Compounds and methods for modulating bruton's tyrosine kinase

1. A compound having the formula:

wherein,

R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —OCX 1 3 , —OCH 2 X 1 , —OCHX 1 2 , —CN, —SO n1 R 1D , —SO v1 NR 1A R 1B , —NHC(O)NR 1A R 1B , —N(O) m1 , —NR 1A R 1B , —C(O)R 1C , —C(O)—OR 1C , —C(O)NR 1A R 1B , —OR 1D , —NR 1A SO 2 R 1D , —NR 1A C(O)R 1C , —NR 1A C(O)OR 1C , —NR 1A OR 1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z1 is an integer from 0 to 5;

R 2 is independently halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —OCX 2 3 , —OCH 2 X 2 , —OCHX 2 2 , —CN, —SO n2 R 2D , —SO v2 NR 2A R 2B , —NHC(O)NR 2A R 2B , —N(O) m2 , —NR 2A R 2B , —C(O)R 2C , —C(O)—OR 2C , —C(O)NR 2A R 2B , —OR 2D , —NR 2A SO 2 R 2D , —NR 2A AC(O)R 2C , —NR 2A C(O)OR 2C , —NR 2A OR 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

z2 is an integer from 0 to 4;

R 3 is hydrogen or —NH 2 ;

Y 1 is N;

Y 2 is N;

L 1 is a bond, —S(O) 2 —, —S(O) 2 -Ph-, —NR—, —O—, —S—, —C(O)—, —C(O)NR—, —NR 6 C(O)—, —NR 6 C(O)NH—, —NHC(O)NR—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R 6 is hydrogen, halogen, —CX 6 3 , —CHX 6 2 , —CH 2 X 6 , —OCX 6 3 , —OCH 2 X 6 , —OCHX 6 2 , —CN, —S n6 R 6D , —SO v6 NR 6A R 6B , —NHC(O)NR 6A R 6B , —N(O) m6 , —NR 6A R 6B , —C(O)R 6C , —C(O)—OR 6C , —C(O)NR 6A R 6B , —OR 6D , —NR 6A SO 2 R 6D , —N 6A C(O)R 6C , —N 6A C(O)OR 6C , —NR 6A OR 6C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L 2 is a bond, —S(O) 2 —, —S(O) 2 -Ph-, —NR 7A —, —O—, —S—, —C(O)—, —C(O)NR 7A —, —NR 7 C(O)—, —NR 7 C(O)NH—, —NHC(O)NR—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R 7 is hydrogen, halogen, —CX 7 3 , —CHX 7 2 , —CH 2 X 7 , —OCX 7 3 , —OCH 2 X 7 , —OCHX 7 2 , —CN, —SO n7 R 7D , —SO v7 NR 7A R 7B , —NHC(O)NR 7A R 7B , —N(O) m7 , —NR 7A R 7B , —C(O)R 7C , —C(O)—OR 7C , —C(O)NR 7A R 7B , —OR 7D , —NR 7A SO 2 7D , —NR 7A C(O)R 7C , —NR 7A C(O)OR 7C , —NR 7A OR 7C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

E is:

R 15 is independently hydrogen, halogen, CX 15 3 , —CHX 15 2 , —CH 2 X 15 , —CN, —SO n15 R 15D , —SO v15 NR 15A R 15B , —NHNR 15A R 15B , —ONR 15A R 15B , —NHC═(O)NHNR 15A R 15B , —NHC(O)NR 15A R 15B , —N(O) m15 , —NR 15A R 15B , —C(O)R 15C , —C(O)—OR 15C , —C(O)NR 15A R 15B , —OR 15D , —NR 15A SO 2 R 15D , —NR 15A C(O)R 15C , —NR 15A C(O)OR 15C , —NR 15A OR 15C , —OCX 15 3 , —OCHX 15 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R 16 is independently hydrogen, halogen, CX 16 3 , —CHX 16 2 , —CH 2 X 16 , —CN, —SO n16 R 16D , —SO v16 NR 16A R 16B , —NHNR 16A R 16B , —ONR 16A R 16B , —NHC═(O)NHNR 16A R 16B , —NHC(O)NR 16A R 16B , —N(O) m16 , —NR 16A R 16B , —C(O)R 16C , —C(O)—OR 16C , —C(O)NR 16A R 16B , —OR 16D , —NR 16A SO 2 R 16D , —NR 16A C(O)R 16C , —NR 16A C(O)OR 16C , —NR 16A OR 16C , —OCX 16 3 , —OCHX 16 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R 17 is independently hydrogen, halogen, CX 17 3 , —CHX 17 2 , —CH 2 X 17 , —CN, —SO n17 R 17D , —SO v17 NR 17A R 17B , —NHNR 17A R 17B , —ONR 17A R 17B , —NHC═(O)NHNR 17A R 17B , —NHC(O)NR 17A R 17B , —N(O) m17 , —NR 17A R 17B , —C(O)R 17C , —C(O)—OR 17C , —C(O)NR 17A R 17B , —OR 17D , —NR 17A SO 2 R 17D , —NR 17A C(O)R 17C , —NR 17A C(O)OR 17C , —NR 17A OR 17C , —OCX 17 3 , —OCHX 17 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R 8 is independently hydrogen, —CX 18 3 , —CHX 18 2 , —CH 2 X 18 , —C(O)R 18C , —C(O)OR 18C , —C(O)NR 18A R 18B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 15A , R 15B , R 15C , R 15D , R 16A , R 16B , R 16C , R 16D , R 17A , R 17B , R 17C , R 17D , R 18A , R 18B , and R 18C is independently hydrogen, —CX 3 , —CN, —COOH, —CONH 2 , —CHX 2 , —CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1A and R 1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 6A and R 6B substituents bond the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 7A and R 7B substituents bonded to the same nitrogen atom may optionally be joined form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 15A and R 18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 16A and R 16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 17A and R 17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 18A and R 18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 1 , X 2 , X 6 , X 7 , X 15 , X 16 , X 17 , and X 18 is independently —F, —Cl, —Br, or —I;

n1, n2, n6, n7, n15, n16, and n17 are independently an integer from 0 to 4; and

m1, m2, m6, m7, m15, m16, m17, v1, v2, v6, v7, v15, v16, and v17 are independently an integer from 1 to 2.

2. The compound of claim 1 having the formula:

3. The compound of claim 1 having the formula:

4. The compound of claim 1 , wherein R 3 is hydrogen.

5. The compound of claim 1 , wherein R 3 is —NH 2 .

6. The compound of claim 1 , wherein R 1 is independently halogen, —CX 1 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —OCX 1 3 , —OCHX 1 2 , —CHX 1 2 , —CH 2 X 1 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

7. The compound of claim 1 , wherein z1 is 0, 1 or 2.

8. The compound of claim 1 , wherein R 2 is independently halogen, —CX 2 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —N 2 , —SH, —OCX 2 3 , —OCHX 2 2 , —CHX 2 2 , —CH 2 X 2 , substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; two adjacent R 2 substituents may optionally be joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

9. The compound of claim 1 , wherein z2 is 0, 1 or 2.

10. The compound of claim 1 , wherein L 1 is a bond, —S(O) 2 —, —S(O) 2 -Ph-, substituted or unsubstituted C 1 -C 8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C 3 -C 8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.

11. The compound of claim 1 , wherein L 1 is a bond.

12. The compound of claim 1 , wherein L 1 is an unsubstituted methylene.

13. The compound of claim 1 , wherein L 2 is —NR 7A — or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.

14. The compound of claim 1 , wherein L 2 is —NR 7A —.

15. The compound of claim 14 , wherein R 7 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

16. The compound of claim 1 , wherein L 2 is substituted or unsubstituted heterocycloalkylene.

17. The compound of claim 1 , wherein L 2 is substituted or unsubstituted azepanylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted pyrrolidinylene.

18. The compound of claim 1 , wherein E is:

19. The compound of claim 1 , wherein R 15 , R 16 , R 17 , and R 18 are hydrogen.

20. The compound of claim 1 , wherein R 1 is independently halogen.

21. The compound of claim 1 , wherein R 2 is independently halogen.

22. The compound of claim 1 , wherein the compound has the formula:

23. The compound of claim 1 , wherein the compound is capable of entering the central nervous system of a patient following administration outside of the central nervous system.

24. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

25. A method of treating a lymphoma or multiple sclerosise, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

26. A Bruton's tyrosine kinase protein covalently bonded to a compound of claim 1 .

27. The compound of claim 1 , wherein -L 1 -L 2 -E is:

28. The method of claim 25 , wherein the lymphoma is diffuse large B-cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or follicular lymphoma.