Inhibitors of Bruton's tyrosine kinase

Patent metadata

Field	Value
Publication number	US-9458105-B2
Application number	US-201314441711-A
Country	US
Kind code	B2
Filing date	Nov 13, 2013
Priority date	Nov 16, 2012
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

This application discloses compounds according to generic Formula (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:
A is phthalazine, optionally substituted with one or more A′;
A′ is tert-butyl, F, or oxo;
each R 1 is independently F or hydroxymethyl;
m is 0, 1 or 2;
R 2 is methyl pyrazolyl;
n is 0 or 1; and
X is a bond or CH 2 ;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , selected from the group consisting of:
6-tert-Butyl-8-fluoro-2-[4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-2H-phthalazin-1-one;
6-tert-Butyl-8-fluoro-2-[2-fluoro-4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-2H-phthalazin-1-one;
6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-3-(2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-2H-phthalazin-1-one;
6-tert-Butyl-2-[2,6-difluoro-4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-8-fluoro-2H-phthalazin-1-one;
6-tert-Butyl-8-fluoro-2-[2-hydroxymethyl-4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-2H-phthalazin-1-one;
6-tert-Butyl-8-fluoro-2-[2-fluoro-4-[6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydro-pyridin-4-yl]-benzyl]-2H-phthalazin-1-one;
6-tert-Butyl-8-fluoro-2-[3-hydroxymethyl-4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-2H-phthalazin-1-one; and
6-tert-Butyl-8-fluoro-2-[2-fluoro-5-hydroxymethyl-4-(2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-2H-phthalazin-1-one.

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

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

5. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient or diluent.

Assignees

• Hoffmann La Roche

Inventors

• Dominique Romyr
• Lopez-Tapia Francisco Javier
• Mertz Eric
• So Sung-Sau

Classifications

• A61P37/08

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

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

• A61P29/02

  without antiinflammatory effect · CPC title