Inhibitors of bruton's tyrosine kinase
View Patent ↗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.
1. A compound of Formula (D3) having the structure:
wherein:
L a is O or S;
Ar is an unsubstituted phenyl;
Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring, or
Y is selected from azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl;
Z is C(═O), OC(═O), NHC(═O), S(═O) x , or NHS(═O) x , where x is 2;
R 8 is H; R 7 is H, unsubstituted C 1 -C 4 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); or
R 7 and R 8 taken together form a bond;
R 6 is H, unsubstituted C 1 -C 4 alkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, or C 1 -C 4 alkyl(phenyl); or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein L a is O.
3. The compound of claim 1 , wherein Z is C(═O), NHC(═O), or S(═O) 2 .
4. The compound of claim 1 , wherein each of R 7 and R 8 is H; or R 7 and R 8 taken together form a bond.
5. The compound of claim 1 , wherein each of R 6 and R 8 is H.
6. The compound of claim 1 having the structure:
7. The compound of claim 1 wherein Y is pyrrolidinyl.
8. The compound of claim 1 wherein Y is piperidinyl.
9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable excipient.