IP Library › Granted Patent US 9,365,584

Granted Patent B2

US 9,365,584 · App. 13/519,407 · Granted Jun 14, 2016

Thieno [2,3-B] pyridinedione activators of AMPK and therapeutic uses thereof

Inventors: Daniel Cravo (Montesson, FR); Sophie Hallakou-Bozec (Montrouge, FR); Sébastien Bolze (Massieux, FR); Franck Lepifre (Saclay, FR); Laurent Faveriel (Longjumeau, FR); Jean-Denis Durand (Montreuil-sous-Bois, FR); Christine Charon (Gometz-le-Chatel, FR)

Assignee: Poxel

C07D495/04

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Quick Facts

Patent No.: US 9,365,584
App. No.: 13/519,407
Granted: Jun 14, 2016
Kind: B2

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Abstract

The invention relates to compounds that are direct activators of AMPK (AMP-activated protein kinase) and their use in the treatment of disorders regulated by activation of AMPK. For instance, compounds according to the invention are useful for the treatment of diabetes, metabolic syndrome, obesity, inflammation, cancer and cardiovascular diseases.

Claims (146)

1. A compound of formula (1)

or a pharmaceutically acceptable salt thereof wherein

R 1 represents a hydrogen atom, an alkyl group or a halogen atom;

R 2 represents an optionally substituted aryl or optionally substituted heteroaryl group;

R 3 is phenyl optionally substituted with by one or more of halogen, alkyl, hydroxyl, alkoxy, aralkyloxy, amino, mono- or di-alkylamino, carboxy, alkyloxycarbonyl, mono- or di-alkylaminocarbonyl, carboxamide, cyano, alkylsulfonyl or trifluoromethyl groups; and

R 4 is fluoro

wherein said aryl or heteroaryl are optionally substituted by one or more atoms or groups selected from the group consisting of halogen atoms, alkyl groups, hydroxyl groups, alkoxy groups, aralkyloxy groups, amino, mono- or di-alkylamino groups, carboxy groups, alkyloxycarbonyl groups, mono- or di-alkylaminocarbonyl groups, carboxamide, cyano, alkylsulfonyl and trifluoromethyl groups.

2. The compound according to claim 1 , wherein R 2 represents an aryl group.

3. The compound according to claim 1 , wherein R 1 represents an alkyl group.

4. The compound according to claim 1 , wherein R 1 represents a halogen atom.

5. The compound according to claim 1 , selected from the group consisting of:

2-chloro-5-fluoro-3,5-diphenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-2-methyl-3,5-diphenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-5-phenyl-3-(3-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-hydroxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(2-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(2-fluoro-4-methoxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluoro-4-hydroxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-(2-methoxyphenyl)-2-methyl-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(m-tolyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-5-phenyl-3-(p-tolyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-5-(3-methylsulfonylphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-5-phenyl-3-(4-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-phenyl-5-[3-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-5-(4-methylsulfonylpheny)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(2-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(2-methoxyphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3,5-diphenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-3-(2-chlorophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluoro-2-hydroxy-3-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluoro-2-hydroxy-3-methyl-phenyl)-5-(4-fluorophenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(p-tolyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-[5-fluoro-3-(2-methoxy-4-methyl-phenyl)-4,6-dioxo-7H-thieno[2,3-b]pyridin-5-yl]benzonitrile

5-fluoro-3-(2-hydroxy-6-methoxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-methoxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(3-methoxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-hydroxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(3-hydroxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-methoxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(2-methoxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-methylsulfonylphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-hydroxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2,6-difluorophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromo-2-hydroxy-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromophenyl)-5-fluoro-5-(4-pyridyl)-7H-thieno[2, 3-b]pyridine-4,6-dione

3-(2-bromophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromo-2-methoxy-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromo-2-methoxy-phenyl)-2,5-difluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(o-tolyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(o-tolyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-phenyl-5-[3-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-phenyl-5-[3-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-phenyl-5-[4-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-phenyl-5-[4-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-phenyl-3-[4-(trifluoromethyl)phenyl]-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(m-tolyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(m-tolyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2-chlorophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-tert-butylphenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-tert-butylphenyl)-2-chloro-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-hydroxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2-benzyloxy-5-fluoro-phenyl)-2-chloro-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2-benzyloxy-5-methoxy-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromo-3-methoxy-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromo-3-methoxy-phenyl)-2,5-difluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-naphthyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(2-naphthyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(3-bromophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(3-bromophenyl)-2,5-difluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(4-fluorophenyl)-5-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromophenyl)-5-fluoro-5-(3-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-(4-methoxyphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-5-(4-methoxyphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-chlorophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-chlorophenyl)-2,5-difluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2-benzyloxy-4-fluoro-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2-benzyloxy-4-fluoro-phenyl)-2,5-difluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(2-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(2,4-difluorophenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(2-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(2-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-(3-methoxyphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-5-(3-methoxyphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(m-tolyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-3-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-3-(3,4-dimethylphenyl)-5-fluoro-5-(m-tolyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-3-(3,4-dimethylphenyl)-5-fluoro-5-(3-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-(4-bromophenyl)-5-fluoro-5-(2-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-fluorophenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluoro-2-hydroxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-fluoro-2-hydroxy-4-methyl-phenyl)-2-methyl-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-phenyl-3-pyrazin-2-yl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-fluoro-4-hydroxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(3-fluoro-4-methoxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-(5-fluoro-4,6-dioxo-5-phenyl-7H-thieno[2,3-b]pyridin-3-yl)benzoic acid

3-(2,5-difluoro-4,6-dioxo-5-phenyl-7H-thieno[2,3-b]pyridin-3-yl)benzoic acid

4-(5-fluoro-4,6-dioxo-5-phenyl-7H-thieno[2,3-b]pyridin-3-yl)benzoic acid

5-fluoro-5-(4-fluorophenyl)-3-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-5-(4-fluorophenyl)-3-(4-methoxyphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(4-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-hydroxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-hydroxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(3-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2,5-difluoro-3-(3-methoxyphenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-(2-methoxyphenyl)-3-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-phenyl-3-(4-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluorophenyl)-5-(m-tolyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-[2-chloro-5-fluoro-3-(3-fluorophenyl)-4,6-dioxo-7H-thieno[2,3-b]pyridin-5-yl]benzonitrile

2-chloro-5-fluoro-3-(3-fluorophenyl)-5-(3-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(2-hydroxy-3-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-5-phenyl-3-(3-pyridyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(3-fluorophenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

3-[2-chloro-3-(3,4-dimethylphenyl)-5-fluoro-4,6-dioxo-7H-thieno[2,3-b]pyridin-5-yl]benzonitrile

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(4-methylsulfonylphenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-(3,4-dimethoxyphenyl)-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-2-methyl-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(5-fluoro-2-hydroxy-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-3-(4-ethyl-2-hydroxy-phenyl)-5-fluoro-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione

3-[2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-4,6-dioxo-7H-thieno[2,3-b]pyridin-5-yl]benzonitrile

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(4-methoxy-3-methyl-phenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-phenyl)-5-(3-thienyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluoro-2-methoxy-4-methyl-phenyl)-5-(4-fluorophenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(3-fluoro-2-hydroxy-4-methyl-phenyl)-5-(4-fluorophenyl)-7H-thieno[2,3-b]pyridine-4,6-dione

2-chloro-5-fluoro-3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione and

2-chloro-5-fluoro-3-(3-fluoro-2-methoxy-4-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione.

6. A pharmaceutical composition comprising at least one compound according to claim 1 in a pharmaceutically acceptable support.

7. The compound according to claim 3 , wherein R 1 represents a methyl group.

8. A compound according to claim 1 , wherein R 2 represents phenyl optionally substituted with by one or more atoms of halogen, alkyl, hydroxyl, alkoxy, aralkyloxy, amino, mono- or di-alkylamino, carboxy, alkyloxycarbonyl, mono- or di-alkylaminocarbonyl, carboxamide, cyano, alkylsulfonyl or trifluoromethyl.

9. A compound according to claim 1 , wherein R 2 represents a group of the formula:

wherein

R p represents hydrogen, halogen, or alkyl;

R S represents hydrogen, halogen, or alkyl; and

R T represents hydrogen, halogen, or hydroxyl.

10. A compound according to claim 8 , wherein R S is methyl or fluoro.

11. A compound according to claim 9 , wherein R p is fluoro.

12. A compound according to claim 10 , wherein R 1 is chloro.

13. A compound according to claim 1 , which is 2-chloro-5-fluoro-3-(4-fluoro-2-hydroxy-3-methyl-phenyl)-5-phenyl-7H-thieno[2,3-b]pyridine-4,6-dione.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 9, 2012

From: CRAVO, DANIEL; HALLAKOU-BOZEC, SOPHIE; BOLZE, SEBASTIEN; LEPIFRE, FRANCK; FAVERIEL, LAURENT; DURAND, JEAN-DENIS; CHARON, CHRISTINE

To: POXEL

Reel/Frame 029269/0209 →

Priority Claims (1)

EP 09306344 · Dec 29, 2009 · regional

Continuity (1)

Related Publication 20130053401A1 · Feb 28, 2013