Pyridine-2-amides useful as CB2 agonists

Patent metadata

Field	Value
Publication number	US-9409866-B2
Application number	US-201314648412-A
Country	US
Kind code	B2
Filing date	Dec 4, 2013
Priority date	Dec 7, 2012
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The invention relates to a compound of formula (I) wherein R 1 to R 4 are defined as in the description and in the claims. The compound of formula (I) is a CB2 agonist and can be used as an active ingredient in a medicament.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is halogen, halophenyl, cycloalkylalkoxy, halophenylalkyl, oxetanyloxy, haloalkoxy, halophenylalkoxy or alkyloxetanylalkoxy;
R 2 is halogen, cycloalkyl, haloazetidinyl, halopyrrolidinyl, cycloalkenyl, halocycloalkyl or halooxetanyl;
one of R 3 and R 4 is hydrogen or alkyl and the other one is —(CR 5 R 6 )—(CR 7 R 8 ) n —R 9 ;
or R 3 and R 4 together with the nitrogen atom to which they are attached form 2-oxo-5-aza-spiro[3.4]octyl, haloazetidinyl or halopyrrolidinyl;
R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkylalkyl, haloalkyl, cycloalkyl, alkylsulfonylalkyl, phenylalkoxyalkyl, hydroxyalkyl, haloazetidinylalkyl, haloazetidinylcarbonyl, 2-oxa-6-azaspiro[3,3]heptanylcarbonyl, alkylaminocarbonyl, di alkylaminocarbonyl, aminocarbonyl, azetidinylcarbonyl, oxetanyl alkyl and alkyl oxetanyl;
or R 5 and R 6 together with the carbon atom to which they are attached form cycloalkyl, oxetanyl, oxanyl or dioxothietanyl;
R 7 and R 8 are independently selected from hydrogen, alkyl and cycloalkyl;
or R 7 and R 8 together with the carbon atom to which they are attached form cycloalkyl;
R 9 is alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, aminocarbonyl, cyano, pyridinyl, alkylaminocarbonyl, thiazol-2-yl, oxazol-2-yl, 5-alkyl-[1,2,4]oxadiazol-3-yl, alkyltetrazolyl, alkylthiazol-2-yl, 1H-tetrazolyl, 5-amino-[1,2,4]-oxadiazol-3-yl, 5-alkyl-[1,3,4]-oxadiazol-2-yl, azetidinylcarbonyl, haloazetidinylcarbonyl, 6-oxa-1-azaspiro[3.3]heptanyl, 5-phenyl-[1,3,4]-oxadiazol-2-yl or haloalkylaminocarbonyl; and
n is 0 or 1;
provided that when R 3 and R 4 are both alkyl at the same time, then R 1 and R 2 are not both halogen at the same time;
or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 , wherein R 1 is haloalkoxy.

3. A compound according to claim 1 , wherein R 1 is trifluoroethoxy, trifluoropropyloxy, difluoroethyloxy, fluoroethyloxy or fluoropropyloxy.

4. A compound according to claim 1 , wherein R 2 is cycloalkyl or haloazetidinyl.

5. A compound according to claim 1 , wherein R 2 is cyclopropyl, cyclobutyl or difluoroazetidinyl.

6. A compound according to claim 1 , wherein one of R 3 and R 4 is hydrogen and the other one is —(CR 5 R 6 )—(CR 7 R 8 ) n —R 9 .

7. A compound according to claim 1 , wherein R 5 and R 6 are independently selected from alkyl, cycloalkylalkyl, alkylsulfonylalkyl and cycloalkyl, or R 5 and R 6 together with the carbon atom to which they are attached form dioxothietanyl.

8. A compound according to claim 1 , wherein R 5 and R 6 are independently selected from methyl, cyclopropylmethyl, methylsulfonylmethyl and cyclopropyl, or R 5 and R 6 together with the carbon atom to which they are attached form dioxothietanyl.

9. A compound according to claim 1 , wherein R 9 is 5-alkyl-[1,2,4]oxadiazol-3-yl or aminocarbonyl.

10. A compound according to claim 1 , wherein R 9 is 5-methyl-[1,2,4]oxadiazol-3-yl or aminocarbonyl.

11. A compound according to claim 1 , R 7 and R 8 are independently selected from hydrogen, methyl and ethyl, or R 7 and R 8 together with the carbon atom to which they are attached form cyclopentyl or cyclohexyl.

12. A compound according to claim 1 , wherein R 7 and R 8 are both hydrogen at the same time.

13. A compound according to claim 1 , wherein n is 0.

14. A compound according to claim 1 selected from
2-[(5-Chloro-4-iodo-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;
5-Chloro-4-(3-chloro-phenyl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
5-Chloro-4-(3-chloro-phenyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxy-cyclohexylmethyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxymethyl-cyclopentyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (cyano-dimethyl-methyl)-amide;
5-Bromo-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-carbamoyl-3-methyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-2-methyl-propyl)-amide;
5-Chloro-4-cyclobutylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Chloro-4-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-hydroxy-2,2-dimethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(2-hydroxy-ethyl)-2-methyl-propyl]-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-cyclopropyl-3-hydroxy-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxymethyl-cyclopentylmethyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-hydroxymethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;
5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxymethyl-1-methyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,3-dimethyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,3-dimethyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1-methyl-propyl)-amide;
Methyl 3-({[5-chloro-4-(cyclopropylmethoxy)pyridin-2-yl]carbonyl}amino)-2,3-dimethylbutanoate
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-hydroxymethyl-1-methyl-butyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1,1-dimethyl-2-methylcarbamoyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1,1-dimethyl-2-methylcarbamoyl-propyl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-oxazol-2-yl-oxetan-3-yl)-amide;
5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1-methyl-butyl)-amide;
5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide;
5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide;
5-Chloro-4-(4-fluoro-benzyloxy)-pyridine-2-

Assignees

• Hoffmann La Roche

Inventors

• Grether Uwe
• Kimbara Atsushi
• Nettekoven Matthias
• Ricklin Fabienne
• Roever Stephan
• Rogers-Evans Mark
• Rombach Didier
• Schulz-Gasch Tanja
• Westphal Matthias

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/04

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