Heterocyclic inhibitors of necroptosis
First Claim
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1. A compound having a structure according to Formula (I) whereinX1 and X2 are, independently, N or CR4;
- X3 is selected from O, S, NR5, or —
(CR5)2;
Y is selected from C(O) or CH2; and
Z is (CR6R7)n,R1 is selected from H, halogen, optionally substituted C1-6 lower alkyl, or optionally substituted C1-6 cycloalkyl, or optionally substituted aryl;
R2 is selected from H or optionally substituted C1-6 lower alkyl;
R3 is optionally substituted aryl;
each R4 is selected from H, halogen, carboxamido, nitro, cyano, optionally substituted lower C1-6 alkyl, or optionally substituted aryl;
R5 is selected from H, halogen, optionally substituted lower C1-6 alkyl, or optionally substituted aryl;
each R6 and R7 is, independently, selected from H or optionally substituted C1-6 lower alkyl; and
n is 0, 1, 2, or 3;
wherein when X1 and X2 are N, X3 is S, Y, is C(O), Z is CH2, R2 is H, and R3 is 2-chloro-6-fluoro-phenyl, R1 is not methyl;
or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof.
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Abstract
The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I) and (Ia)-(Ie) and are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring the compounds of the invention. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.
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Citations
27 Claims
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1. A compound having a structure according to Formula (I)
wherein X1 and X2 are, independently, N or CR4; -
X3 is selected from O, S, NR5, or —
(CR5)2;Y is selected from C(O) or CH2; and Z is (CR6R7)n, R1 is selected from H, halogen, optionally substituted C1-6 lower alkyl, or optionally substituted C1-6 cycloalkyl, or optionally substituted aryl; R2 is selected from H or optionally substituted C1-6 lower alkyl; R3 is optionally substituted aryl; each R4 is selected from H, halogen, carboxamido, nitro, cyano, optionally substituted lower C1-6 alkyl, or optionally substituted aryl; R5 is selected from H, halogen, optionally substituted lower C1-6 alkyl, or optionally substituted aryl; each R6 and R7 is, independently, selected from H or optionally substituted C1-6 lower alkyl; and n is 0, 1, 2, or 3; wherein when X1 and X2 are N, X3 is S, Y, is C(O), Z is CH2, R2 is H, and R3 is 2-chloro-6-fluoro-phenyl, R1 is not methyl; or any pharmaceutically acceptable salt or solvate thereof, or stereoisomer thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)
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Specification