from H, halogen, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R.sub.A7, R.sub.A14 and R.sub.A15 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.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) ##STR00191## wherein R.sub.B1 is selected from H, optionally substituted C.sub.1-6 alkyl, C(O)R.sub.B18, C(O)OR.sub.B18, or C(O)NR.sub.B18R.sub.B19; R.sub.B2 is selected from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, or optionally substituted C.sub.2-6 alkynyl; each R.sub.B3 and R.sub.B4 is selected, independently from H, optionally substituted C.sub.1-6 alkyl, or R.sub.B3 and R.sub.B4 combine to form a bridging group having the structure (CH.sub.2).sub.n(CR.sub.B13CR.sub.B14).sub.o(CH.sub.2).sub.p; each n, o, and p is, independently, 0 or 1; each R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 is selected, independently, from H, halogen, CN, NO.sub.2, N.sub.3, R.sub.B13, OR.sub.B13, SR.sub.B13, NR.sub.B13R.sub.B14, C(O)R.sub.B15, C(O)OR.sub.B15, C(O)NR.sub.B15R.sub.B16, OC(O)R.sub.B15, OC(O)OR.sub.B15, OC(O)NR.sub.B15R.sub.B16, NR.sub.B15C(O)R.sub.B15, NR.sub.B15C(O)OR.sub.B16, NR.sub.B15C(O)NR.sub.B16R.sub.B17, C(S)R.sub.B15, C(S)NR.sub.B15R.sub.B16, NR.sub.B15C(S)R.sub.B16, NR.sub.B15C(S)NR.sub.B16R.sub.B17, C(NR.sub.B13)NR.sub.B15R.sub.B16, NR.sub.B15C(NR.sub.B13)R.sub.B16, NR.sub.B15C(NR.sub.B13)NR.sub.B16 R.sub.B17; each R.sub.B13 and R.sub.B14 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sub.B18, C(O)OR.sub.B18, or C(O)NR.sub.B18R.sub.B19, and each R.sub.B15, R.sub.B16, R.sub.B17, R.sub.B18, and R.sub.B19 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; where when each n, o, and p is 0, R.sub.B3 and R.sub.B4 combine to form a single bond, and where R.sub.B1 is not H or CH.sub.3 when R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 are each H, R.sub.B2 is ethyl, ethenyl, 2-haloethenyl, ethynyl, haloethynyl, propynyl, or CCC(OH)(CH.sub.3).sub.2, and when R.sub.B3 and R.sub.B4 are each H or combine to form a bond, CH.sub.2CH.sub.2 or CHCH; where R.sub.B1 is not H when R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B10, and R.sub.B11 are each H, at least one of R.sub.B9 or R.sub.B12 is fluoro, R.sub.B2 is ethynyl, and when R.sub.B3 and R.sub.B4 combine to form CH.sub.2CH.sub.2; and wherein R.sub.B1 is not H when R.sub.B5, R.sub.B7, R.sub.B9, and R.sub.B11 are H and one or two of R.sub.B6, R.sub.B8, R.sub.B10, and R.sub.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) ##STR00192## wherein each R.sub.C1, R.sub.C2, and R.sub.C3 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, YR.sub.C7, or R.sub.C1 and R.sub.C2 combine to form a (O) or a (S) group, or R.sub.C1 and R.sub.C3 combine to form a carbon-nitrogen double bond; R.sub.C4 is selected from H, halogen, CN, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or C(O)ZR.sub.C8, each R.sub.C5 and R.sub.C6 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, or R.sub.C5 and R.sub.C6 combine to form an optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; each R.sub.C7, R.sub.C8, R.sub.C9, R.sub.C10, R.sub.C11, and R.sub.C12 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; X is CR.sub.C11CR.sub.C12, O, S, or NR.sub.C9; Y is, independently, a single bond, (CR.sub.C8R.sub.C9).sub.n, O, S, or NR.sub.C10; and Z is a single bond, O, S, or NR.sub.C10; n is an integer between 0-4; and where when X is S, R.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4 is H, and R.sub.C5 and R.sub.C6 combine to form unsubstituted cyclopentyl, R.sub.C3 is not CH.sub.2R.sub.C7, where R.sub.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.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4 is H, and R.sub.C5 and R.sub.C6 are each CH.sub.3, R.sub.C3 is not CH.sub.2R.sub.C7, where R.sub.C7 is unsubstituted phenyl; and where when X is CHCH, R.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4 is H, and R.sub.C5 and R.sub.C6 are H, R.sub.C3 is not CH.sub.2(4-halophenyl); or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof; or (b) ##STR00193## where each X.sub.D1 and X.sub.D2 is selected, independently, from O, S, NR.sub.D5, or CR.sub.D6R.sub.D7; Y.sub.D1 is selected from a covalent bond, C(O), S(O), or S(O).sub.2; Y.sub.D2 is selected from a covalent bond, C(O), OC(O), NR.sub.D8C(O), S(O), S(O).sub.2, OS(O), OS(O).sub.2, NR.sub.D8S(O), NR.sub.D8S(O).sub.2, or C(S); A is selected from optionally substituted aryl or optionally substituted heteroaryl; G.sub.D1 is selected from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sub.D9, or NR.sub.D9R.sub.D10; each R.sub.D1, R.sub.D2, R.sub.D3, R.sub.D4, R.sub.D6, R.sub.D7, is selected, independently, from H, halogen, CN, NC, N.sub.3, NO.sub.2, OR.sub.D11, SR.sub.D11, NR.sub.D11R.sub.D12, COR.sub.D13, CO.sub.2R.sub.D13, CONR.sub.D13R.sub.D14, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.D1 and R.sub.D4, or R.sub.D1 and R.sub.D5, or R.sub.D1 and R.sub.D6, or R.sub.D3 and R.sub.D5, or R.sub.D3 and R.sub.D6 combine to form a double bond; each R.sub.D5, R.sub.D8, R.sub.D9, R.sub.D10, R.sub.D13, R.sub.D14, R.sub.D15, and R.sub.D16 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.D9 and R.sub.D10 combine to form a heterocyclyl; and each R.sub.D11 and R.sub.D12 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, COR.sub.D15, CO.sub.2R.sub.D15, CONR.sub.D15R.sub.D16, S(O)R.sub.D15, S(O)OR.sub.D15, S(O)NR.sub.D15R.sub.D16, S(O).sub.2R.sub.D15, S(O).sub.2OR.sub.D15, S(O).sub.2NR.sub.D15R.sub.D16; where Y.sub.D1 and Y.sub.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) ##STR00194## where each X.sub.E1 and X.sub.E3 is selected, independently, from N or CR.sub.E4; each X.sub.E4 and X.sub.E5 is selected, independently, from O, S, or NR.sub.E5; X.sub.E2 is selected from O, S, or N; each Z.sub.E1, R.sub.E2, and Z.sub.E3 is selected, independently, from a single bond, (CR.sub.E6R.sub.E7).sub.n, C(O), S(O), or S(O).sub.2, or Z.sub.E1R.sub.E1 and Z.sub.E2R.sub.E2 combine to form a double bond; each R.sub.E1, R.sub.E2, R.sub.E3, R.sub.E4, R.sub.E5, R.sub.E6, and R.sub.E7 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.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.sub.E2 is O or S, Z.sub.E2R.sub.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) ##STR00195## wherein Z.sub.F1 is selected from a single bond, (CR.sub.F10R.sub.F11).sub.n, C(O), S(O), or S(O).sub.2; each R.sub.F1, R.sub.F2, R.sub.F4, R.sub.F10, R.sub.F11, R.sub.F12, and R.sub.F13, is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.F2 and R.sub.F4 combine to form a carbon-carbon double bond; each R.sub.F3 and R.sub.F5 is selected, independently, from H, halogen, CN, CO.sub.2R.sub.F12, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each R.sub.F6, R.sub.F7, R.sub.F8, and R.sub.F9 is selected, independently, from H, halogen, CN, NC, N.sub.3, NO.sub.2, OR.sub.F12, SR.sub.F12, NR.sub.F12R.sub.F13, CO.sub.F12, CO.sub.2 F12, CONR.sub.F12R.sub.F13, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.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) ##STR00196## where X.sub.G1 is selected from O, N, or (CR.sub.G9R.sub.G10).sub.n; X.sub.G2 and X.sub.G3 are selected, independently, from N or CR.sub.G11; each R.sub.G1, R.sub.G2, R.sub.G3, R.sub.G4, R.sub.G5, R.sub.G6, R.sub.G7, R.sub.G8, R.sub.G9, R.sub.G10, and R.sub.G11 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.G1 and R.sub.G2, or R.sub.G3 and R.sub.G4, or R.sub.G5 and R.sub.G6, or R.sub.G7 and R.sub.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: ##STR00197## 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: ##STR00198## 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: ##STR00199## 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: ##STR00200## 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: ##STR00201## 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: ##STR00202## 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: ##STR00203## 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.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0206] We have discovered a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-)-induced necroptosis. The heterocyclic compounds of the invention include, for example, compounds of Formulas (I)(VIII), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, and are shown to inhibit TNF- induced necroptosis in FADD-deficient variant of human Jurkat T cells. Still other useful necrostatins include Compounds (1)-(45). Compounds of the invention can be synthesized according to methods known in the art or by the methods provided in the examples below. Pharmaceutical compositions including the compounds of the invention are also described. The invention also features kits and methods of treatment featuring the compounds and compositions of the invention.

[0207] Compounds of Formula (I)

[0208] Certain compounds of the invention can be described by Formula (I):

##STR00023##

where

[0209] each X.sub.H1 and X.sub.H2 is selected, independently, from O, S, or NR.sub.H9;

[0210] Y.sub.H1 is selected, independently, from O, S, or NR.sub.H10;

[0211] each R.sub.H1, R.sub.H2, R.sub.H3, R.sub.H4, R.sub.H5, R.sub.H6, R.sub.H7, and R.sub.H8, is selected, independently from H, halogen, cyano, nitro, azido, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, C(O)R.sub.H12, C(O)OR.sub.H12, C(O)NR.sub.H12R.sub.H13, C(S)R.sub.H12, C(S)NR.sub.H12R.sub.H13, C(NR.sub.H14)R.sub.H12, C(NR.sub.H14)NR.sub.H12R.sub.H13, or [Z.sub.H1(CR.sub.H15R.sub.H16).sub.n{C(X.sub.H2)}.sub.oZ.sub.H12R.sub.H17], or R.sub.H1 and R.sub.H3, or R.sub.H5 and R.sub.H7 combine to form a carbon-carbon double bond;

[0212] each Z.sub.H1 and Z.sub.H2 is selected, independently, from a single bond, O, S, or NR.sub.H11;

[0213] each R.sub.H9, R.sub.H10, R.sub.H11, R.sub.H12, R.sub.H13, R.sub.H14, R.sub.H15, R.sub.H16, and R.sub.H17, is selected, independently from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

[0214] n is an integer between 0-6; and

[0215] o is 0 or 1;

[0216] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0217] Certain compounds of the invention can be described by Formula (I-A):

##STR00024##

where each R.sub.H1, R.sub.H12, R.sub.H3, R.sub.H4, R.sub.H5, R.sub.H10, R.sub.H17, X.sub.H2, Z.sub.H1, Z.sub.H2, and n is as defined for Formula (I), or by Formula (I-B)

##STR00025##

where

[0218] each R.sub.H1 and R.sub.H3 is selected, independently, from H, halogen, cyano, nitro, azido, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, C(O)R.sub.H12, C(O)OR.sub.H12, or C(O)NR.sub.H12R.sub.H13, or R.sub.H1 and R.sub.H3 combine to form a carbon-carbon double bond;

[0219] each R.sub.H4 and R.sub.H17 is selected, independently, from optionally substituted aryl or optionally substituted heteroaryl;

[0220] R.sub.H5 is selected from H, CN, C(O)OR.sub.H12, or C(O)NR.sub.H12R.sub.H13;

[0221] each R.sub.H10, R.sub.H11, R.sub.H12, and R.sub.H13 is selected from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

[0222] Z.sub.H1 is selected from a single bond or S;

[0223] Z.sub.H2 is selected from a single bond or NR.sub.H11; and

[0224] X.sub.H2 is O or S;

[0225] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0226] In some embodiments of Formula (I), the compound has a structure according to the following formula:

##STR00026##

where R.sub.H4 is as according to Formula (I-A) or (I-B).

[0227] In some embodiments of Formula (I), when R.sub.H1 is H, R.sub.H2 is H or CO.sub.2Me, R.sub.H3 is H, R.sub.H4 is unsubstituted phenyl or phenyl substituted with 1, 2, or 3 substituents selected from methoxy, ethoxy, methyl, isopropyl, chloro, or fluoro, R.sub.H5 is CN, R.sub.H6 and R.sub.H8 is H, R.sub.H10 is H, X.sub.H1 is O, Y.sub.H1 is NH, and R.sub.H7 is [S(CH.sub.2){C(O)}.sub.oZ.sub.H2R.sub.17], Z.sub.H2R.sub.H17 is not OCH.sub.3 or NHR.sub.H17, where R.sub.H17 is H, unsubstituted 2-thiazolyl, unsubstituted phenyl, 4-methoxyphenyl, 4-fluorophenyl, or 2,4,6-trimethylphenyl.

[0228] Compounds of Formulas (I), (I-A), (I-B), and (I-C) can be prepared according to methods known in the art. An exemplary method of synthesis that can be used is shown in Scheme 1 and is based on protocols disclosed in Russian Chemical Bulletin, 48(12): 2308-2311 (1999) and in Chemistry of Heterocyclic Compounds, 38(10): 1269-1275 (2002). In Scheme 1, R and R can be, for example, an optionally substituted aryl or an optionally substituted heteroaryl group. Still other substituent patterns can be obtained by variation of the thioamide starting material that is condensed with the aldehyde.

##STR00027##

[0229] Compounds of Formula (I) (e.g., (I-A), (I-B), or (I-C)) or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). Exemplary compounds useful in the methods, compositions, and kits of the invention, include but are not limited to those shown in Table 1. Other compounds of Formula 1 are shown in Table 2. In some embodiments, Formulas (I), (I-A), (I-B), or (I-C) do not include any of Compounds (1)-(12).

TABLE-US-00001 TABLE 1 Com- pound Structure (1) [00028] embedded image (2) [00029] (3) [00030] (4) [00031] (5) [00032] (6) [00033] (7) [00034]

TABLE-US-00002 TABLE 2 (8) [00035] embedded image (9) [00036] (10) [00037] (11) [00038] (12) [00039]

[0230] Compounds of Formula (II)

[0231] Select compounds of the invention can be described by Formula (II)

##STR00040##

where

[0232] each R.sub.A1, R.sub.A2, R.sub.A3, R.sub.A4, R.sub.A5, and R.sub.A6 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a group having the structure X.sub.A1-G.sub.A1-X.sub.A2C(Y.sub.A1)-G.sub.A2-X.sub.A3R.sub.A7, or R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond;

[0233] each X.sub.A1, X.sub.A2, and X.sub.A3 is, independently, absent or selected from O, S, or NR.sub.A8;

[0234] G.sub.A1 is absent or (CR.sub.A9R.sub.A10).sub.m;

[0235] G.sub.A2 is absent or (CR.sub.A11R.sub.A12).sub.n;

[0236] Y.sub.A1 is O, S, or NR.sub.A13;

[0237] each R.sub.A8 and R.sub.A13 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, COR.sub.A14, CO.sub.2R.sub.A14, or CONR.sub.A14R.sub.A15;

[0238] each R.sub.A9, R.sub.A10, R.sub.A11, and R.sub.A12 is selected, independently, from H, halogen, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0239] each R.sub.A7, R.sub.A14 and R.sub.A15 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; and

[0240] each m and n is, independently, 1, 2, or 3;

[0241] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0242] In some embodiments of Formula (II), when R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond, R.sub.A2 is H, R.sub.A3 is CH.sub.3, and R.sub.A6 is CO.sub.2H, R.sub.A5 is not CH.sub.2(2-chlorophenyl).

[0243] In some embodiments of Formula (II), when R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond, R.sub.A2 is H, R.sub.A6 is CH.sub.3 or .sup.tBu, and R.sub.A3 is NHC(O)NHR.sub.A7, R.sub.A7 is not chlorophenyl or dichlorophenyl.

[0244] Certain compounds of Formula (II) may be described further according to Formula (II-A)

##STR00041##

where

[0245] each R.sub.A1, R.sub.A3, R.sub.A4, and R.sub.A7 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond;

[0246] G.sub.A2 is absent or is (CR.sub.A11R.sub.A1R.sub.A12).sub.n;

[0247] X.sub.A3 is absent or is O, S, or NR.sub.A8;

[0248] each R.sub.A11, R.sub.A12, and R.sub.A8 is selected, independently, from H or optionally substituted C.sub.1-6 alkyl; and

[0249] n is 1 or 2;

[0250] or according to Formula (II-R)

##STR00042##

where

[0251] R.sub.A5 is H;

[0252] each R.sub.A1, R.sub.A2, R.sub.A3, R.sub.A4, and R.sub.A6 is selected, independently, from H, optionally substituted aryl, optionally substituted heteroaryl, C(O)X.sub.A3R.sub.A7, or R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond;

[0253] each R.sub.A7 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0254] each X.sub.A3 is, independently, absent, O, or NR.sub.A8,

[0255] or any pharmaceutically acceptable salt or solvate thereof or any stereoisomer thereof.

[0256] In some embodiments of Formula (II) (e.g., (II-A) and (II-B)), when one of R.sub.A1 and R.sub.A4 is H and the other is selected from H or CO.sub.2Et, and R.sub.A3 is unsubstituted phenyl, G.sub.A2-X.sub.A3R.sub.A7 is not NHC.sub.6H.sub.5, NH(p-C.sub.6H.sub.4F), NH(p-C.sub.6H.sub.4OH), NH(p-C.sub.6H.sub.4OMe), NH(3-OH-4-ClC.sub.6H.sub.4), CH.sub.2(O-p-C.sub.6H.sub.4Me), CH.sub.2(4-ethylpiperazinyl), CH.sub.2S(2-phenyltetrazolyl), CH.sub.2S(4-chlorophenyl), CH.sub.2S(2-benzothiazolyl), CH.sub.2S(2-(N-methylimidazolyl)), CH.sub.2S(4,6-dimethylquinazolinyl), adamantyl, or optionally substituted oxiranyl.

[0257] Other compounds of Formula (II) include compounds of Formula (II-C):

##STR00043##

where

[0258] each R.sub.A1, R.sub.A2, R.sub.A4, and R.sub.A6 is selected, independently, from H, C(O)X.sub.A3R.sub.A7, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond;

[0259] each X.sub.A3 is, independently, absent, O, or NR.sub.A8,

[0260] each R.sub.A8 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, COR.sub.A14, CO.sub.2R.sub.A14, or CONR.sub.A14R.sub.A15; and

[0261] each R.sub.A7, R.sub.A14 and R.sub.A15 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl.

[0262] In some embodiments of Formula (II-C), wherein when R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond and R.sub.A2 is H, R.sub.A6 is not 4-chlorophenyl, 4-methoxyphenyl, or 4-(NHCO.sub.2.sup.tBu)phenyl. In other embodiments, when R.sub.A1 is H, R.sub.A4 is H or CO.sub.2Et, R.sub.A2 is unsubstituted phenyl, R.sub.A6 is not C(O)-(unsubstituted phenyl) or C(O)-(4-methylphenyl). In still other embodiments, when R.sub.A1 is H, R.sub.A4 is C(O)-(unsubstituted phenyl), R.sub.A2 is 4-chlorophenyl, R.sub.A6 is not CO.sub.2Et.

[0263] Compounds of Formula (II) (e.g., (II-A)-(II-C)) can be prepared according to methods known in the art. Exemplary methods of synthesis are shown in Schemes 2-5.

##STR00044##

[0264] Scheme 2A shows a method that can be used to prepare pyrazole compounds of Formula (II). Terminal alkynes can be reacted with trimethylsilyldiazomethane (TMS-diazomethane) to afford compounds of Formula (II) where R.sub.A1 and R.sub.A4 combine to form a carbon-carbon double bond and R can be, for example, optionally substituted aryl or optionally substituted heteroaryl. Scheme 2B shows the preparation of Compound (13) using the method in Scheme 2A in which the aniline NH.sub.2 group is protected prior to the reaction with TMS-diazomethane.

##STR00045##

[0265] Scheme 3A depicts another method that can be used to synthesize pyrazoline compounds of Formula (II) according to methods described in J. Chem. Soc. 4686-90 (1952) and J. Med. Chem. 2127-2137 (2006). For example, substituted acroleins (e.g., R can be optionally substituted aryl or optionally substituted heteroaryl) can be treated with ethanolic hydrazine (Step (a)) to afford a pyrazoline intermediate. The pyrazoline can then be treated with an electrophilic compound having a suitable leaving group (e.g., alkyl halides, acid cholorides. or acid anhydrides) and an optional chemical promotoer to afford N-substituted pyrazolines. Scheme 3B shows a method that can be used to prepare Compound (14) where an acid chloride can be used in Step (b) as shown.

##STR00046##

[0266] Scheme 4 shows Compound (15) which can be prepared according to the procedure described in J. Am. Chem. Soc., page 165 (1943). This method can also be used to prepare other pyrazoline compounds of Formula (II), where R.sub.A6 is C(O)R.sub.A7 and R.sub.A2 and R.sub.A7 are, independently, optionally substituted aryl or optionally substituted heteroaryl.

##STR00047##

[0267] Scheme 5A depicts a method by which tetrazole compounds of Formula (II) can be prepared using methods described in WO2005115147 and in J. Med. Chem., 4686-90 (1952). For example, a tetrazole compound that includes a carboxylic acid group can be activated (e.g., treatment with PCl.sub.5 as in Step (a)) and subsequently treated with a nucleophile R as in Step (b). Scheme 5B shows that 5-Phenyl-4,5-dihydro-1H-pyrazole can be used as the nucleophile in step (b) to afford Compound (16).

[0268] Compounds of Formula (II) (e.g., (II-A) and (II-B) and compounds (13)-(16)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). Additional exemplary compounds useful in, for example, the methods, compositions, and kits of the invention, include but are not limited to those shown in Table 3. Other compounds of Formula (II) are shown in Table 4. In some embodiments, Formula (II), (II-A), and (II-B) do not include any of compounds (13)-(26).

TABLE-US-00003 TABLE 3 Compound Structure (17) [00048] embedded image (18) [00049] (19) [00050] (20) [00051] (21) [00052]

TABLE-US-00004 TABLE 4 Compound Structure (22) [00053] embedded image (23) [00054] (24) [00055] (25) [00056] (26) [00057]

[0269] Compounds of Formula (III)

[0270] Select compounds of the invention can be described by Formula (III)

##STR00058##

where

[0271] R.sub.B1 is selected from H, optionally substituted C.sub.1-6 alkyl, C(O)R.sub.B18, C(O)OR.sub.B18, or C(O)NR.sub.B18R.sub.B19;

[0272] R.sub.B2 is selected from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, or optionally substituted C.sub.2-6 alkynyl;

[0273] each R.sub.B3 and R.sub.B4 is selected, independently from H, optionally substituted C.sub.1-6 alkyl, or R.sub.B3 and R.sub.B4 combine to form a bridging group having the structure (CH.sub.2).sub.n(CR.sub.B13CR.sub.B14).sub.o(CH.sub.2).sub.p;

[0274] each n, o, and p is, independently, 0 or 1;

[0275] each R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 is selected, independently, from H, halogen, CN, NO.sub.2, N.sub.3, R.sub.B13, OR.sub.B13, SR.sub.B13, NR.sub.B13R.sub.B14, C(O)R.sub.B15, C(O)OR.sub.B15, C(O)NR.sub.B15R.sub.B16, OC(O)R.sub.B15, OC(O)OR.sub.B15, OC(O)NR.sub.B15R.sub.B16, NR.sub.B15C(O)R.sub.B15, NR.sub.B15C(O)OR.sub.B16, NR.sub.B15C(O)NR.sub.B16R.sub.B17, C(S)Z.sub.B15, C(S)NR.sub.B15R.sub.B16, NR.sub.B15C(S)R.sub.B16, NR.sub.B15C(S)NR.sub.B16R.sub.B17, C(NR.sub.B13)NR.sub.B15R.sub.B16, NR.sub.B15C(NR.sub.B13)R.sub.B16, NR.sub.B15C(NR.sub.B13)NR.sub.B16R.sub.B17;

[0276] each R.sub.B13 and R.sub.B14 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, C(O)R.sub.B18, C(O)OR.sub.B18, or C(O)NR.sub.B18R.sub.B19;

[0277] each R.sub.B15, R.sub.B16, R.sub.B17, R.sub.B18, and R.sub.B19 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0278] where when each n, o, and p is 0, R.sub.B3 and R.sub.B4 combine to form a single bond,

[0279] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0280] Select compounds of Formula (III) can also be described by Formula (III-A)

##STR00059##

where R.sub.B1 is as described in Formula (III), R.sub.B2 is ethyl, ethenyl, or ethynyl and each R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 is selected, independently, from H and halogen,

[0281] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0282] In some embodiments, R.sub.B1 is H.

[0283] Still other compounds of Formula (III) are described by Formula (III-B)

##STR00060##

where R.sub.B1 is as described in Formula (III), R.sub.B2 is ethyl, ethenyl, or ethynyl and each R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 is selected, independently, from H and halogen,

[0284] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0285] In some embodiments, R.sub.B1 is H.

[0286] In some embodiments of Formula (III), R.sub.B1 is not H or CH.sub.3 when R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B9, R.sub.B10, R.sub.B11, and R.sub.B12 are each H, R.sub.B2 is ethyl, ethenyl, ethynyl, propynyl, 2-haloethynyl, (CCC(OH)(CH.sub.3).sub.2), and when R.sub.B3 and R.sub.B4 are each H or combine to form a bond, CH.sub.2CH.sub.2 or CHCH. In other embodiments of Formula (III), R.sub.B1 is not H when R.sub.B5, R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B10, and R.sub.B11 are each H, at least one of R.sub.B9 or R.sub.B12 is fluoro, R.sub.B2 is ethynyl, and when R.sub.B3 and R.sub.B4 combine to form CH.sub.7CH.sub.2. In still other embodiments of Formula (III), R.sub.B1 is not H when R.sub.B6, R.sub.B7, R.sub.B8, R.sub.B10, and R.sub.B11 are H and one or two of R.sub.B6, R.sub.B8, R.sub.B10, and R.sub.B12 is halogen, nitro, or methyl.

##STR00061##

[0287] Scheme 6A depicts a method by which compounds of Formula (III) can be prepared. A ketone derivative can be treated with an anionic carbon nucleophile (e.g., lithium trimethylsilylacetylide formed in step (a)). The resulting alkoxide can be trapped using a protic quench or by the addition of an electrophilic reagent. Finally, the trimethylsilyl group can be deprotected using basic conditions. If desired, the alkyne group can be further manipulated (e.g., subjected to hydrogenation conditions to afford the corresponding alkene or alkyl group or treated with a metal catalyst/and organic electrophile in cross-coupling reactions). Scheme 6B shows Compound (27), which can be prepared using these conditions.

[0288] Compounds of Formula (III) (e.g., (III-A) and (III-B) and compound (27)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). Additional exemplary compounds useful in, for example, the methods, compositions, and kits of the invention, include but are not limited to those shown in Table 5. Other compounds of Formula (III) include Compounds (35)-(36), (39)-(40), and (42)-(47) shown in Table 6. In some embodiments, Formula (III) does not include any of Compounds (27)-(33), (35)-(36), (39)-(40), or (42)-(47).

TABLE-US-00005 TABLE 5 Compound Structure (28) [00062] embedded image (29) [00063] (30) [00064] (31) [00065] (32) [00066] (33) [00067]

TABLE-US-00006 TABLE 6 Compound Structure (34) [00068] embedded image (35) [00069] (36) [00070] (37) [00071] (38) [00072] (39) [00073] (40) [00074] (41) [00075] (42) [00076] (43) [00077] (44) [00078] (45) [00079] (46) [00080] (47) [00081]

[0289] Compounds of Formula (IV)

[0290] Still other compounds can be described according to Formula (IV)

##STR00082##

where

[0291] each R.sub.C1, R.sub.C2, and R.sub.C3 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, YR.sub.C7, or R.sub.C1 and R.sub.C2 combine to form a (O) or a (S) group, or R.sub.C1 and R.sub.C3 combine to form a carbon-nitrogen double bond;

[0292] R.sub.C4 is selected from H, halogen, CN, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or C(O)ZR.sub.C8,

[0293] each R.sub.C5 and R.sub.C6 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, or R.sub.C1 and R.sub.C2 combine to form an optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0294] each R.sub.C7, R.sub.C8, R.sub.C9, R.sub.C10, R.sub.C11, and R.sub.C12 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0295] X is CR.sub.C11CR.sub.C12, O, S, or NR.sub.C9;

[0296] Y is, independently, a single bond, (CR.sub.C8R.sub.C9), O, S, or NR.sub.C10;

[0297] Z is a single bond, O, S, or NR.sub.C10;

[0298] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0299] In some embodiments of Formula (IV), when X is S, R.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4 is H, and R.sub.C5 and R.sub.C6 combine to form unsubstituted cyclopentyl, R.sub.C3 is not CH.sub.2R.sub.C7, where R.sub.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. In other embodiments of Formula (IV), when X is S, R.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4 is H, and R.sub.C5 and R.sub.C6 are each Me, R.sub.C3 is not CH.sub.2R.sub.C7, where R.sub.C7 is unsubstituted phenyl. In other embodiments of Formula (IV), when X is CHCH, R.sub.C1 and R.sub.C2 combine to form a (O) group, R.sub.C4, R.sub.C5 and R.sub.C6 are H, R.sub.C3 is not CH.sub.2(4-halophenyl).

[0300] Select compounds of Formula (IV) can also be described by Formula (IV-A)

##STR00083##

where X, R.sub.C1, R.sub.C2, R.sub.C3, and R.sub.C4 are as defined for Formula (IV) and n is an integer between 0-3,

[0301] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

##STR00084##

[0302] Scheme 7A depicts a method by which compounds of Formula (IV) (e.g., compounds of Formula (IV-A)) can be prepared. A heterocyclic derivative can be deprotonated using a base such as NaH and subsequently treated with an electrophile (e.g., an alkyl halide such as benzyl bromide, an acid chloride, or an acid anhydride) to afford a compound of Formula (IV) such as Compound (48) shown in Scheme 7B.

[0303] Compounds of Formula (IV) (e.g., (IV-A) and Compound (48)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). Additional exemplary compounds useful in, for example, the methods, compositions, and kits of the invention, include but are not limited to those shown in Table 7. In some embodiments, Formula (IV) does not include any of Compounds (48)-(57).

TABLE-US-00007 TABLE 7 Compound Structure (49) [00085] embedded image (50) [00086] (51) [00087] (52) [00088] (53) [00089] (54) [00090] (55) [00091] (56) [00092] (57) [00093]

[0304] Compounds of Formula (V)

[0305] Other compounds of the invention can be described by Formula (V)

##STR00094##

where

[0306] each X.sub.D1 and X.sub.D2 is selected, independently, from O, S, NR.sub.D5, or CR.sub.D6R.sub.D7;

[0307] Y.sub.D1 is selected from a covalent bond, C(O), S(O), or S(O).sub.2;

[0308] Y.sub.D2 is selected from a covalent bond, C(O), OC(O), NR.sub.D8C(O), S(O), S(O).sub.2, OS(O), OS(O).sub.2, NR.sub.D8S(O), NR.sub.D8S(O).sub.2, or C(S);

[0309] A is selected from optionally substituted aryl or optionally substituted heteroaryl;

[0310] G.sub.D1 is selected from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, OR.sub.D9, or NR.sub.D9R.sub.D10;

[0311] each R.sub.D1, R.sub.D2, R.sub.D3, R.sub.D4, R.sub.D6, R.sub.D7, is selected, independently, from H, halogen, CN, NC, N.sub.3, NO.sub.2, OR.sub.D11, SR.sub.D11, NR.sub.D11R.sub.D12, COR.sub.D13, CO.sub.2R.sub.D13, CONR.sub.D13R.sub.D14, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.D1 and R.sub.D4, or R.sub.D1 and R.sub.D5, or R.sub.D1 and R.sub.D6, or R.sub.D3 and R.sub.D5, or R.sub.D3 and R.sub.D6 combine to form a double bond;

[0312] each R.sub.D5, R.sub.D8, R.sub.D9, R.sub.D10, R.sub.D13, R.sub.D14, R.sub.D15, and R.sub.D16 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.D9 and R.sub.D10 combine to form a heterocyclyl;

[0313] each R.sub.D11 and R.sub.D12 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, COR.sub.D15, CO.sub.2R.sub.D15, CONR.sub.D15R.sub.D16, S(O)R.sub.D15, S(O)OR.sub.D15, S(O)NR.sub.D15R.sub.D16, S(O).sub.2R.sub.D15, S(O).sub.2OR.sub.D15, S(O).sub.2NR.sub.D15R.sub.D16;

[0314] where Y.sub.D1 and Y.sub.D2 are each covalently bound to a carbon center in A;

[0315] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0316] Still other compounds of Formula (V) can be described by Formula (V-A)

##STR00095##

where

[0317] each Y.sub.D1 and Y.sub.D2 is selected, independently, from C(O) or S(O).sub.2;

[0318] A is phenyl having 0, 1, 2, 3, or 4 additional substituents;

[0319] R.sub.D2 and R.sub.D3 are selected, independently from H, halogen, CN, NC, N.sub.3, NO.sub.2, COR.sub.D13, CO.sub.2R.sub.D13, CONR.sub.D13R.sub.D14, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0320] each R.sub.D5, R.sub.D9, R.sub.D10, R.sub.D13, and R.sub.D14 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.D9 and R.sub.D10 combine to form a heterocyclyl; or by Formula (V-B)

##STR00096##

where

[0321] each R.sub.D2, R.sub.D3, R.sub.D17, R.sub.D18, R.sub.D19, and R.sub.D20, is selected, independently from H, halogen, CN, NC, N.sub.3, NO.sub.2, COR.sub.D13, CO.sub.2R.sub.D13, CONR.sub.D13R.sub.D14, optionally substituted C.sub.1-6 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0322] each R.sub.D9 and R.sub.D10 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, or optionally substituted aryl, or R.sub.D9 and R.sub.D10 combine to form a heterocyclyl;

[0323] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0324] In some embodiments of Formula (V), when R.sub.D1 and R.sub.D4 combine to form a double bond, R.sub.D2 and R.sub.D3 are H, X.sub.D1 is NH, X.sub.D2 is S, Y.sub.D1 is (CO), Y.sub.D2 is (SO.sub.2), G.sub.D1 is N(Et).sub.2, and A is phenyl having no additional substituents, Y.sub.D1 and Y.sub.D2 are not para to each other.

##STR00097##

[0325] Compounds of Formula (V) (e.g., compounds of Formula (V-A) or (V-B)) can be prepared, for example, by treating an aryl or heteroaryl compound that has two electrophilic groups successively with nucleophilic reagents to afford the desired compound. For example, as shown in Scheme 8 and using procedures adapted from Heterocyclic Communications, 12(6): 453-456 (2006) and Organic Synthesis, Collective Vol. 6, page 818, the difunctional benzene derivative 4-CO.sub.2H phenylsulfonyl chloride can be treated with a nucleophile such as diethylamine to afford the corresponding sulfonamide. This compound can then be esterified prior to treatment with a second nucleophile (e.g., methanolic ammonia). Finally, the compound afforded by step (c) can then be condensed with a carbonyl-containing compound to afford compounds of Formula (V) such as Compound (58).

[0326] Compounds of Formula (V) (e.g., (V-A) and (V-B) and compound (34)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). In some embodiments, Formulas (V), (V-A), and (V-B) do not include Compounds (58).

[0327] Compounds of Formula (VI)

[0328] Still other compounds of the invention can be described by Formula (VI)

##STR00098##

where

[0329] each X.sub.E1 and X.sub.E3 is selected, independently, from N or CR.sub.E4;

[0330] each X.sub.E4 and X.sub.E5 is selected, independently, from O, S, or NR.sub.E5;

[0331] X.sub.E2 is selected from O, S, or N;

[0332] each Z.sub.E1, R.sub.E2, and Z.sub.E3 is selected, independently, from a single bond, (CR.sub.E6R.sub.E7).sub.n, C(O), S(O), or S(O).sub.2, or Z.sub.E1R.sub.E1 and Z.sub.E2R.sub.E2 combine to form a double bond;

[0333] each R.sub.E1, R.sub.E2, R.sub.E3, R.sub.E4, R.sub.E5, R.sub.E6, and R.sub.E7 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0334] p is 0 or 1; and

[0335] n is an integer between 1-6; and

[0336] where when X.sub.E2 is O or S, Z.sub.E2R.sub.E2 is not present;

[0337] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0338] In some embodiments, each R.sub.E1, R.sub.E2, R.sub.E3, R.sub.E4, R.sub.E5, R.sub.E6, and R.sub.E7 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl

[0339] In some embodiments, R.sub.E3 is selected from substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0340] In some embodiments of Formula (VI), when p is 0, X.sub.E1 is CH, Z.sub.E1R.sub.E1 is CH.sub.2(indol-3-yl), X.sub.E4 and X.sub.E5 are O, and X.sub.E2Z.sub.E2R.sub.E2 is NH, X.sub.E3Z.sub.E3R.sub.E3 is not NCH.sub.2(p-ClC.sub.6H.sub.4) or NCH.sub.2CH.sub.2O(p-FC.sub.6H.sub.4).

[0341] In other embodiments, when X.sub.E1Z.sub.E1R.sub.E1 is NH, X.sub.E2Z.sub.E2 is CHCH.sub.2, R.sub.E2 is unsubstituted 3-indolyl, p is 0, X.sub.E4 is S, X.sub.E5 is O, X.sub.E3 is N, and Z.sub.E3 is CH.sub.2, R.sub.E3 is not CH.sub.2CH.sub.2(4-morpholine).

[0342] In still other embodiments, when X.sub.E1Z.sub.HR.sub.E1 is NH, X.sub.E2Z.sub.E2 is CHCH.sub.2, R.sub.E2 is unsubstituted or substituted 3-indolyl, p is 0 or 1, both X.sub.E4 and X.sub.E5 are O or X.sub.E4 is S and X.sub.E5 is O, X.sub.E3 is N, and Z.sub.E3 is CH.sub.2, R.sub.E3 is not H, unsubstituted C.sub.1-6 alkyl, or CH.sub.2CHCH.sub.2.

[0343] In any of the compounds of Formula (VI) described herein (e.g., any compound having a structure according to Formulas (VI), (VI-A), (VI-B), (VI-C), or (VI-D)), the R.sub.E3 group can be unsubstituted. In some embodiments, a substituted R.sub.E3 group includes 1, 2, 3, 4, or 5 substituents selected from, for example, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, azido(N.sub.3), alkoxy (OR), amido (NRC(O)R or C(O)NRR), amino (NRR), carbamoyl (OC(O)NRR or NRC(O)OR), hydroxy (OH), or isocyano (NC), where each R or R is selected, independently, from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. In other embodiments, the substituted R.sub.E3 group includes 1, 2, 3, or 4 substituents that are electron donating groups (e.g., hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, and amino groups).

[0344] Certain compounds of Formula (VI) may be described by Formula (VI-A) or Formula (VI-B)

##STR00099##

wherein

[0345] each Z.sub.E2 and Z.sub.E3 is selected, independently, from a single bond, (CR.sub.E6R.sub.E7), C(O), or R.sub.E! and Z.sub.E2R.sub.E2 combine to form a double bond;

[0346] each R.sub.E1, R.sub.E2, R.sub.E3, and R.sub.E4 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0347] each R.sub.E6 and R.sub.E7 is selected, independently, from H or optionally substituted C.sub.1-6 alkyl; and

[0348] n is an integer between 1-6;

[0349] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0350] In some embodiments, each R.sub.E1, R.sub.E2, R.sub.E3, and R.sub.E4 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0351] In some embodiments, R.sub.E3 is selected from substituted C.sub.1-6 alkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0352] In some embodiments of Formula (VI-A), when R.sub.E1 and R.sub.E4 are H, Z.sub.E2 and Z.sub.E3 are each CH.sub.2, and R.sub.E2 is unsubstituted 3-indolyl, R.sub.E3 is not 4-chlorophenyl.

[0353] In certain embodiments, the compounds of Formula (VI) are described by the following formula:

##STR00100##

where

[0354] each X.sub.E4 and X.sub.E5 is, independently, O or S;

[0355] X.sub.E2 is O or N;

[0356] each Z.sub.E2 and Z.sub.E3 is selected, independently, from a single bond or (CR.sub.E6R.sub.E7).sub.n;

[0357] each R.sub.E2 and R.sub.F3 is, independently, H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl;

[0358] each R.sup.3 and R.sup.4 is, independently, H, halogen, or optionally substituted C.sub.1-6 alkyl;

[0359] each R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is selected, independently, from H, halogen, CN, NO.sub.2, OR.sup.13, NR.sup.13R.sup.14, COR.sup.15, CO.sub.2R.sup.15, optionally substituted C.sub.1-6 alkyl, or optionally substituted aryl;

[0360] R.sup.10 is selected from H, halogen, CN, NO.sub.2, OR.sup.13, NR.sup.13R.sup.14, COR.sup.15, CO.sub.2R.sup.15, optionally substituted C.sub.1-6 alkyl, optionally substituted aryl, optionally substituted alkenyl, or optionally substituted alkynyl;

[0361] each R.sup.13 and R.sup.14 is selected, independently, from H, COR.sup.16, CO.sub.2R.sup.16, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0362] each R.sup.11, R.sup.12, R.sup.15, and R.sup.16 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0363] where, independently, n is 0, 1, 2, 3, 4, or 5, and p is 0 or 1;

[0364] or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

[0365] In some embodiments, p is 0.

[0366] In some embodiments, R.sub.E3 is selected from substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted C.sub.2-6 alkenyl, optionally substituted C.sub.2-6 alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

[0367] Select compounds of Formula (VI-C) can also be described by Formula (VI-D):

##STR00101##

where

[0368] X.sub.E5 is O or S;

[0369] Z.sub.E3R.sub.E3 is optionally substituted C.sub.1-4 alkaryl;

[0370] each R.sup.3, R.sup.4, and R.sup.10 is, independently, H or optionally substituted C.sub.1-6 alkyl;

[0371] R.sup.9 is H, halogen, CN, NO.sub.2, OR.sup.13, NR.sup.13R.sup.14, COR.sup.15, CO.sub.2R.sup.15, or optionally substituted C.sub.1-6 alkyl;

[0372] each R.sup.13 and R.sup.14 is selected, independently, from H, COR.sup.16, CO.sub.2R.sup.16, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0373] each R.sup.11, R.sup.12, R.sup.15, and R.sup.16 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0374] where n is 1 or 2;

[0375] or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.

[0376] In some embodiments, the compound has a structure according to the following formula:

##STR00102##

or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof, where n, Z.sub.E3, R.sub.E3, R.sup.3, R.sup.4, R.sup.9, and R.sup.10 are as defined for Formula (IV-D).

[0377] In the compounds of the invention, the sp.sup.3-hybridized carbon to which G is attached (e.g., the chiral center marked with an asterisk in any of Formulas (VI-A), (VI-B-1), (VI-B-2), (VI-C), (VI-D), or (VI-E)) can have the (R)- or the (S)-configuration. For example, compounds of the invention include

##STR00103##

[0378] or any pharmaceutically acceptable salt or solvate thereof.

[0379] In any embodiment of Formulas (VI-C), (VI-D), or (VI-E), n=1 and R.sup.3 and R.sup.4 are each H. In another embodiment, R.sup.10 is H or CH.sub.3. In still other embodiments, R.sup.9 is H, halogen, optionally substituted C.sub.1-6 alkyl, OH, or O (optionally substituted C.sub.1-6 alkyl).

[0380] In any embodiment of Formulas (VI-C), (VI-D), or (VI-E), Z.sub.E3R.sub.E3 is optionally substituted benzyl. In one embodiment, Z.sub.E3R.sub.E3 is unsubstituted benzyl. In another embodiment, Z.sub.E3R.sub.E3 is benzyl having 1, 2, 3, 4, or 5 substituents. In some embodiments, the substituents are selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, azido(N.sub.3), alkoxy (OR), amido (NRC(O)R or C(O)NRR), amino (NRR), carbamoyl (OC(O)NRR or NRC(O)OR), hydroxy (OH), and isocyano (NC), as described herein. In a further embodiment, Z.sub.E3R.sub.E3 is CH.sub.2-(p-XC.sub.6H.sub.4), where X is halogen. In some embodiments, X is F or Cl.

[0381] In any of the embodiments described herein, one or both of Z.sub.E3 and R.sub.E3 do not include substituents selected from the group consisting of: halogen (e.g., F, Cl, Br, or I); nitro (NO.sub.2), cyano (CN), acyloxy(OC(O)R), acyl (C(O)R), carboxylic acid (CO.sub.2H), carboxylic ester (CO.sub.2R), sulfonate (S(O).sub.2OR), sulfonamide (S(O).sub.2NRR or NRS(O).sub.2R), or sulfonyl (S(O).sub.2R), where each R or R is selected, independently, from H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, as described herein.

##STR00104##

[0382] Compounds of Formula (VI) (e.g., compounds of Formulas (VI-A), (VI-B), (VI-C), or (VI-D)) can be prepared, for example, by treating hydantoin compound that has, for example, a substituent R at the 5-position with a base followed by trapping with an electrophilic reagent (Scheme 9A). For example, Scheme 9B shows that the synthesis of Compound (59) can be achieved by the use of 4-chlorobenzylbromide as the electrophile.

[0383] In some embodiments, Formula (VI) (e.g., compounds of Formulas (VI-A), (VI-B), (VI-C), or (VI-D)) does not include any of the compounds or formulas disclosed in U.S. Pat. Nos. 6,756,394 and 7,253,201, in U.S. Patent Publication No. 20050119260, and in pending U.S. application Ser. Nos. 12/077,320 and 12/086,792, each of which is hereby incorporated by reference.

[0384] Compounds of Formula (VI) (e.g., (VI-A)-(VI-D) and compound (59)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits).

[0385] In some embodiments, Formula (VI) does not include compound (59).

[0386] Compounds of Formula (VII)

[0387] Still other compounds can be described according to Formula (VII)

##STR00105##

where

[0388] Z.sub.F1 is selected from a single bond, (CR.sub.F10R.sub.F11).sub.n, C(O), S(O), or S(O).sub.2;

[0389] each R.sub.F1, R.sub.F2, R.sub.F4, R.sub.F10, R.sub.F11, R.sub.F12, and R.sub.F13, is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.F2 and R.sub.F4 combine to form a carbon-carbon double bond;

[0390] each R.sub.F3 and R.sub.F5 is selected, independently, from H, halogen, CN, CO.sub.2R.sub.F12, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0391] each R.sub.F6, R.sub.F7, R.sub.F8, and R.sub.F9 is selected, independently, from H, halogen, CN, NC, N.sub.3, NO.sub.2, OR.sub.F12, SR.sub.F12, NR.sub.F12R.sub.F13, CO.sub.F12, CO.sub.2 F12, CONR.sub.F12R.sub.F13, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and where n is an integer between 1-6;

[0392] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0393] Certain compounds of Formula (VII) can also be described by Formula (VII-A)

##STR00106##

where

[0394] Z.sub.F1 is selected from a single bond, (CH.sub.2), C(O), or S(O).sub.2;

[0395] R.sub.F1 is selected from H, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0396] R.sub.F2 and R.sub.F4 are each H, or R.sub.F2 and R.sub.F4 combine to form a carbon-carbon double bond;

[0397] each R.sub.F6, R.sub.F7, R.sub.F8, and R.sub.F9 is selected, independently, from H, halogen, CN, NC, N.sub.3, NO.sub.2, OR.sub.F12, SR.sub.F12, NR.sub.F12R.sub.F13, COR.sub.F12, CO.sub.2 F12, CONR.sub.F12R.sub.F13, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and

[0398] each R.sub.F12 and R.sub.F13, is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0399] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0400] In some embodiments of Formula (VII-A), when R.sub.F2, R.sub.F4, R.sub.F6, R.sub.F7, R.sub.F8, and R.sub.F9 are each H and Z.sub.F1 is C(O), R.sub.R is not -(unsubstituted 1,4-benzodioxane) or CH.sub.2(O-(unsubstituted phenyl)).

##STR00107##

[0401] Scheme 10 provides a method by which compounds of Formula (VII) such as Compound (60) can be prepared. For example, a nucleophilic compound such as indoline can be treated with an electrophile (e.g., a compound containing a carboxylic acid) in the presence of an optional promoter such as DEAD/PPh.sub.3 to afford the requisite compound. Another compound of Formula (VIII) is Compound (61) (Scheme 11).

##STR00108##

[0402] Compounds of Formula (VII) (e.g., (VII-A) and compound (60)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits). In some embodiments, Formulas (VII) and (VII-A) do not include compounds (60) or (61).

[0403] Compounds of Formula (VIII)

[0404] Still other compounds useful in the invention are described by Formula (VIII):

##STR00109##

where

[0405] X.sub.G1 is selected from O, N, or (CR.sub.G9R.sub.G10).sub.n;

[0406] X.sub.G2 and X.sub.G3 are selected, independently, from N or CR.sub.G11;

[0407] each R.sub.G1, R.sub.G2, R.sub.G3, R.sub.G4, R.sub.G5, R.sub.G6, R.sub.G7, R.sub.G8, R.sub.G9, R.sub.G10, and R.sub.G11 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.G1 and R.sub.G2, or R.sub.G3 and R.sub.G4, or R.sub.G5 and R.sub.G6, or R.sub.G7 and R.sub.G8 combine to form an optionally substituted cycloalkyl or heterocyclyl; and

[0408] n is 1 or 2;

[0409] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0410] Select compounds of Formula (VIII) can also be described by Formula (VIII-A):

##STR00110##

wherein each R.sub.G1, R.sub.G2, R.sub.G5, and R.sub.G6 is selected, independently, from H, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-10 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or R.sub.G1 and R.sub.G2, or R.sub.G5 and R.sub.G6 combine to form an optionally substituted cycloalkyl or heterocyclyl,

[0411] or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

[0412] In some embodiments of Formula (VIII-A), when R.sub.G1 is unsubstituted phenyl and R.sub.G2 is H, R.sub.G5 and R.sub.G6 do not combine to form unsubstituted cyclopentyl,

[0413] Methods by which compounds of Formula (VIII) (e.g., compounds of Formula (VIII-A) can be prepared are known in the art. For example, Compound (62) shown in Scheme 12, can be prepared according to methods described in Synthesis, pages 771-783 (2002).

##STR00111##

[0414] Compounds of Formula (VIII) (e.g., (VIII-A) and compound (62)), or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof, can also be used as described herein (e.g., in pharmaceutical compositions, as inhibitors of necroptosis, in methods of treatment, and in kits).

[0415] In some embodiments, Formulas (VIII) and (VIII-A) do not include compound (62).

[0416] Additional Inhibitors of Necroptosis

[0417] Other compounds useful in the compositions, kits, and methods of the invention are described in U.S. Pat. Nos. 6,756,394 and 7,253,201, in U.S. Patent Publication No. 20050119260, and in pending U.S. application Ser. Nos. 12/077,320 and 12/086,792, each of which is hereby incorporated by reference. In addition to the compounds described by Formulas (I)(VIII), other inhibitors of necroptosis include, but are not limited to, the structures depicted in Table 8, or any pharmaceutically acceptable salt or solvate thereof, or any stereoisomer thereof.

TABLE-US-00008 TABLE 8 Compound Structure (63) [00112] embedded image (64) [00113] (65) [00114] (66) [00115] (67) [00116] (68) [00117] (69) [00118] (70) [00119]

Pharmaceutical Compositions

[0418] The necrostatins described herein (e.g., compounds of Formulas (I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) can be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a pharmaceutically acceptable excipient. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (200320.sup.th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0419] The compounds may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

Pharmaceutically Acceptable Excipients

[0420] Pharmaceutically acceptable excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

Oral Administration

[0421] Any of the compounds described herein (e.g., compounds of Formulas (I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Parenteral Administration

[0422] A compound may also be administered parenterally. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.

Nasal Administration

[0423] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

Buccal or Sublingual Administration

[0424] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0425] The compounds of the invention may be administered to an animal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Dosage Amounts

[0426] The amount of active ingredient (e.g., a compound of Formulas (I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) in the compositions of the invention can be varied. One skilled in the art will appreciate that the exact individual dosages may be adjusted somewhat depending upon a variety of factors, including the protein being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the nature of the subject's conditions, and the age, weight, health, and gender of the patient. Generally, dosage levels of between 0.1 g/kg to 100 mg/kg of body weight are administered daily as a single dose or divided into multiple doses. Desirably, the general dosage range is between 250 g/kg to 5.0 mg/kg of body weight per day. Wide variations in the needed dosage are to be expected in view of the differing efficiencies of the various routes of administration. For instance, oral administration generally would be expected to require higher dosage levels than administration by intravenous injection. Variations in these dosage levels can be adjusted using standard empirical routines for optimization, which are well known in the art. In general, the precise therapeutically effective dosage will be determined by the attending physician in consideration of the above identified factors.

Therapeutic Uses and Screening Methods

[0427] The compounds disclosed herein (e.g., compounds of Formulas (I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) can be used to treat disorders where necroptosis is likely to play a substantial role (e.g., cerebral ischemia, traumatic brain injury, 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). Compounds of the invention can also be used in screening methods to identify targets of necroptosis and to identify additional inhibitors of necroptosis, as well as in assay development.

[0428] Compounds disclosed herein can be evaluated for their pharmacological properties in animal models of disease. The compounds identified to decrease necrosis or necroptosis may be structurally modified and subsequently used to decrease necrosis or necroptosis, or to treat a subject with a condition in which necrosis or necroptosis occurs. The methods used to generate structural derivatives of the small molecules that decrease necrosis or necroptosis are readily known to those skilled in the fields of organic and medicinal chemistry.

[0429] Therapy according to the invention may be performed alone or in conjunction with another therapy, for example in combination with apoptosis inhibitors, and may be provided at home, the doctor's office, a clinic, a hospital's outpatient department, or a hospital. Treatment generally begins at a hospital so that the doctor can observe the therapy's effects closely and make any adjustments that are needed. The duration of the therapy depends on the age and condition of the patient, as well as how the patient responds to the treatment. Additionally, a person having a greater risk of developing a condition may receive prophylactic treatment to inhibit or delay symptoms of the disease.

[0430] In some embodiments, the compounds and methods of the invention can be used to treat any of the following disorders where necroptosis is likely to play a substantial role: 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, and any condition in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor.

Conditions Caused by Alteration in Cell Proliferation, Differentiation, or Intracellular Signalling

[0431] Conditions in which alteration in cell proliferation, differentiation or intracellular signaling is a causative factor include cancer and infection, e.g., by viruses (e.g., acute, latent and persistent), bacteria, fungi, or other microbes.

[0432] Exemplary viruses are human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), cytomegalovirus (CMV)5 human herpesviruses (HHV), herpes simplex viruses (HSV), human T-Cell leukemia viruses (HTLV)5 Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK), hepatitis viruses, adenovirus, parvoviruses, and human papillomaviruses. Exemplary diseases caused by viral infection include, but are not limited to, chicken pox, Cytomegalovirus infections, genital herpes, Hepatitis B and C, influenza, and shingles.

[0433] Exemplary bacteria include, but are not limited to Campylobacter jejuni, Enterobacter species, Enterococcus faecium, Enterococcus faecalis, Escherichia coli (e.g., E. coli O157:H7), Group A streptococci, Haemophilus influenzae, Helicobacter pylori, listeria, Mycobacterium tuberculosis, Pseudomonas aeruginosa, S. pneumoniae, Salmonella, Shigella, Staphylococcus aureus, and Staphylococcus epidermidis. Exemplary diseases caused by bacterial infection include, but are not limited to, anthrax, cholera, diphtheria, foodborne illnesses, leprosy, meningitis, peptic ulcer disease, pneumonia, sepsis, tetanus, tuberculosis, typhoid fever, and urinary tract infection.

Neurodegenerative Diseases

[0434] Exemplary neurodegenerative diseases are 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. Exemplary muscular dystrophies or related diseases are Becker's muscular dystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (Steinert's disease), myotonia congenita, Thomsen's disease, and Pompe's disease. Muscle wasting can be associated with cancer, AIDS, congestive heart failure, and chronic obstructive pulmonary disease, as well as include necrotizing myopathy of intensive care.

[0435] Compounds and methods of the invention can additionally be used to boost the immune system, whether or not the patient being treated has an immunocompromising condition. For example, the compounds described herein can be used in a method to strengthen the immune system during immunization, e.g., by functioning as an adjuvant, or by being combined with an adjuvant.

Kits

[0436] Any of the compounds or pharmaceutical compositions of the invention (e.g., those that include a compound of Formulas (I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) can be used together with a set of instructions, i.e., to form a kit. The kit may include instructions for use of the compounds of the invention in a screening method or as a therapy as described herein.

[0437] The following non-limiting examples are illustrative of the present invention.

EXAMPLES

Example 1: Determination of Necroptosis Inhibitory Activity

[0438] Evaluation of necroptosis inhibitory activity was performed using a FADD-deficient variant of human Jurkat T cells or with L929 cells treated with TNF- as previously described (Degterev et al., Nat. Chem. Biol. 1:112 (2005) and Jagtap et al., J. Med. Chem. 50: 1886 (2007)). Utilizing these conditions the cells efficiently underwent necroptosis. For EC.sub.50 value determinations, cells were treated with 10 ng/mL of human TNF- in the presence of increasing concentration of test compounds for 24 hours followed by ATP-based viability assessment.

[0439] ATP-based viability assessment: Briefly, necroptosis activity was performed using a FADD-deficient variant of human Jurkat T cells or L929 cells treated with TNF-. For EC.sub.50 value determinations, cells (500,000 cells/mL, 100 L per well in a 96-well plate) were treated with 10 ng/mL of human TNF- in the presence of increasing concentration of test compounds for 24 hours at 37 C. in a humidified incubator with 5% CO.sub.2 followed by ATP-based viability assessment. Stock solutions (30 mM) in DMSO were initially prepared and then diluted with DMSO to give testing solutions, which were added to each test well. The final DMSO concentration was 0.5%. Eleven compound test concentrations (0.030-100 M) were used. Each concentration was done in duplicate.

[0440] Cell viability assessments were performed using a commercial luminescent ATP-based assay kit (CellTiter-Glo, Promega, Madison, Wis.) according to the manufacturer's instructions. Briefly, 40 L of the cell lysis/ATP detection reagent was added to each well. Plates were incubated on a rocking platform for 10 minutes at room temperature and luminescence was measured using a Wallac Victor 3 plate-reader (Perkin Elmer, Wellesley, Mass.). Cell viability was expressed as a ratio of the signal in the well treated with TNF- and compound to the signal in the well treated with compound alone. This was done to account for nonspecific toxicity, which in most cases was <10%. EC.sub.50 values were calculated using nonlinear regression analysis of sigmoid dose-response (variable slope) curves from plots of log [I] verses viability values.

[0441] Results obtained using these procedures are shown in Table 9.

TABLE-US-00009 TABLE 9 EC.sub.50 LD.sub.50 Compound Fadd / EC.sub.50 Fadd / no. Structure Jurkat L929 Jurkat (1) [00120] embedded image 0.4769 0.1971 >2000 (2) [00121] 0.7690 (3) [00122] 0.8232 (4) [00123] 0.3540 (5) [00124] 24.98 (6) [00125] Partial activity (7) [00126] 2.379 (8) [00127] inactive (9) [00128] inactive (10) [00129] inactive (11) [00130] inactive (12) [00131] inactive (13) [00132] 5.379 0.89 539.4 (14) [00133] embedded image 0.4101 4.202 396.9 (15) [00134] 0.3688 4.02 799.5 (16) [00135] 0.6289 72.97 247.7 (17) [00136] inconclusive (18) [00137] 0.4101 (19) [00138] 0.3688 (20) [00139] 3.211 (21) [00140] 1.557 (22) [00141] Inactive (23) [00142] Inactive (24) [00143] Inactive (25) [00144] Inactive (26) [00145] embedded image Inactive (27) [00146] 3.227 0.659 541.3 (28) [00147] 2.98 (29) [00148] 31.78 (30) [00149] 5.833 (31) [00150] 2.954 (32) [00151] 2.002 (33) [00152] 4.788 (34) [00153] Inactive (35) [00154] Inactive (36) [00155] Inactive (37) [00156] Inactive (38) [00157] Inactive (39) [00158] embedded image Inactive (40) [00159] Inactive (41) [00160] Inactive (42) [00161] Inactive (43) [00162] Inactive (44) [00163] Inactive (45) [00164] Inactive (46) [00165] Inactive (47) [00166] Inactive (48) [00167] 0.2161 8.66 188.9 (49) [00168] 3.803 (50) [00169] >30 (51) [00170] 10.88 (52) [00171] embedded image 3.046 (53) [00172] >30 (54) [00173] 0.8606 (55) [00174] >30 (56) [00175] >30 (57) [00176] 0.9363 (58) [00177] 8.958 1.11 >2000 (59) [00178] 0.3431 7.458 115.7 (60) [00179] 0.6289 23.04 356.5 (61) [00180] Inactive (62) [00181] 0.6683 10.09 754 (63) [00182] 2.364 13.7 1364 (64) [00183] embedded image 14.14 Inactive 1788 (65) [00184] 3.621 Inactive 138.6 (66) [00185] 2.616 47.12 256.8 (67) [00186] 2.245 10.02 697.8 (68) [00187] 1.633 Inactive 252.3 (69) [00188] 7.724 Inactive 1571 (70) [00189] 0.9077 Inactive >2000

[0442] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[0443] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0444] Other embodiments are within the claims.

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