Tertiary alcohol imidazopyrazine BTK inhibitors
View Patent ↗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.
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; and
(1R,3R,5S,6R)-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;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.