Novel pyridine derivatives

Patent metadata

Field	Value
Publication number	US-2016376262-A1
Application number	US-201615260826-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 A and 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
A is —CH— or nitrogen;
R 1 is halophenyl, halophenylalkyl, haloalkoxy, halogen, alkoxyalkoxy, oxopyrrolidinyl or cycloalkylalkoxy;
R 2 is hydrogen, halophenylamino, cycloalkyl or haloazetidinyl;
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 aminocarbonylthiomorpholinyl;
R 5 and R 6 are independently selected from hydrogen and alkyl;
R 7 is 5-cycloalkyl-1,3,4-oxadiazolyl, 3-cycloalkyl-1,2,4-oxadiazolyl, 5-phenyl-1,3,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiyzolyl, 5-alkyl-1,3,4-oxadiazolyl, 3-alkoxyalkoxyalkyl-1,2-oxazolyl, 1-hydroxyalkylpyrazolyl, 3-hydroxy-1-adamantyl, alkoxycarbonylmorpholinyl, 3-oxanyloxyalkyl-1,2-oxazol-5-yl, 3-azidoalkyl-1,2-oxazol-5-yl or 5-(4-fluorophenyl)-1,3,4-oxadiazolyl;
m is 0 or 1;
n is 0 or 1;
or a pharmaceutically acceptable salt or ester thereof;
provided that 6-chloro-N-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-pyridinecarboxamide is excluded.

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

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

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

5 . A compound according to claim 4 , wherein R 2 is dichlorophenylamino or cyclopropyl.

6 . A compound according to claim 1 , wherein R 5 and R 6 are both alkyl at the same time.

7 . A compound according to claim 6 , wherein R 5 and R 6 are both methyl at the same time.

8 . A compound according to claim 1 , wherein R 7 is 5-phenyl-1,3,4-oxadiyzolyl, 3-alkoxyalkoxyalkyl-1,2-oxazolyl or 3-azidoalkyl-1,2-oxazol-5-yl.

9 . A compound according to claim 1 selected from
6-(4-chlorophenyl)-N-[1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-methylpropan-2-yl]pyridine-2-carboxamide;
6-(4-chlorophenyl)-N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]-6-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide;
6-(4-chlorophenyl)-N-[2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]pyridine-2-carboxamide;
N-[2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-6-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide;
6-(3-chlorophenyl)-N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
6-(3-chlorophenyl)-N-[1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-methylpropan-2-yl]pyridine-2-carboxamide;
6-(3-chlorophenyl)-N-[2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]pyridine-2-carboxamide;
6-chloro-5-(2,4-dichloroanilino)-N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
6-(4-chlorophenyl)-5-cyclopropyl-N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
6-(2-methoxyethoxy)-N-[2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]pyridine-2-carboxamide;
N-[2-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-6-(2-oxopyrrolidin-1-yl)pyridine-2-carboxamide;
6-(3-chlorophenyl)-N-[1-(5-cyclobutyl-1,3,4-oxadiazol-2-yl)-2-methylpropan-2-yl]pyridine-2-carboxamide;
6-(2,4-dichlorophenyl)-N-[2-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
6-(2,4-dichlorophenyl)-N-[2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[3-[1-(2-methoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-methoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-(1-hydroxy-2-methylpropan-2-yl)-1,2-oxazol-5-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-ethoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide;
6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(3-hydroxy-1-adamantyl)pyridine-2-carboxamide;
tert-butyl 2-[[[5-cyclopropyl-6-[(4-fluorophenyl)methyl]pyridine-2-carbonyl]amino]methyl]morpholine-4-carboxylate;
(3S)-4-[5-cyclopropyl-6-(cyclopropylmethoxy)pyrazine-2-carbonyl]thiomorpholine-3-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-(1-hydroxy-2-methylpropan-2-yl)-1,2-oxazol-5-yl]pyrazine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-[2-methyl-1-(oxan-2-yloxy)propan-2-yl]-1,2-oxazol-5-yl]pyrazine-2-carboxamide;
N-[3-(1-azido-2-methylpropan-2-yl)-1,2-oxazol-5-yl]-5-cyclopropyl-6-(cyclopropylmethoxy)pyrazine-2-carboxamide;
6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-[1-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropan-2-yl]pyridine-2-carboxamide;
5-Cyclopentyl-6-(cyclopropylmethoxy)-N-[1-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]-2-methylpropan-2-yl]pyridine-2-carboxamide;
5-Cyclopentyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-methoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide; and
5-Cyclopentyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-ethoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide.

10 . A compound according to claim 1 selected from
6-chloro-5-(2,4-dichloroanilino)-N-[2-methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-methoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide;
5-cyclopropyl-6-(cyclopropylmethoxy)-N-[3-[1-(2-ethoxyethoxy)-2-methylpropan-2-yl]-1,2-oxazol-5-yl]pyridine-2-carboxamide; and
N-[3-(1-azido-2-methylpropan-2-yl)-1,2-oxazol-5-yl]-5-cyclopropyl-6-(cyclopropylmethoxy)pyrazine-2-carboxamide.

11 . A process for the preparation of a compound according to claim 1 , comprising one of the following steps:
(a) the reaction of a compound of formula (A)

in the presence of NHR 3 R 4 , an amide coupling agent and a base, wherein A and R 1 to R 4 are as defined in claim 1 ;
(b) the reaction of a compound of formula (B)

in the presence of R 1 —Y, a palladium catalyst and a base, wherein X is Cl, Br, I or trifluoromethanesulfonate, Y is a trifluoroborate group, a boronic acid group or a boronic acid pinacol ester group, R 1 is halophenyl or halophenylalkyl and A and R 2 to R 4 are as defined in claim 1 ; or
(c) the reaction of a compound of formula (C)

in the presence of R 2 -M, a palladium catalyst and a base, wherein R 1 is halophenyl, halophenylalkyl or oxopyrrolidinyl, R 2 is cycloalkyl, A and R 3 -R 4 are as defined in any one of claims 1 to 8 and M is a trifluoroborate group, a boronic acid group or a boronic acid pinacol ester group.

12 . A pharmaceutical composition comprising a compound in accordance with claim 1 and a therapeutically inert carrier.

13 . A method for the treatment or prophylaxis of pain, neuropathic pain, asthma, osteoporosis, inflammation, psychiatric diseases, psychosis, oncology, encephalitis, malaria, allergy, immunological disorders, arthritis, gastrointestinal disorders, psychiatric disorders rheumatoid arthritis, psychosis or allergy, which method

Assignees

• Hoffmann La Roche

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/08

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