Inhibitor of apoptosis protein (IAP) antagonists

Patent metadata

Field	Value
Publication number	US-10544188-B2
Application number	US-201816031837-A
Country	US
Kind code	B2
Filing date	Jul 10, 2018
Priority date	Nov 30, 2012
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

Provided herein are compounds that modulate the activity of inhibitor of apoptosis proteins (IAPs), compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.

First claim

What is claimed is:

1. A compound having 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 and X 2 are C and are members of a fused substituted 6 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
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;
R 4 is —N(R 5 ) 2 , —N + (R 5 ) 3 , or —OR 5 ;
each R 5 is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
R 7 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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, and substituted or unsubstituted aryl;
or:
R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
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 selected 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;
or:
R 8a and R 8b are as defined above, and R 8c and R 8d 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, 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 methylene dioxy or ethylene dioxy ring substituted or unsubstituted with halogen, —OH, or C 1 -C 3 alkyl;
wherein each heterocycloalkyl is independently selected from a monocyclic, fused bicyclic, and bridged bicyclic ring, where the heterocycloalkyl is partially or fully saturated and has from 2 to 10 carbons in the ring and heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each heterocycloalkyl is independently selected from dihydrothiophen-2(3H)-onyl, imidazolidin-2-onyl, pyrrolidin-2-onyl, dihydrofuran-2(3H)-onyl, 1,3-dioxolan-2-onyl, thiazolidinyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydrofuranyl, 4,5-dihydrooxazolyl, oxiranyl, pyrrolidinyl, pyrazolidinyl, tetrahydro-2H-pyranyl, thiomorpholinyl, tetrahydro-2H-thiopyranyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, indolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, chromanyl, 2,3-dihydrobenzo[b]thiophenyl, thiochromanyl, piperidinyl, morpholinyl, 4H-1,4-thiazinyl, 1,2,3,4-tetrahydropyridinyl, piperazinyl, 1,3-oxazinan-2-onyl, 7-oxabicyclo[2.2.1]heptanyl, octahydro-1H-quinolizinyl, and 1,3-diazabicyclo[2.2.2]octanyl; and
wherein each heteroaryl is independently selected from a monocyclic and fused bicyclic ring, wherein the heteroaryl is a 5- to 14-membered ring system comprising one to thirteen carbon atoms, and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

2. The compound of claim 1 , 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 6 alkyl; and
R 8c and R 8d are H.

3. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the following structure:

wherein,
X 1 and X 2 are C and are members of a fused substituted 6 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
R 3 is C 1 -C 3 alkyl;
R 4 is —N(R 5 ) 2 or —N + (R 5 ) 3 ;
each R 5 is independently selected from H, C 1 -C 3 alkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl); and
R 8a and R 8b are independently selected from H and C 1 -C 3 alkyl.

4. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having one of the following structures:

wherein,
X 1 and X 2 are C and are members of a fused substituted 6 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
R 1 is H or methyl;
R 3 is C 1 -C 3 alkyl;
R 4 is —N(R 5 ) 2 or —N + (R 5 ) 3 ; and
each R 5 is independently selected from H, C 1 -C 3 alkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl).

5. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, having the following structures:

wherein,
Ring A is a fused substituted 6 membered aryl ring or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
R 1 is H or methyl;
R 3 is C 1 -C 3 alkyl;
R 4 is —N(R 5 ) 2 or —N + (R 5 ) 3 ; and
each R 5 is independently selected from H, C 1 -C 3 alkyl, and —C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl).

6. The compound of claim 5 , or pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:
Ring A is a fused substituted 6 membered aryl ring.

7. The compound of claim 1 , or pharmaceutically acceptable salt, N-oxide

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Cosford Nicholas David Peter
• Vamos Mitchell Dennis

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title