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US 10,208,047 B2Granted
Tertiary alcohol imidazopyrazine BTK inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsJian Liu, Joseph A. Kozlowski, Brian M. Andresen, Sobhana Babu Boga, Xiaolei Gao, Deodial Guy Guiadeen, Jiaqiang Cai, Shilan Liu, Dahai Wang, Hao Wu, Chundao Yang
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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.
Claims8
A compound according to Formula I or a pharmaceutically acceptable salt thereof
- wherein:
- n is 0, 1 or 2;
- R1 is (1-3C)alkyl, optionally substituted with one, two or three halogen;
- R2 is independently selected from the group consisting of methoxy, ethoxy, halogen, and hydroxyl;
- R3 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[3.2.2.02,4]nonanyl;
- and
- j) tetrahydropyranyl;
- each optionally substituted with one to four R4,
- wherein R4 is hydrogen, oxo, fluoro or (1-6C)alkyl.
16 more elements
A compound of Formula 1a, or a pharmaceutically acceptable salt thereof
- wherein:
- R1 is (1-3C)alkyl, optionally substituted with one, two or three halogen;
- R2 is hydrogen or (1-3C)alkoxy;
- R3 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[3.2.2.02,4]nonanyl;
- and
- j) tetrahydropyranyl;
- each optionally substituted with one to four R4,
- wherein R4 is hydrogen, oxo, fluoro or (1-6C)alkyl.
15 more elements
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.
35 more elements
Dependencies are inferred from the claim text.