Inhibitors of Bruton's tyrosine kinase
Disclosed herein are imidazo[1,5-f][1,2,4]triazine compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). The imidazo[1,5-f][1,2,4]triazine compounds described are irreversible inhibitors of Btk. Methods for the preparation of the imidazo[1,5-f][1,2,4]triazine compounds are disclosed. Also disclosed are pharmaceutical compositions that include the imidazo[1,5-f][1,2,4]triazine compounds. Methods of using the imidazo[1,5-f][1,2,4]triazine 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 (E) 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 a 4-, 5-, 6-, or 7-membered monocyclic nitrogen-containing heterocycloalkyl ring;
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 2 , wherein:
Z is C(═O), NHC(═O), or S(═O) 2 .
4. The compound of claim 3 , 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 3 , wherein:
each of R 6 and R 8 is H.
6. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
7. A pharmaceutical composition comprising a compound of claim 2 , and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition comprising a compound of claim 3 , and a pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising a compound of claim 4 , and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising a compound of claim 5 , and a pharmaceutically acceptable excipient.
11. The compound of claim 1 having the structure:
12. A pharmaceutical composition comprising a compound of claim 11 , and a pharmaceutically acceptable excipient.