Iap antagonists

Patent metadata

Field	Value
Publication number	US-2016376307-A1
Application number	US-201414903306-A
Country	US
Kind code	A1
Filing date	Jul 10, 2014
Priority date	Jul 12, 2013
Publication date	Dec 29, 2016
Grant date	—

Abstract

There are disclosed compounds that modulate the activity of inhibitors of apoptosis (IAPs), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.

First claim

1 . A compound of Formula (I)

wherein

X is a direct bond, —NH—, —O—, —NHCO—, —CONH— or
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;
R 1 and R 2 are independently optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, —(CH 2 ) v COR 20 , —CH 2 CHR 21 COR 22 or —CH 2 R 23 ,
wherein:
v=1-3,
R 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 ,
R 21 is NR 24 R 25 ,
R 23 is optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen,
R 24 is hydrogen or optionally substituted alkyl,
R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, —CH 2 (OCH 2 CH 2 O) m CH 3 , or a polyamine chain, such as spermine or spermidine,
R 26 is optionally substituted alkyl, and
w=1-8,

where the optional substituents are OH, halogen or NH 2 ;
R 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen or OH;
R 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

2 . The compound according to claim 1 of the formula

wherein
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;
R 1 and R 2 are independently optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, —(CH 2 ) v COR 20 , —CH 2 CHR 21 COR 22 or —CH 2 R 23 ,
wherein:
v=1-3,
R 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 ,
R 21 is NR 24 R 25 ,
R 23 is optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen,
R 24 is hydrogen or optionally substituted alkyl,
R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, —CH 2 (OCH 2 CH 2 O) m CH 3 , or a polyamine chain, such as spermine or spermidine,
R 26 is optionally substituted alkyl, and
w=1-8,

where the optional substituents are OH, halogen or NH 2 ;
R 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen or OH;
R 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3 . The compound according to claim 1 of the formula

wherein
R 1 is optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted aryl;
R 2 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;
R 1 and R 2 are independently optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, —(CH 2 ) v COR 20 , —CH 2 CHR 21 COR 22 or —CH 2 R 23 ,
wherein:
v=1-3,
R 20 and R 22 are independently selected from OH, NR 24 R 25 or OR 26 ,
R 21 is NR 24 R 25 ,
R 23 is optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen,
R 24 is hydrogen or optionally substituted alkyl,
R 25 is hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, —CH 2 (OCH 2 CH 2 O) m CH 3 , or a polyamine chain, such as spermine or spermidine,
R 26 is optionally substituted alkyl, and
w=1-8,

where the optional substituents are OH, halogen or NH 2 ;
R 3 and R 4 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, alkoxy, halogen or OH;
R 5 , R 6 , R 7 and R 8 are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

4 . The compound according to claim 2 wherein
R 3 and R 4 are independently optionally substituted aryl, wherein the substituents are alkyl, alkoxy, halogen or OH; and
R 5 , R 6 , R 7 and R 8 are independently optionally substituted alkyl.

5 . The compound according to claim 4 wherein
R 3 and R 4 are independently 1,2,3,4-tetrahydronaphthalenyl, and
R 5 , R 6 , R 7 and R 8 are independently C 1 -C 3 alkyl.

6 . The compound according to claim 3 wherein
R 3 and R 4 are independently optionally substituted aryl, wherein the substituents are alkyl, alkoxy, halogen or OH; and
R 5 , R 6 , R 7 and R 8 are independently optionally substituted alkyl.

7 . The compound according to claim 6 wherein
R 3 and R 4 are independently 1,2,3,4-tetrahydronaphthalenyl, and
R 5 , R 6 , R 7 and R 8 are independently C 1 -C 3 alkyl.

8 . The compound according to claim 2 wherein
R 2 is optionally substituted thioalkyl.

9 . The compound according to claim 3 wherein
R 2 is optionally substituted thioalkyl.

10 . A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

11 . A compound according to claim 1 for use in therapy.

12 . Use of a compound according to claim 1 for the treatment of a proliferati

Assignees

• Bristol Myers Squibb Co

Inventors

• Kim Kyoung S
• Zhang Liping
• Stang Erik M

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K5/0806 Primary

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title

• A61K38/06

  Tripeptides · CPC title

• C07K14/8139

  Cysteine protease (E.C. 3.4.22) inhibitors, e.g. cystatin · CPC title

• C07K14/4747

  Apoptosis related proteins · CPC title