Maleimide derivatives as modulators of wnt pathway

Patent metadata

Field	Value
Publication number	US-9981964-B2
Application number	US-201415105312-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 17, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention relates to compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein R 1 represents optionally substituted alkyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkoxy); optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1 -6alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or -alkylaryl; R 2 represents H; or alkyl; R 3 represents H; or alkyl; U, V and W represent —(CH 2 )—; or U and V together represent —CH═CH— and W represents C═O; Y represents aryl; heteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); and Z represents aryl; heteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl).

First claim

The invention claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein:
R 1 represents optionally substituted alkyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkoxy); optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or -alkylaryl;
R 2 represents H; or alkyl;
R 3 represents H; or alkyl;
U, V and W represent —(CH 2 )—; or U and V together represent —CH═CH—and W represents C═O;
Y represents aryl; heteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl); and
Z represents aryl; heteroaryl; optionally substituted carbocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo); or optionally substituted heterocyclyl (wherein optional substituents include one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl).

2. The compound of claim 1 , wherein the compounds is of Formula (I),

or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof, wherein:
R 1 represents alkyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkoxy; carbocyclyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and halo; or -alkylaryl;
R 2 represents H; or alkyl;
R 3 represents H; or alkyl;
U, V and W each represent —(CH 2 )—; or U and V together represent —CH═CH—and W represents C═O;
Y represents aryl; heteroaryl; carbocyclyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g. fluoromethyl), C 1-6 haloalkoxy and halo; or heterocyclyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl; and
Z represents aryl; heteroaryl; carbocyclyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl (e.g. fluoromethyl), C 1-6 haloalkoxy and halo; or heterocyclyl which is optionally substituted by one or more substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl.

3. A compound according to claim 1 wherein R 1 represents C 1-3 alkyl or C 3-4 cycloalkyl.

4. A compound according to claim 1 wherein R 2 represents H.

5. A compound according to claim 1 wherein R 3 represents H.

6. A compound according to claim 1 wherein U, V and W each represent —(CH 2 )—.

7. A compound according to claim 1 wherein Y represents phenyl or monocyclic heteroaryl comprising one or two nitrogen ring atoms or 6-membered heteroaryl.

8. A compound according to claim 7 wherein Z and —NR 3 are positioned on ring Y at the 1- and 4- positions relative to each other.

9. A compound according claim 1 wherein Y is unsubstituted or monosubstituted.

10. A compound according to claim 1 wherein Z is phenyl or monocyclic heteroaryl comprising one or two nitrogen atoms.

11. A compound as defined in any one of examples 1 to 158:

Cpd ID
Structure
IUPAC Name

1

N-([2,3′-bipyridin]-6′-yl)-2-(6-methyl- 5,7-dioxo-2,3,4,5,6,7-hexahydro-1H- pyrrolo[3,4-b]pyridin-1-yl)acetamide

2

2-(6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)-N-(4-(thiazol-2-yl)phenyl)acetamide

3

2-(6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)-N-(6-phenylpyridazin-3- yl)acetamide

4

N-(6-(4-fluorophenyl)pyridazin-3-yl)-2- (6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)acetamide

5

2-(6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)-N-(5-phenylpyridin-2-yl)acetamide

6

2-(6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)-N-(5-(thiazol-2-yl)pyridin-2- yl)acetamide

7

N-(5-(4-fluorophenyl)pyridin-2-yl)-2- (6-methyl-5,7-dioxo-2,3,4,5,6,7- hexahydro-1H-pyrrolo[3,4-b]pyridin-1- yl)acetamide

8

Assignees

• Agency Science Tech & Res

Inventors

• Alam Jenefer
• Poulsen Anders
• Ho Soo Yei
• Wang wei ling
• Duraiswamy Athisayamani Jeyaraj

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · 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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title