Novel pyridine derivatives

Patent metadata

Field	Value
Publication number	US-2016376237-A1
Application number	US-201615260819-A
Country	US
Kind code	A1
Filing date	Sep 9, 2016
Priority date	Apr 4, 2014
Publication date	Dec 29, 2016
Grant date	—

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) can be used as a medicament.

First claim

1 . A compound of formula (I)

wherein
R 1 is alkylsulfanyl, cycloalkylalkoxy, halophenyl or halogen;
R 2 is phenyl, halophenyl, cycloalkylalkoxy, alkoxyazetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, (haloalkyl)(hydroxy)pyrrolidinyl, halo-5-azaspiro[2.4]heptyl, (alkyl)(halo)azetidinyl or (cycloalkyl)(halo)azetidinyl;
one of R 3 and R 4 is hydrogen and the other one is —(CR 5 R 6 ) m —(CH 2 ) n —R 7 ;
or R 3 and R 4 together with the nitrogen atom to which they are attached form aminocarbonyl-dioxo-thiazolidinyl or (aminocarbonyl)(halo)pyrrolidinyl;
R 5 and R 6 are independently selected from hydrogen, alkyl, cycloalkylalkyl and alkylsulfanylalkyl;
or R 5 and R 6 together with the carbon atom to which they are attached form oxetanyl;
R 7 is alkoxycarbonyl, oxazol-2-yl, 5-alkyl-1,2,4-oxadiazol-3-yl, aminocarbonyl, alkylaminocarbonyl, thiazol-2-yl, 5-halophenyl-1,3,4-oxadiazol-2-yl or hydroxycycloalkyl, haloalkylaminocarbonyl or haloazetidinylcarbonyl;
m is 0 or 1;
n is 0 or 1;
or a pharmaceutically acceptable salt or ester thereof.

2 . A compound according to claim 1 , wherein R 1 is cycloalkylalkoxy or halophenyl.

3 . A compound according to claim 2 , wherein R 1 is cyclopropylmethoxy or chlorophenyl.

4 . A compound according to claim 1 , wherein R 2 is phenyl, halophenyl, cycloalkylalkoxy or alkoxyazetidinyl.

5 . A compound according to claim 4 , wherein R 2 is phenyl, chlorophenyl, cyclopropylmethoxy or methoxyazetidinyl.

6 . A compound according to claim 1 , wherein R 5 and R 6 are independently selected from hydrogen and alkyl.

7 . A compound according to claim 6 , wherein R 5 and R 6 are independently selected from hydrogen, methyl, ethyl and isobutyl.

8 . A compound according to claim 1 , wherein R 7 is alkoxycarbonyl, oxazol-2-yl, thiazol-2-yl or aminocarbonyl.

9 . A compound according to claim 8 , wherein R 7 is methoxycarbonyl, oxazol-2-yl, thiazol-2-yl or aminocarbonyl.

10 . A compound according to claim 1 selected from
Methyl 2-[[5-(4-chlorophenyl)-6-methylsulfanylpyridine-2-carbonyl]amino]-2-methylpropanoate;
Methyl 2-[[5-(4-chlorophenyl)-6-(cyclopropylmethoxy)pyridine-2-carbonyl]amino]-2-methylpropanoate;
5-(4-Chlorophenyl)-6-(cyclopropylmethoxy)-N-[2-(1,3-oxazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
5-(4-Chlorophenyl)-6-(cyclopropylmethoxy)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[2-(1,3-oxazol-2-yl)propan-2-yl]-5-phenylpyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[3-(methylcarbamoyl)pentan-3-yl]-5-phenylpyridine-2-carboxamide;
6-(3-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[3-(methylcarbamoyl)pentan-3-yl]pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]pyridine-2-carboxamide;
6-(3-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]pyridine-2-carboxamide;
N-[(2S)-1-amino-3-cyclopropyl-1-oxopropan-2-yl]-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine-2-carboxamide;
6-(3-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
N-[(2S)-1-amino-3-cyclopropyl-1-oxopropan-2-yl]-5,6-bis(cyclopropylmethoxy)pyridine-2-carboxamide;
N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-6-chloro-5-(cyclopropylmethoxy)pyridine-2-carboxamide;
6-Chloro-5-(cyclopropylmethoxy)-N-[3-(methylcarbamoyl)pentan-3-yl]pyridine-2-carboxamide;
6-Chloro-5-(cyclopropylmethoxy)-N-[(1S)-2-cyclopropyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl]pyridine-2-carboxamide;
3-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;
Ethyl 2-[[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-ethylbutanoate;
6-(Cyclopropylmethoxy)-N-[1-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropan-2-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
N-[3-(2-Amino-2-oxoethyl)oxetan-3-yl]-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)-N-[3-(methylcarbamoyl)pentan-3-yl]pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[(1-hydroxycyclohexyl)methyl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[3-(2-fluoroethylcarbamoyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[3-(3-fluoroazetidine-1-carbonyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
6-(Cyclopropylmethoxy)-N-[3-(3-fluoropropylcarbamoyl)pentan-3-yl]-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
(2S)-1-[6-(Cyclopropylmethoxy)-5-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;
N-[(2S)-1-Amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine-2-carboxamide;
N-[(2S)-1-Amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-(2,2-difluoro-5-azaspiro[2.4]heptan-5-yl)pyridine-2-carboxamide;
(2S)-1-[6-(Cyclopropylmethoxy)-5-(2,2-difluoro-5-azaspiro[2.4]heptan-5-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;
N-[3-(2-Amino-2-oxoethyl)oxetan-3-yl]-6-(cyclopropylmethoxy)-5-(2,2-difluoro-5-azaspiro[2.4]heptan-5-yl)pyridine-2-carboxamide;
N-[(2S)-1-Amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)pyridine-2-carboxamide;
(2S)-1-[6-(Cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;
N-[3-(2-Amino-2-oxoethyl)oxetan-3-yl]-6-(cyclopropylmethoxy)-5-(3-fluoro-3-methylazetidin-1-yl)pyridine-2-carboxamide;
N-[(2S)-1-Amino-4-methyl-1-oxopentan-2-yl]-5-(3-cyclopropyl-3-fluoroazetidin-1-yl)-6-(cyclopropylmethoxy)pyridine-2-carboxamide;
(2S)-1-[5-(3-Cyclopropyl-3-fluoroazetidin-1-yl)-6-(cyclopropylmethoxy)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;
N-[3-(2-Amino-2-oxoethyl)oxetan-3-yl]-5-(3-cyclopropyl-3-fluoroazetidin-1-yl)-6-(cyclopropylmethoxy)pyridine-2-carboxamide;
(2S)-1-[6-(4-Chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carbonyl]-4,4-difluoropyrrolidine-2-carboxamide;
6-(4-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl]pyridine-2-carboxamide;
5-(3-Cyclopropyl-3-fluoroazetidin-1-yl)-6-(cyclopropylmethoxy)-N-[3-(3-fluoropropylcarbamoyl)pentan-3-yl]pyridine-2-carboxamide; and
N-[(2S)-1-Amino-4-methyl-1-oxopentan-2-yl]-6-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carboxamide.

11 . A compound according to claim 1 selected from
Methyl 2-[[5-(4-chlorophenyl)-6-(cyclopropylmethoxy)pyridine-2-carbonyl]amino]-2-methylpropanoate;
6-(Cyclopropylmethoxy)-N-[2-(1,3-oxazol-2-yl)propan-2-yl]-5-phenylpyridine-2-carboxamide;
6-(3-Chlorophenyl)-5-(cyclopropylmethoxy)-N-[2-(1,3-thiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
N-[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]-6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide;
3-[6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide;
Ethyl 2-[[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-

Assignees

• Hoffmann La Roche

Inventors

• Gobbi Luca
• Grether Uwe
• Nettekoven Matthias
• Roever Stephan
• Rogers-Evans Mark
• Slavik Roger

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title