Trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease

Patent metadata

Field	Value
Publication number	US-9670193-B2
Application number	US-201214360013-A
Country	US
Kind code	B2
Filing date	Nov 26, 2012
Priority date	Nov 28, 2011
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention relates to novel trifluoromethyl-oxadiazole derivatives of formula (I), and pharmaceutically acceptable salts thereof, in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, pharmaceutical combinations thereof, and their use as medicaments, particularly for the treatment of neurodegeneration, muscle atrophy or diabetes/metabolic syndrome via inhibition of HDAC4.

First claim

The invention claimed is:

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

wherein
X 1 represents N or CR 1 ;
X 2 represents N or CR 2 ;
X 3 represents N or CH;
X 4 represents N or CH;
and wherein at least one of X 1 , X 2 , X 3 and X 4 is N and not more than two of X 1 , X 2 , X 3 and X 4 are N;
R 1 and R 2 independently represent hydrogen, chloro or C 1-3 alkyl;
L 1 represents a bond or —C(═O)—;
L 2 represents a bond;
R 3 represents hydrogen or C 1-3 alkyl;
n represents 0, 1, 2 or 3;
R 4 and R 5 independently on each occurrence represent hydrogen, or C 1-3 alkyl;
R 6 represents —NR 7 R 8 , phenyl or a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O and S and wherein said phenyl or heteroaryl is optionally substituted by 1, 2, 3, 4 or 5 substituents, which may be the same or different, selected from R 9 ;
R 7 and R 8 independently represent hydrogen, C 1-4 alkyl or benzyl wherein the benzene ring is optionally substituted by 1, 2, 3, 4 or 5 substituents, which may be the same or different, selected from R 9 ; and
R 9 represents cyano, amino, halogen, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogenC 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, aminocarbonyl, aminocarbonylC 1-4 alkyl, C 1-4 alkylaminocarbonyl, diC 1-4 alkylaminocarbonyl or C 1-4 alkoxycarbonylamino.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently represent hydrogen or chloro.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 represents hydrogen or methyl.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n represents 0, 1 or 2.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 independently on each occurrence represent hydrogen or C 1-3 alkyl.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 represents phenyl or a 6-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O and S and wherein said phenyl or heteroaryl is optionally substituted by 1, 2 or 3 substituents, which may be the same or different, selected from R 9 .

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 represents NR 7 R 8 .

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 represents cyano, amino, halogen, hydroxy or C 1-3 alkyl.

9. A compound according to claim 1 , which is selected from:
N-methyl-N-(pyridin-4-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-benzyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-((2-chloropyridin-4-yl)methyl)-N-methyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(pyridin-4-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-((6-methylpyridin-3-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(1-(pyridin-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(pyridin-3-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-((6-methylpyridin-2-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
(R)—N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
(R)—N-(1-phenylpropyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-methyl-N-(2-(pyridin-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(1-(pyridin-4-yl)propyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-(1-(2-methylpyridin-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
N-methyl-N-((2-methylpyridin-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-2-amine;
(R)—N-(1-(dimethylamino)propan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
N-(1-(dimethylamino)propan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
(R)—N-(1-(benzyl(methyl)amino)propan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
(R)—N-(1-(diethylamino)-3-methylbutan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
(R)—N-(1-(diethylamino)propan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
(R)—N-(1-(dimethylamino)propan-2-yl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide;
(R)-3-chloro-N-(1-(dimethylamino)propan-2-yl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)picolinamide;
(R)—N-(1-(dimethylamino)propan-2-yl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidine-5-carboxamide;
N-benzyl-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-3-amine;
N-benzyl-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
N-(pyridin-3-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
N-((6-methylpyridin-3-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
N-benzyl-3-chloro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
(R)-3-chloro-N-(1-phenylethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-chloro-N-(pyridin-4-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-chloro-N-(1-(pyridin-4-yl)ethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-chloro-N-(pyridin-3-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-Chloro-N-((6-methylpyridin-3-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
3-chloro-N-(pyridin-2-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
N-benzyl-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridazin-3-amine;
(R)—N-(1-Phenylethyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-5-amine;
(S)—N-(1-Phenylethyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-5-amine;
N-(Pyridin-4-ylmethyl)-2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrimidin-5-amine;
(R)—N-(Pyridin-4-yl)ethyl)-5-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)pyridin-2-amine;
(R)—N-(1-(Pyridin-4-yl)ethyl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridazin-3-amine;
(R)—N-(1-(benzyl(methyl)amino)propan-2-yl)-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide;
or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, as active pharmaceutical ingredient in association with at least one pharmaceutically acceptable carrier or diluent.

11. A method for the treatment of neurodegeneration, or metabolic syndrome, in a subject in need of such treatment, comprising administering to such subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of muscle atrophy, in a subject in need of such treatment, comprising administering to such subject an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound N-(pyridine-4-ylmethyl)-5-(5-(trifluoromethy

Assignees

• Hebach Christina
• Kallen Joerg
• Nozulak Joachim
• Tintelnot-Blomley Marina
• Widler Leo
• Novartis Ag

Inventors

• Hebach Christina
• Kallen Joerg
• Nozulak Joachim
• Tintelnot-Blomley Marina
• Widler Leo

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title