Inhibitors of bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9556147-B2
Application number	US-201414768488-A
Country	US
Kind code	B2
Filing date	Mar 3, 2014
Priority date	Mar 5, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

This application discloses compounds according to generic Formula I: (I) wherein all variables are defined as described herein, which inhibit BTK. The compounds disclosed herein are useful to modulate the activity of BTK and treat diseases associated with excessive BTK activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

First claim

The invention claimed is:

1. A compound of Formula I,

wherein:
X is halo;
Y is H or lower alkyl;
R is —R 1 —R 2 —R 3 ;
R 1 is heteroaryl;
R 2 is —C(═O) or absent;
R 3 is heterocycloalkyl, optionally substituted with one or more R 3′ ; and
each R 3′ is independently lower alkyl, halo, lower alkoxy, or lower haloalkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is F.

3. The compound of claim 1 , wherein R 1 is pyridyl.

4. The compound of claim 1 , wherein R 2 is —C(═O).

5. The compound of claim 1 , wherein R 3 morpholinyl.

6. The compound of claim 1 , wherein Y is H.

7. The compound of claim 1 , wherein Y is tert-butyl.

8. The compound of claim 3 , wherein R 2 is absent.

9. The compound of claim 8 , wherein R 3 is pyrrolidinyl, optionally substituted with one or more R 3′ .

10. The compound of claim 9 , wherein R 3′ is methyl.

11. The compound of claim 8 , wherein Y is H.

12. The compound of claim 8 , wherein Y is tert-butyl.

13. The compound of claim 1 , selected from the group consisting of:
8-(6-tert-butyl-8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one;
8-(6-tert-butyl-8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-[(2S)-1-methylpyrrolidin-2-yl]pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one;
(6S)-8-(6-tert-butyl-8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one;
(6R)-8-(6-tert-butyl-8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one;
8-(8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one;
(6S)-8-(8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one; and
(6R)-8-(8-fluoro-1-oxophthalazin-2-yl)-6-hydroxy-4-methyl-2-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6,7-dihydro-5H-benzo[1,2]cyclohepta[6,7-d]pyridin-3-one.

14. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

15. A method for treating rheumatoid arthritis, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating asthma, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Assignees

• Hoffmann La Roche
• Hoffmann-La Inc

Inventors

• Brotherton-Pleiss Christine E
• Kondru Rama K
• Lopez-Tapia Francisco Javier
• Lou Yan

Classifications

• A61P43/00

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

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title