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

Patent metadata

Field	Value
Publication number	US-10864217-B2
Application number	US-201916421966-A
Country	US
Kind code	B2
Filing date	May 24, 2019
Priority date	Jun 4, 2014
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

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).

First claim

What is claimed is:

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

Assignees

• Sanford Burnham Prebys Medical Discovery Inst
• Salk Inst For Biological Studi

Inventors

• Pache Lars
• Chanda Sumit K
• Vamos Mitchell Dennis
• Cosford Nicholas David Peter
• Teriete Peter
• Marlett John
• Diaz Arturo
• Young John A T

Classifications

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P31/18

  for HIV · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61K31/554

  having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title