Wnt pathway modulators

Patent metadata

Field	Value
Publication number	US-10189842-B2
Application number	US-201415105224-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 17, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to dihydropyrazolo[1,5-a]pyrimidine compounds of formula I, defined herein, as WNT pathways modulators, processes for making them, and pharmaceutical compositions comprising them. Methods of treatment of conditions mediated by WNT pathway signalling including cancer, fibrosis, stem cell and diabetic retinopathy, rheumatoid arthritis, psoriasis and myocardial infarction, comprising the compounds of formula I are also provided.

First claim

The invention claimed is:

1. A compound of formula (I),

or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, and stereoisomers thereof wherein:
R 1 represents H; optionally substituted alkyl wherein optional substituents are one or more substituents each independently selected from 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; optionally substituted alkyl wherein optional substituents are one or more substituents each independently selected from C 1-6 alkoxy, NH 2 , —NHC 1-3 alkyl and —N(C 1-3 alkyl) 2 ; -alkylaryl; optionally substituted carbocyclyl wherein optional substituents are 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; optionally substituted heterocyclyl wherein optional substituents are 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); —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.

2. A compound according to claim 1 wherein R 1 represents H, methyl, ethyl, —C(O)OMe, CF 3 .

3. A compound according to any one of claims 1 wherein each R 2 independently represents H or alkyl.

4. A compound according to any one of claims 1 wherein W and X each represent C═O.

5. A compound according to any one of claims 1 wherein Y is monosubstituted or unsubstituted.

6. A compound according to claim 1 , that is any one 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

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

29

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

32

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

33

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

34

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

35

4-(2-methyl-6,7- dihydropyrazolo[1,5- alpyrimidin-4(5H)-yl)-4-oxo- N-(4-(pyridin-3- yl)phenyl)butanamide

36

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

37

4- 2-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrimidin-4- yl}-4-oxo-N-[4-(pyr

Assignees

• Agency Science Tech & Res

Inventors

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

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title