Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy
AssigneesSanford Burnham Prebys Medical Discovery Institute, The Salk Institute for Biological Studies
InventorsLars Pache, Sumit K. Chanda, Mitchell Dennis Vamos, Nicholas David Peter Cosford, Peter Teriete, John Marlett, Arturo Diaz, John A. T. Young
Life of this patent
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Abstract
Provided herein is the use of compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), alone or in combination with other therapeutic agents, in the treatment of human immunodeficiency virus (HIV).
Claims9
A method of treating human immunodeficiency virus (HIV) in an individual in need thereof comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist, wherein the IAP antagonist is a small molecule that has the following structure of Formula B-I, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:
- wherein,
- R1 is H, C1-C6alkyl, C3-C6cycloalkyl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted aryl), or —C1-C6alkyl-(substituted or unsubstituted heteroaryl);
- X1 is O;
- X2 is CR2cR2d;
- X3 is CR2aR2b;
- W1 is C(R8a)(R8b);
- W2 is C(R8c)(R8d),
- R2a, R2b, R2c, and R2d are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), and —C(═O)RB;
- RB is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), or —NRDRE;
- RD and RE are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C6cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), and —C1-C6alkyl-(substituted or unsubstituted heteroaryl);
- m is 0, 1, or 2;
- —U— is —NHC(═O)— or —C(═O)NH—;
- R3 is C1-C3alkyl or C1-C3fluoroalkyl;
- R4 is —NHR5;
- each R5 is independently selected from H, C1-C3alkyl, C1-C3haloalkyl, C1-C3heteroalkyl, and —C1-C3alkyl-(C3-C5cycloalkyl);
- R6 is —C(═O)NHR7;
- each R7 is independently selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, a substituted or unsubstituted C3-C10cycloalkyl, a substituted or unsubstituted C2-C10heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C1-C6alkyl-(substituted or unsubstituted C3-C10cycloalkyl), —C1-C6alkyl-(substituted or unsubstituted C2-C10heterocycloalkyl), —C1-C6alkyl-(substituted or unsubstituted aryl), —C1-C6alkyl-(substituted or unsubstituted heteroaryl), —(CH2)p—CH(substituted or unsubstituted aryl)2, —(CH2)p—CH(substituted or unsubstituted heteroaryl)2, —(CH2)p—CH(substituted or unsubstituted aryl)(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted aryl), -(substituted or unsubstituted aryl)-(substituted or unsubstituted heteroaryl), -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted aryl), and -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
- p is 0, 1, or 2;
- R8a, R8b, R8c, and R8d are independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, and substituted or unsubstituted aryl;
- or:
- R8a and R8d are as defined above, and R8b and R8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1-3 heteroatoms selected from S, O, and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1-3 heteroatoms elected from S, O, and N;
- or:
- R8c and R8d are as defined above, and R8a and R8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;
- where each substituted alkyl, heteroalkyl, fused ring, spirocycle, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted with 1-3 R9;
- and
- each R9 is independently selected from halogen, —OH, —SH, (C═O), CN, C1-C4alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, —NH2, —NH(C1-C4alkyl), —N(C1-C4alkyl)2, —C(═O)OH, —C(═O)NH2, —C(═O)C1-C3alkyl, —S(═O)2CH3, —NH(C1-C4alkyl)-OH, —NH(C1-C4alkyl)-O-(C1-C4alkyl), —O(C1-C4alkyl)-NH2, —O(C1-C4alkyl)-NH—(C1-C4alkyl), and —O(C1-C4alkyl)-N-(C1-C4alkyl)2;
- or two R9 together with the atoms to which they are attached form a methylenedioxy or ethylenedioxy ring substituted or unsubstituted with halogen, —OH, or C1-C3alkyl.
Dependencies are inferred from the claim text.