Niclosamide analogues and therapeutic use thereof

Patent metadata

Field	Value
Publication number	US-11987579-B2
Application number	US-201917263769-A
Country	US
Kind code	B2
Filing date	Jul 30, 2019
Priority date	Jul 30, 2018
Publication date	May 21, 2024
Grant date	May 21, 2024

Abstract

Described are niclosamide analogue compounds, pharmaceutical compositions thereof, and method of using the corner pounds and compositions for treating a disease associated with dysregulation of the Wnt/Frizzled signaling pathway, such as cancer, fatty liver, antibiotic resistance, and viral infection. The disclosed compounds and compositions may also be used for modulating mitochondrial function and for treating certain non-cancer diseases and/or diorders, such as diabetes, fibrotic disease, primary sclerosing cholangitis.

First claim

What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein,

is

X 1 is N or CR x1 ;
X 2 is N;
X 3 is N or CR x3 ;
Z is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1, 2, 3, or 4R Z ;
R A1 and R A2 are haloalkyl, halogen, oxo, cyano, nitro, —OH, alkoxy, or —C(O)alkyl;
R x1 and R x3 are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, —OH, alkoxy, —OR 4 , —SR 5 , —NR 6 R 7 , and —NR 8 —SO 2 —R 9 ;
R z at each occurrence is independently selected from the group consisting of halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, —OH, alkoxy, —OR 4 , —SR 5 , —NR 6 R 7 , —SO 2 —R 9 , and —NR 8 —SO 2 —R 9 ;
R 4 is selected from —C(O)-alkyl, —C(O)-alkenyl, —C(O)-heteroalkyl, —C(O)-heteroaryl, —C(O)-alkoxyalkyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkenyl, and —C(O)—O— alkoxyalkyl;
R 5 , R 6 and R 7 are each independently selected from hydrogen, alkyl, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)-alkoxyalkyl, —C(O)—NH-alkyl, —C(O)-heterocycle, -alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from hydrogen and alkyl; and
R 9 is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle and heteroarylalkyl,
provided that Z is not benzo[d]thiazole or substituted benzo[d]thiazole.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CR x1 and X 3 is CR x3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of X 1 and X 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is C 1-4 haloalkyl.

6. The compound of any claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is —CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a phenyl optionally substituted with 1, 2, 3, or 4 R z .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R z is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, halogen, cyano, or nitro.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R z is —CF 3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is a monocyclic heteroaryl or a bicyclic heteroaryl.

12. The compound of claim 1 , wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt there, and a pharmaceutically acceptable carrier.

14. A method of treating a disease associated with dysregulation of the Wnt/Frizzled signaling pathway in a subject in need thereof, the method comprising
administering to the subject an effective amount of a compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein,

is

X 1 is N or CR x1 ;
X 2 is N;
X 3 is N or CR x3 ;
Z is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1, 2, 3, or 4 R z ;
R A1 and R A2 are haloalkyl, halogen, oxo, cyano, nitro, —OH, alkoxy, or —C(O)alkyl;
R x1 and R x3 are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, —OH, alkoxy, —OR 4 , —SR, —NR 6 R 7 , and —NR 8 —SO 2 —R 9 ;
R Z at each occurrence is independently selected from the group consisting of halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, —OH, alkoxy, —OR 4 , —SR 5 , —NR 6 R 7 , —SO 2 —R 9 , and —NR 9 —SO 2 —R 9 ;
R 4 is selected from —C(O)-alkyl, —C(O)-alkenyl, —C(O)-heteroalkyl, —C(O)-heteroaryl, —C(O)-alkoxyalkyl, —C(O)—O-heteroalkyl, —C(O)—O-heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkenyl, and —C(O)—O— alkoxyalkyl;
R 5 , R 1 and R 7 are each independently selected from hydrogen, alkyl, —C(O)-alkyl, —C(O)—O-alkyl, —C(O)—O-alkenyl, —C(O)-alkoxyalkyl, —C(O)—NH-alkyl, —C(O)-heterocycle, -alkenyl, alkynyl, and heteroalkyl;
R 8 is selected from hydrogen and alkyl; and
R 9 is selected from hydrogen, alkyl, aryl, heteroaryl, arylalkyl, heterocycle and heteroarylalkyl.

15. The method of claim 14 , wherein the disease is selected from the group consisting of cancer, fatty liver, antibiotic resistance, bacterial infection, viral infection, diabetes, fibrotic disease, and primary sclerosing cholangitis.

16. The method of claim 14 , wherein the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

17. A method of modulating the Wnt/Frizzled signaling pathway in a subject, the method comprising
administering to the subject an effective amount of a compound of formula (I′), or a pharmaceutically acceptable salt thereof,

wherein,

is

X 1 is N or CR x1 ;
X 2 is N;
X 3 is N or CR x3 ;
Z is aryl or heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1, 2, 3, or 4 R z ;
R A1 and R A2 are haloalkyl, halogen, oxo, cyano, nitro, —OH, alkoxy, or —C(O)alkyl;
R x1 and R x3 are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, cyano, haloalkyl, alkoxyalkyl, heteroalkyl, alkenyl, alkynyl, heterocycle, carboxyl, heterocyclealkyl, —OH, alkoxy, —OR 4 , —SRS, —NR R 7 , and —NR 8 —SO 2 —R 9 ;
R z at each occurrence is independently selected from the group consis

Assignees

• Univ Duke

Inventors

• Mook Robert A
• Chen Wei
• Wang Jiangbo
• Ren xiu-rong
• Lyerly Herbert Kim

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06 Primary

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

• A61P35/04

  specific for metastasis · CPC title

• C07D235/10

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D249/18

  Benzotriazoles · CPC title