WNT pathway modulators

Patent metadata

Field	Value
Publication number	US-10870653-B2
Application number	US-201816226398-A
Country	US
Kind code	B2
Filing date	Dec 19, 2018
Priority date	Dec 17, 2013
Publication date	Dec 22, 2020
Grant date	Dec 22, 2020

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 each of R 1 , R 2 , R 3 , R 4 , R 5 , W, X, Y, Z, and n is as defined herein.

First claim

The invention claimed is:

1. A method of modulating WNT activity comprising exposing a WNT protein or a WNT receptor to an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, or 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 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 of the -arylheterocyclyl 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 according to claim 1 wherein the method is an in vivo method.

3. A method of treating a tumor 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, or 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.

4. The method of claim 3 , wherein the tumor is selected from the group consisting of cervical cancer, colon cancer, breast cancer, bladder cancer, head and neck cancer, gastric cancer, lung cancer, ovarian cancer, prostate cancer, thyroid cancer, non-small-cell lung cancer, mesothelioma, melanoma, pancreatic adenocarcinoma, basal cell carcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor, and medulloblastoma.

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

Compound

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

Assignees

• Agency Science Tech & Res

Inventors

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

Classifications

• A61P19/04

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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P43/00

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