Inhibitors of Bruton's tyrosine kinase
View Patent ↗Disclosed herein are pyrazolo[3,4-d]pyrimidines 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 (A) having the structure:
wherein:
A is N;
R 1 is L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);
R 2 and R 3 are independently selected from H or lower alkyl;
R 4 is L 3 -X-L 4 -G, wherein,
L 3 is optional, and when present is a bond, or an optionally substituted or unsubstituted alkyl;
X is a bond;
L 4 is a substituted or unsubstituted nitrogen containing heterocycle;
or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring; and
G is a Michael acceptor moiety;
or a pharmaceutically acceptable solvate, hydrate, or salt thereof.
2. The compound of claim 1 , wherein G is bound to a nitrogen atom in L 4 .
3. The compound of claim 2 , wherein G is bound to a nitrogen atom in L 4 to form a substituted acrylamide.
4. The compound of claim 3 , wherein R 1 is L 2 -substituted aryl; and L 2 is a bond.
5. The compound of claim 4 , wherein R 2 and R 3 are independently H.
6. The compound of claim 5 , wherein L 3 is optionally substituted or unsubstituted alkyl.
7. The compound of claim 6 , wherein L 3 is methylene and L 4 is pyrrolidine or piperidine.
8. The compound of claim 5 , wherein the compound of Formula (A) has the structure of Formula (B):
wherein:
Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;
each R a is independently H, halogen, —CF 3 , —CN, —NO 2 , OH, NH 2 , -L a -(substituted or unsubstituted alkyl), -L a -(substituted or unsubstituted alkenyl), -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is a bond, O, S, —S(═O), —S(═O) 2 , NH, C(O), CH 2 , —NHC(O)O, —NHC(O), or —C(O)NH; and
G together with the nitrogen atom to which it is bound forms a substituted acrylamide;
or a pharmaceutically acceptable solvate, hydrate, or salt thereof.
9. The compound of claim 8 , wherein each R a is independently H, halogen, -L a -(substituted or unsubstituted heteroaryl), or -L a -(substituted or unsubstituted aryl), wherein L a is O, —NHC(O), or —C(O)NH.
10. The compound of claim 9 , wherein each R a is independently H, F, or -L a -(substituted or unsubstituted aryl), wherein L a is O.
11. The compound of claim 10 , wherein one R a is F, and one R a is —O-(unsubstituted phenyl).
12. The compound of claim 10 , wherein one R a is —O-(substituted phenyl) and —O-(substituted phenyl) is substituted with one or more F.
13. The compound of claim 8 , wherein Y and R 12 taken together form a piperidine ring.
14. The compound of claim 8 , wherein Y and R 12 taken together form a pyrrolidine ring.