Inhibitors of bruton's tyrosine kinase
AssigneesHoffman-La Roche Inc., Chugai Pharamceutical Co.
InventorsRomyr Dominique, Norman Kong, Yan Lou, Francisco Javier Lopez-Tapia, Sung-Sau So
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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 useful for the treatment of oncological, auto-immune, and inflammatory diseases caused by aberrant B-cell activation. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.
Claims23
A compound of Formula I,
- wherein:
- R1 is lower alkyl, phenyl, cycloalkyl, or pyridyl, optionally substituted with one or more R1′;
- each R1′ is independently lower alkyl, halo, —C(═O)NH2, or cyano;
- R2 is hydrogen, halo, lower alkoxy, hydroxy, or lower alkyl;
- R3 is hydrogen, halo, lower alkoxy, hydroxy, or lower alkyl;
- R4 is hydrogen or heterocycloalkyl lower alkylenyl;
- X is CH or N;
- and
- Y is CH or N;
- or a pharmaceutically acceptable salt thereof.
A compound, selected from the group consisting of:
- [5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- {5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
- {5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
- 5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- {5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- [5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;
- {5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
- {5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;
- 2-{(4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile;
- 3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile;
- 3-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide;
- {5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone;
- [5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone;
- and
- 3-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile,
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.