Inhibitors of bruton'S tyrosine kinase
View Patent ↗Disclosed herein are compounds, including compounds having the structure of Formula (A), (B), (C), and (D), as described in further detail herein, 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.
1. A compound having the structure:
2. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the structure:
3. A compound having the structure:
4. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable excipient.
5. A process for the preparation of (R)-tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (intermediate 3, R-isomer) comprising coupling of intermediate 2 and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate:
under Mitsunobu reaction conditions to give intermediate 3 (R-isomer):
6. The process of claim 5 , wherein the process comprises coupling of intermediate 2 and (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate in the presence of diisopropyl azodicarboxylate and polymer-bound triphenylphosphine in tetrahydrofuran.
7. A process for the preparation of (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-din-1-yl)prop-2-en-1-one (compound 13) comprising treating intermediate 3 (R-isomer) of claim 5 with an acid and then a base, followed by coupling with acryloyl chloride to give compound 13:
8. A process for the preparation of (S)-tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (intermediate 3, S-isomer) comprising coupling of intermediate 2 and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate:
under Mitsunobu reaction conditions to give intermediate 3 (S-isomer):
9. The process of claim 8 , wherein the Mitsunobu reaction conditions comprises coupling of intermediate 2 and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate in the presence of diisopropyl azodicarboxylate and polymer-bound triphenylphosphine in tetrahydrofuran.
10. A process for the preparation of (S)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-din-1-yl)prop-2-en-1-one (compound 14) comprising treating intermediate 3 (S-isomer) of claim 8 with an acid and then a base, followed by coupling with acryloyl chloride to give compound 14:
11. A process for the preparation of tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (intermediate 3) comprising coupling of intermediate 2 and tert-butyl 3-hydroxypiperidine-1-carboxylate:
under Mitsunobu reaction conditions to give intermediate 3:
12. The process of claim 11 , wherein the Mitsunobu reaction conditions comprises coupling of intermediate 2 and tert-butyl 3-hydroxypiperidine-1-carboxylate in the presence of diisopropyl azodicarboxylate and polymer-bound triphenylphosphine in tetrahydrofuran.
13. A process for the preparation of 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperi-din-1-yl)prop-2-en-1-one (compound 4) comprising treating intermediate 3 of claim 11 with an acid and then a base, followed by coupling with acryloyl chloride to give compound 4: