INHIBITORS OF BRUTON'S TYROSINE KINASE
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Abstract
Disclosed herein are compounds that form covalent bonds with Bruton'"'"'s tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
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Citations
23 Claims
- 1. A compound of Formula (D) having the structure:
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8. A compound selected from among:
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound
4);
(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one (Compound
5);
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)sulfonylethene (Compound
6);
1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-yn-1-one (Compound
8);
1-(4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound
9);
N-((1s,4s)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexyl)acrylamide (Compound
10);
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound
11);
1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Compound
12);
1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 13);
1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound
14); and
(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound
15).
- 10. An inhibited tyrosine kinase comprising a Bruton'"'"'s tyrosine kinase, a Bruton'"'"'s tyrosine kinase homolog, or a Btk tyrosine kinase cysteine homolog bound to an inhibitor having the structure:
- 12. A method for treating an autoimmune disease comprising comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton'"'"'s tyrosine kinase, a Bruton'"'"'s tyrosine kinase homolog, or a Btk tyrosine kinase cysteine homolog.
- 14. A method for treating a heteroimmune condition or disease comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of the Bruton'"'"'s tyrosine kinase or with a homologous cysteine sidechain of the Bruton'"'"'s tyrosine kinase homolog.
- 16. A method for treating an inflammatory disease comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton'"'"'s tyrosine kinase, a Bruton'"'"'s tyrosine kinase homolog, or a Btk tyrosine kinase cysteine homolog.
- 18. A method for treating a cancer comprising comprising administering to a subject in need thereof a composition containing a therapeutically effective amount of a compound that forms a covalent bond with a cysteine sidechain of a Bruton'"'"'s tyrosine kinase, a Bruton'"'"'s tyrosine kinase homolog, or a Btk tyrosine kinase cysteine homolog.
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22. A compound of Formula (E) having the structure:
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23. A compound of Formula (F) having the structure:
Specification