Oxazoline and isoxazoline derivatives as CRAC modulators

Patent metadata

Field	Value
Publication number	US-9737534-B2
Application number	US-201514840118-A
Country	US
Kind code	B2
Filing date	Aug 31, 2015
Priority date	Oct 30, 2010
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

The present invention relates to compounds of Formula (I),

along with processes for their preparation that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions associated with the modulation of CRAC. The invention further relates to methods of treating, preventing managing and/or lessening the diseases, disorders, syndromes or conditions associated with the modulation of CRAC of Formula (I).

First claim

The invention claimed is:

1. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of Formula (I):

wherein:
R 1 , which may be same or different at each occurrence, is independently selected from halogen, alkyl, haloalkyl, alkoxy and cycloalkyl;
R 2 is selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R is alkyl; and
p is an integer ranging from 0 to 2, both inclusive;
or a pharmaceutically acceptable salt thereof or stereoisomers thereof.

2. The method of claim 1 , wherein the method comprises administering to the subject a therapeutically effective amount of a compound selected from:
2,6-Difluoro-N-(2′-methyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(5′-(4-Ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(2′-methyl-5′-(5-oxo-4-propyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(2′-Ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2-Chloro-N-(2′-ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-6-fluorobenzamide,
N-(2′-Ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2-fluoro-6-methylbenzamide,
2,6-Difluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Chloro-6-fluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Fluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-6-methylbenzamide,
4-Ethyl-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(2′-(Difluoromethoxy)-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
N-(2′-Chloro-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Chloro-6-fluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(2′-ethyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
or pharmaceutically acceptable salt thereof.

3. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound which is 2,6-Difluoro-N-(2′-methyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide.

4. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound which is N-(5′-(4-Ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide.

5. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound which is 2,6-Difluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide.

6. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound which is 2-Chloro-6-fluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide.

7. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutical composition comprising a compound of Formula (I):

wherein:
R 1 , which may be same or different at each occurrence, is independently selected from halogen, alkyl, haloalkyl, alkoxy and cycloalkyl;
R 2 is selected from hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R is alkyl; and
p is an integer ranging from 0 to 2, both inclusive;
or a pharmaceutically acceptable salt thereof or stereoisomers thereof.

8. A method of treating rheumatoid arthritis in a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutical composition comprising a compound selected from:
2,6-Difluoro-N-(2′-methyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(5′-(4-Ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2′-methyl-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(2′-methyl-5′-(5-oxo-4-propyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(2′-Ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2-Chloro-N-(2′-ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-6-fluorobenzamide,
N-(2′-Ethyl-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2-fluoro-6-methylbenzamide,
2,6-Difluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Chloro-6-fluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Fluoro-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-6-methylbenzamide,
4-Ethyl-N-(2′-methoxy-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
N-(2′-(Difluoromethoxy)-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
N-(2′-Chloro-5′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
2,6-Difluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
2-Chloro-6-fluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide,
and N-(2′-ethyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-2,6-difluorobenzamide,
or a pharmaceutically acceptable salt thereof.

Assignees

• Lupin Ltd

Inventors

• Irlapati Nageswara Rao
• Deshmukh Gokul Keruji
• Karche Vijay Pandurang
• Jachak Santosh Madhukar
• Sinha Neelima
• Palle Venkata P
• Kamboj Rajender Kumar

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

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

• A61P35/00

  Antineoplastic agents · CPC title