Btk inhibitors

Patent metadata

Field	Value
Publication number	US-10214546-B2
Application number	US-201515538971-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 31, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula (I), or pharmaceutically acceptable salts thereof, or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds of Formula (I) in the treatment of Btk mediated disorders.

First claim

What is claimed is:

1. A compound according to Formula I, or a pharmaceutically acceptable salt, thereof

wherein:
L is selected from the group consisting of:

R 1 is H, cyano, halogen, (1-4C)alkyl, (3-6C)cycloalkyl, (1-3C)alkoxy, (3-6C)cycloalkoxy, morpholino, aryl or imidazolyl,
wherein (1-4C)alkyl or (1-3C)alkoxy may optionally be substituted with one, two or three halogens;

R 2 is selected from H, (1-3C)alkyl, (1-3C)alkoxy, cyclopropyl, aminocarbonyl,
wherein the (1-3C)alkyl or (1-3C)alkoxy may optionally be substituted with hydroxyl or one, two or three halogen;

R 2a is hydrogen or methyl;
R 3a , R 3b , R 3c and R 3d are each independently selected from H, halogen, (1-3C)alkyl, (1-6C)alkoxy, and (3-6C)cycloalkyl, wherein (1-3C)alkyl may be substituted with hydroxyl or one, two or three halogen;
R 4 is independently selected from the group consisting of:
a) H,
b) halogen, and
c) haloalkyl;

wherein in ring system J-K:
Q is C═O or CH 2 ;
T is C(R e ) 2 , O, NR e , or a bond;
U is C(R d ) 2 , O, or NR d ;
V is CH 2 or O;
R c is independently selected from H, fluoro, methyl or trifluoromethyl,
or two R c groups can join to form a spirofused cyclopropyl group with the carbon atom to which they are attached;

R d is independently selected from H, (1-3C)alkyl or trifluoromethyl;
R e is independently selected from H or (1-6C)alkyl,
or two R e groups can join to form a spirofused cyclopropyl group with the carbon atom to which they are attached;

when T is a bond, Q is C═O and U is C(R d )2,
R c and R d can join to form a 3-6 membered ring with the carbons to which they are attached; and
with the proviso that:
when Q is CH 2 , then T is C(R e ) 2 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring system J-K is selected from the group consisting of

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is trifluoromethyl.

5. The compound of claim 1 having Formula Ia

or a pharmaceutically acceptable salt thereof.

6. A compound selected from the group consisting of:
(6R,8aS)-6-(8-amino-1-{4-[(1S)-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[(1R)-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-5-chloro-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-5-chloro-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2-dimethylhexahydroindolizin-3 (2H)-one;
(1 S,6R,8aS)-6-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyltetrahydro-1H-[1,3]oxazolo[4,3-c][1,4]oxazin-3-one;
(1R,6R,8aS)-6-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyltetrahydro-1H-[1,3]oxazolo[4,3-c][1,4]oxazin-3-one;
(6R,8aS)-6-[8-amino-1-(2-methoxy-4-{2,2,2-trifluoro-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(2-methoxy-4-{2,2,2-trifluoro-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[4-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[4-(1-hydroxy-1,2-dimethylpropyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{1-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[1-(3-fluorophenyl)-1-hydroxyethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[4-(1-hydroxy-1-pyridin-2-ylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[4-(1-hydroxy-1-pyridin-3-ylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[1-(4-fluorophenyl)-1-hydroxyethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[2-(hydroxymethyl)-4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[2-(hydroxymethyl)-4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(2-ethoxy-6-fluoro-4-{1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[4-(1-hydroxy-1-phenylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-{8-amino-1-[2-fluoro-4-(1-hydroxy-1-phenylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[(1R)-2,2,2-trifluoro-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{2,2,2-trifluoro-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{2,2,2-trifluoro-1-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[2,2,2-trifluoro-1-(3-fluorophenyl)-1-hydroxyethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3(2H)-one;
(6R,8aS)-6-{8-amino-1-[2-fluoro-4-(2,2,2-trifluoro-1-hydroxy-1-phenylethyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{1-hydroxy-1-[2-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{4-[2,2,2-trifluoro-1-(4-fluorophenyl)-1-hydroxyethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3(2H)-one;
(6R,8aS)-6-(8-amino-1-{2-methoxy-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-(8-amino-1-{2-methoxy-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-phenylethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)hexahydroindolizin-3 (2H)-one;
(6R,8aS)-6-[8-amino-1-(4-{1-hydroxy-1-[1-methyl-5-(triflu

Assignees

• Merck Sharp & Dohme

Inventors

• Liu Jian
• Kozlowski Joseph A
• Boga Sobhana Babu
• Gao Xiaolei
• Guiadeen Deodial Guy
• Cai Jiaqiang
• Liu Shilan
• Wang Dahai
• Wu Hao
• Yang Chundao

Classifications

• A61P19/02

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

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title