Use of inhibitor of apoptosis protein (IAP) antagonists in HIV therapy

1. 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,

R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 alkyl-(substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);

X 1 is O;

X 2 is CR 2c R 2d ;

X 3 is CR 2a R 2b ;

W 1 is C(R 8a )(R 8b );

W 2 is C(R 8c )(R 8d ),

R 2a , R 2b , R 2c , and R 2d are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, 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), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), 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), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), or —NR D R E ;

R D and R E are independently selected from H, 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), and —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);

m is 0, 1, or 2;

—U— is —NHC(═O)— or —C(═O)NH—;

R 3 is C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;

R 4 is —NHR 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 6 is —C(═O)NHR 7 ;

each R 7 is independently selected from 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), and -(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 8c 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:

R 8c and R 8d are as defined above, and R 8a and R 8b 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 R 9 ; and

each R 9 is independently selected from halogen, —OH, —SH, (C═O), 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 methylenedioxy or ethylenedioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl.

2. The method of claim 1 , wherein the compound of Formula B-I has the following structure of Formula B-III-1, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

3. The method of claim 1 , wherein the compound of Formula B-I has the following structure of Formula B-VII-2, or a pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

4. The method of claim 1 , wherein the compound of Formula B-I has the following structure of Formula B-XII, or 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 of Formula B-I has the following structure of Formula B-XVI-1 or Formula B-XVI-3 or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

6. The method of claim 1 , wherein the compound of Formula B-I has the structure of Formula B-XXII, or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof:

wherein,

W 2 is C(R 8c )(R 8d );

R 1 is H or C 1 -C 6 alkyl;

X 1 is O;

R 2a and R 2b 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, —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), —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl), or —NR D R E ;

R D and R E are independently selected from H, 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), and —C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);

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);

each R 7 is independently selected from 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), and -(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, (C═O), 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.

7. The method of claim 1 , wherein the compound of Formula B-I has one of the following structures:

or pharmaceutically acceptable salt, N-oxide, racemate or stereoisomer thereof.

8. 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.

9. The method of claim 1 , wherein the individual is receiving concomitant antiretroviral therapy.