WNT pathway modulators

Patent metadata

Field	Value
Publication number	US-11434245-B2
Application number	US-202017084507-A
Country	US
Kind code	B2
Filing date	Oct 29, 2020
Priority date	Dec 17, 2013
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

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.

First claim

The invention claimed is:

1. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I),

or a pharmaceutically acceptable salt, solvate polymorph, tautomers or stereoisomers thereof wherein;
R 1 represents H; alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ; —C(O)Oalkyl; haloalkyl; haloalkoxy; or -alkylaryl;
each R 2 independently represents H; alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ); -alkylaryl; carbocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and halo; heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl; —C(O)NHC 1-6 alkyl); —NHalkyl; —N(alkyl) 2 ; amino; hydroxyl; alkoxy or halo;
n represents 0, 1 or 2;
R 3 represents H or alkyl;
R 4 represents H or alkyl;
R 5 represents H or alkyl;
W and X each independently represent C═O; C═S; or CH 2 ;
Y represents aryl; heteroaryl; carbocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and halo; or heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of 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 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl, and —N(C 1-3 alkyl) 2 ; aryl; heteroaryl; -alkylaryl; -alkylheteroaryl; carbocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and halo; heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of 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; -alkylcarbocyclyl wherein carbocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and halo; -alkylheterocyclyl wherein heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl, and —C(O)NHC 1-6 alkyl; -arylcarbocyclyl wherein carbocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and halo; or -arylheterocyclyl wherein heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, —C(O)OC 1-6 alkyl, —C(O)C 1-6 alkyl and —C(O)NHC 1-6 alkyl.

2. A method of treating fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt, solvate, polymorph, tautomer and stereoisomer thereof wherein;
R 1 represents H; alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl, and —N(C 1-3 alkyl) 2 ; —C(O)Oalkyl; haloalkyl; haloalkoxy; or -alkylaryl;
each R 2 independently represents H; alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl, and —N(C 1-3 alkyl) 2 ; -alkylaryl; carbocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and halo; heterocyclyl optionally substituted with one or more substituents each independently selected from the group consisting of 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; —NHalkyl; —N(alkyl) 2 ; amino; hydroxyl; alkoxy; or halo;
n represents 1;
R 3 represents H or alkyl;
R 4 represents H or alkyl;
R 5 represents H or alkyl;
W and X each independently represent C═O; C═S; or CH 2 ;
Y represents optionally substituted phenyl or optionally substituted 6-membered heteroaryl; and
Z represents optionally substituted aryl or optionally substituted heteroaryl.

3. The method of claim 2 , wherein the compound of formula (I) is selected from the group consisting of:

Cpd ID
Structure
IUPAC Name

14

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo- N-(4′-(trifluoromethyl)-[1,1′- biphenyl]-4-yl)butanamide

24

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4- (oxazol-5-yl)phenyl)-4- oxobutanamide

25

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-N-(4- (oxazol-5-yl)phenyl)-4- oxobutanamide

26

4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4-oxo- N-(5-(thiazol-2-yl)pyridin-2- yl)butanamide

27

N-(4-(1H-imidazol-1- yl)phenyl)-4-(2-methyl-6,7- dihydropyrazolo[1,5- a]pyrimidin-4(5H)-yl)-4- oxobutanamide

28

Assignees

• Agency Science Tech & Res

Inventors

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

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title