Tertiary alcohol imidazopyrazine BTK inhibitors

Patent metadata

Field	Value
Publication number	US-10208047-B2
Application number	US-201515538910-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 31, 2014
Publication date	Feb 19, 2019
Grant date	Feb 19, 2019

Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I, or pharmaceutically acceptable salts thereof, Formula I 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:
n is 0, 1 or 2;
R 1 is (1-3C)alkyl, optionally substituted with one, two or three halogen;
R 2 is independently selected from the group consisting of methoxy, ethoxy, halogen, and hydroxyl;
R 3 is hydrogen, halogen or C(1-3) alkyl;
X is selected from the group consisting of:
a) cyclopropyl;
b) cyclopentyl;
c) cyclohexyl;
d) bicyclo[2.2.2]octanyl;
e) bicyclo[3.2.1]octanyl;
f) bicyclo[2.2.1]heptanyl;
g) bicyclo[3.2.2]nonanyl;
h) bicyclo[3.1.0]hexanyl;
i) tricyclo[3.2.2.0 2,4 ]nonanyl; and
j) tetrahydropyranyl;

each optionally substituted with one to four R 4 ,
wherein R 4 is hydrogen, oxo, fluoro or (1-6C)alkyl.

2. A compound of Formula 1a, or a pharmaceutically acceptable salt thereof

wherein:
R 1 is (1-3C)alkyl, optionally substituted with one, two or three halogen;
R 2 is hydrogen or (1-3C)alkoxy;
R 3 is hydrogen or halogen;
X is selected from the group consisting of:
a) cyclopropyl;
b) cyclopentyl;
c) cyclohexyl;
d) bicyclo[2.2.2]octanyl;
e) bicyclo[3.2.1]octanyl;
f) bicyclo[2.2.1]heptanyl;
g) bicyclo[3.2.2]nonanyl;
h) bicyclo[3.1.0]hexanyl;
i) tricyclo[3.2.2.0 2,4 ]nonanyl; and
j) tetrahydropyranyl;

each optionally substituted with one to four R 4 ,
wherein R 4 is hydrogen, oxo, fluoro or (1-6C)alkyl.

3. The compound of claim 1 , wherein the compound is a compound having Formula Ib

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is a compound having Formula Ic

or a pharmaceutically acceptable salt thereof.

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein R 3 is fluoro or chloro.

7. A compound selected from the group consisting of:
(R)-4-(8-amino-1-(4-(1-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)-1,4-dimethylcyclohexanecarboxylic acid;
4-[8-amino-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[2.2.2]octane-1-carboxylic acid;
4-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[2.2.2]octane-1-carboxylic acid;
(1S,3S)-3-[8-amino-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
(1S,3S)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
4-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,5-dioxobicyclo[2.2.2]octane-1-carboxylic acid;
1-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl] cyclopropanecarboxylic acid;
4-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[2.2.1]heptane-1-carboxylic acid;
5-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[3.2.2]nonane-1-carboxylic acid;
4-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]tetrahydro-2H-pyran-4-carboxylic acid;
(1S,3R)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
4-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2,5,5-tetrafluorobicyclo[2.2.2]octane-1-carboxylic acid;
(1R,3S)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
(1S,3R)-3-[8-amino-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;
(1R,3S)-3-[8-amino-1-(4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;
(1S,3S)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;
(1R,3S)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;
(1S,3R)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;
4-(8-amino-1-{2-ethoxy-4-[1-hydroxy-1-(3-methylphenyl)ethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.2]octane-1-carboxylic acid;
4-(8-amino-1-{2-ethoxy-4-[1-hydroxy-1-(3-methylphenyl)ethyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)bicyclo[2.2.2]octane-1-carboxylic acid;
(1R,2R,5R)-5-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;
5-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]tricyclo[3.2.2.0˜2,4˜]nonane-1-carboxylic acid;
(1S,2S,5S)-5-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;
(1S,3R)-3-[8-amino-5-fluoro-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
(3-endo,8-syn)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[3.2.1]octane-8-carboxylic acid;
(3-exo, 8-syn)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[3.2.1]octane-8-carboxylic acid;
(1S,3R)-3-[8-amino-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{(1S)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
(1S,3R)-3-[8-amino-5-chloro-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
(1R,3S)-3-[8-amino-5-chloro-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
(1S,3S)-3-[8-amino-5-chloro-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
(1R,3R)-3-[8-amino-5-chloro-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;
4-[8-amino-1-(4-{(R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl)}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;
(1S,3R)-3-[8-amino-1-(4-{(1R)-1-[3-(difluoromethyl)phenyl]-1-hydroxyethyl}phenyl)-5-fluoroimidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;
(1R,3R,5S,6S)-3-[8-amino-1-(4-{(1R)-1-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]bicyclo[3.1.0]hexane-6-carboxylic acid; an

Assignees

• Liu Jian
• Kozlowski Joseph A
• Andresen Brian M
• Boga Sobhana Babu
• Gao Xiaolei
• Guiadeen Deodial Guy
• Cai Jiaqiang
• Liu Shilan
• Wang Dahai
• Wu Hao
• Yang Chundao
• Merck Sharp & Dohme

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

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

• A61K31/4985

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