Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy
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). Described herein is the use of IAP antagonists in the treatment of human immunodeficiency virus (HIV) in a mammal, alone or in combination with other therapeutic agents used in HIV therapy. In one aspect, provided herein is 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.
1. A method of treating human immunodeficiency virus (HIV) in an individual comprising administering a therapeutically effective amount of at least one inhibitor of apoptosis proteins (IAP) antagonist to the individual in need thereof, wherein the IAP antagonist has the following structure, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
R 1 is H or C 1 -C 6 alkyl;
X 1 is S, S(═O), or S(═O) 2 ; and X 2 is CR 2c R 2d ;
R 2a , R 2b , R 2c , and R 2d are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, and —C(═O)R B ;
R B is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 5 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
R 3 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;
R 4 is —NHR 5 , —N(R 5 ) 2 , or —OR 5 ;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), —(CH 2 ) p —CH(substituted or unsubstituted aryl) 2 , —(CH 2 ) p —CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) 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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p is 0, 1, or 2;
R 8a , R 8b , R 8c , and R 8d are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, and substituted or unsubstituted aryl;
or:
R 8a and R 8d are as defined above, and R 8b and R R8c together form a bond;
where each substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1-3 R 9 ; and
each R 9 is independently selected from halogen, —OH,—SH, CN, C 1 -C 4 alkyl, C 1 C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)-NH 2 , —O(C 1 -C 4 alkyl) -NH—(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 , or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl.
2. The method of claim 1 , wherein the method comprises reducing dormant, replication competent human immunodeficiency virus (HIV) in the individual, or making dormant, replication competent human immunodeficiency virus (HIV) susceptible to immune system clearance in the individual, or making dormant, replication competent human immunodeficiency virus (HIV) susceptible to the effects of antiretroviral therapy in the individual, or eliminating replication competent human immunodeficiency virus (HIV) in the individual, or inducing long term control of human immunodeficiency virus (HIV) replication and growth in the absence of antiretroviral therapy in the individual, or activating human immunodeficiency virus (HIV) transcription in latently infected cells in the individual, or reducing human immunodeficiency virus (HIV) reservoirs of latently infected cells in the individual.
3. The method of claim 1 , wherein the individual is receiving concomitant antiretroviral therapy.
4. The method of claim 1 , wherein the compound has the following structure, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein R 8a and R 8b are independently selected from H and C 1 -C 3 alkyl.
5. The method of claim 1 , wherein the compound has the following structure, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:
wherein,
R 1 is H or C 1 -C 6 alkyl;
X 1 is S, S(O), or S(O) 2 ;
R 2a and R 2b are independently selected from H, and substituted or unsubstituted C 1 -C 6 alkyl;
R 3 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, a substituted or unsubstituted C 3 -C 10 cycloalkyl, a substituted or unsubstituted C 2 -C 10 heterocycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 10 cycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted C 2 -C 10 heterocycloalkyl), —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), —(CH 2 ) p —CH(substituted or unsubstituted aryl) 2 , —(CH 2 ) p —CH(substituted or unsubstituted heteroaryl) 2 , —(CH 2 ) 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), or -(substituted or unsubstituted heteroaryl)-(substituted or unsubstituted heteroaryl);
p is 0, 1, or 2;
R 8a and R 8b are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;
R 8c and R 8d are independently selected from H, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl;
where each substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 1-3 R 9 ; and
each R 9 is independently selected from halogen, —OH, —SH, CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)C 1 -C 3 alkyl, —S(═O) 2 CH 3 , —NH(C 1 -C 4 alkyl)-OH, —NH(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O(C 1 -C 4 alkyl)-NH 2 , —O(C 1 -C 4 alkyl) -NH-(C 1 -C 4 alkyl), and —O(C 1 -C 4 alkyl)-N—(C 1 -C 4 alkyl) 2 , or two R 9 together with the atoms to which they are attached form a methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl.
6. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.
7. The method of claim 1 , wherein the compound has one of the following structures, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof: