Inhibitors of bruton's tyrosine kinase
View Patent ↗Described herein are kinase inhibitor compounds, methods for synthesizing such inhibitors, and methods for using such inhibitors in the treatment of diseases. Further described herein are methods, assays and systems for determining an appropriate inhibitor of a protein, including a kinase.
1. A compound having the structure of Formula (I):
wherein:
R a , R b , R c , R d and R e are each independently selected from H, F, Cl, Br, I, —CN, —SR 2 , —OR 3 , —N(R 3 ) 2 , and —CO 2 R 3 ; or
R a or R b together with one of R c , R d and R e and the carbon atoms to which they are attached form an epoxide; wherein R a , R b , R c , R d , and R e cannot all be H;
X is F, Cl, Br, I, or CF 3 ;
Y is F, Cl, Br, or I; or —OC 1 -C 2 alkyl optionally substituted with halogen or —OC 1 -C 2 alkyl; or an optionally substituted C 2 -C 5 heterocycle;
R 2 is selected from H, C 1 -C 4 alkyl, a cysteine amino acid fragment, and a glutathione fragment;
each R 3 is independently selected from H, C 1 -C 4 alkyl, phenyl, and benzyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 wherein R a is H.
3. The compound of claim 2 wherein R b is —OR 3 .
4. The compound of claim 3 wherein R 3 is H.
5. The compound of claim 1 wherein at least two of R c , R d , and R e are H.
6. The compound of claim 5 wherein R c and R d are both H.
7. The compound of claim 6 wherein R e is —OR 3 .
8. The compound of claim 7 wherein R 3 is H.
9. The compound of claim 8 wherein R a and R b are both H.
10. The compound of claim 8 wherein R a is H and R b is —OR 3 .
11. The compound of claim 10 wherein R 3 is H.
12. The compound of claim 5 wherein R c , R d , and R e are each independently H.
13. The compound of claim 12 wherein R a is H and R b is —OR 3 .
14. The compound of claim 13 wherein R 3 is H.
15. The compound of claim 1 wherein R a or R b together with one of R c , R d and R e and the carbon atoms to which they are attached form an epoxide.
16. A compound having the structure of Formula (II):
wherein:
R a , R b , R c , R d and R e are each independently selected from H, F, Cl, Br, I, —CN, —SR 2 , —OR 3 , —N(R 3 ) 2 , and —CO 2 R 3 ; or
R a or R b together with one of R c , R d and R e and the carbon atoms to which they are attached form an epoxide; wherein R a , R b , R c , R d , and R e cannot all be H;
R 2 is selected from H, C 1 -C 4 alkyl, a cysteine amino acid fragment, and a glutathione fragment;
each R 3 is independently selected from H, C 1 -C 4 alkyl, phenyl, and benzyl;
or a pharmaceutically acceptable salt or solvate thereof.
17. A compound having the structure
or a pharmaceutically acceptable salt or solvate thereof.
18. A pharmaceutical composition comprising a compound having the structure of Formula (I):
wherein:
R a , R b , R c , R d and R e are each independently selected from H, F, Cl, Br, I, —CN, —SR 2 , —OR 3 , —N(R 3 ) 2 , and —CO 2 R 3 ; or
R a or R b together with one of R c , R d and R e and the carbon atoms to which they are attached form an epoxide; wherein R a , R b , R c , R d , and R e cannot all be H;
X is F, Cl, Br, I, or CF 3 ;
Y is F, Cl, Br, or I; or —OC 1 -C 2 alkyl optionally substituted with halogen or —OC 1 -C 2 alkyl; or an optionally substituted C 2 -C 5 heterocycle;
R 2 is selected from H, C 1 -C 4 alkyl, a cysteine amino acid fragment, and a glutathione fragment;
each R 3 is independently selected from H, C 1 -C 4 alkyl, phenyl, and benzyl;
or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient, binder or carrier.
19. The compound of claim 1 wherein the compound is in an isolated form.