Compounds and methods for modulating interleukin-2-inducible t-cell kinase

1. A compound having the formula:

wherein,

Ring A is

R 1 is independently hydrogen, 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;

R 2 is independently hydrogen, 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 C(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;

R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCX 3 3 , —OCH 2 X 3 , —OCHX 3 2 , —CN, —SO n3 R 3D , —SO v3 NR 3A R 3B , —NHC(O)NR 3A R 3B , —N(O) m3 , —NR 3A R 3B , —C(O)R 3C , —C(O)—OR 3C , —C(O)NR 3A R 3B , —OR 3D , —NR 3A SO 2 R 3D , —NR 3A C(O)R 3C , —NR 3A C(O)OR 3C , —NR 3A OR 3C , 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 4 is independently hydrogen, halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —OCX 4 3 , —OCH 2 X 4 , —OCHX 4 2 , —CN, —SO n4 R 4D , —SO v4 NR 4A R 4B , —NHC(O)NR 4A R 4B , —N(O) m4 , —NR 4A R 4B , —C(O)R 4C , —C(O)—OR 4C , —C(O)NR 4A R 4B , —OR 4D , —NR 4A SO 2 R 4D , —NR 4A C(O)R 4C , —NR 4A C(O)OR 4C , —NR 4A OR 4C , 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 5 is independently 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 1 is —O—, —S—, or substituted or unsubstituted C 1 -C 2 alkylene, or substituted or unsubstituted 2 membered heteroalkylene;

L 2 is a bond, —NH—, or —NHC(O)—;

L 3 is a bond, —S(O) 2 —, —N(R 6 )—, —O—, —S—, —C(O)—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )C(O)NH—, —NHC(O)N(R 6 )—, —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 independently hydrogen, —CX 6 3 , —CHX 6 2 , —CH 2 X 6 , —CN, —C(O)R 6C , —C(O)OR 6C , —C(O)NR 6A R 6B , 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 4 is substituted or unsubstituted heterocycloalkylene;

E is

each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 6A , R 6B , and R 6C 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 3A and R 3B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R 4A and R 4B 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 bonded to 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 to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

each X, X 1 , X 2 , X 3 , X 4 , and X 6 is independently —F, —Cl, —Br, or —I;

n1, n2, n3, and n4 are independently an integer from 0 to 2;

m1, m2, m3, m4, v1, v2, v3, and v4 are independently 1 to 2;

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 18 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;

R 15A , R 15B , R 15C , R 15D , R 16A , R 16B , R 16C , R 16D , R 17A , R 17B , R 17D , R 18A , R 18B , and R 18C are 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 15A and R 15B 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 15 , X 16 , X 17 and X 18 is independently —F, —Cl, —Br, or —I;

n15, n16, and n17 are independently an integer from 0 to 2;

v15, v16, and v17 are independently 1 or 2; and

m15, m16, and m17 are independently 1 or 2.

2. The compound of claim 1 , wherein L 1 is —O—, —S—, or substituted or unsubstituted methylene.

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

4. The compound of claim 1 , having the formula:

5. The compound of claim 1 , having the formula:

6. The compound of claim 1 , wherein R 1 is independently hydrogen, halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —OCX 1 3 , —OCH 2 X 1 , —OCHX 1 2 , substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

7. The compound of claim 1 , wherein R 1 is hydrogen, halogen, —CH 3 , —CH 2 CH 3 , —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —OCH 3 , —OCX 1 3 , —OCH 2 X 1 , —OCHX 1 2 , —SCH 3 , —SCX 1 3 , —SCH 2 X 1 , or —SCHX 1 2 .

8. The compound of claim 1 , wherein R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCX 3 3 , —OCH 2 X 3 , —OCHX 3 2 , —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

9. The compound of claim 1 , wherein R 3 is hydrogen, halogen, —CH 3 , —CH 2 CH 3 , —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —OCH 3 , —OCX 3 3 , —OCH 2 X 3 , —OCHX 3 2 , —CN, —SCH 3 , —SCX 3 3 , —SCH 2 X 3 , or —SCHX 3 2 .

10. The compound of claim 1 , wherein R 5 is independently substituted or unsubstituted (C 1 -C 8 ) alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

11. The compound of claim 1 , wherein R 5 is independently unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl.

12. The compound of claim 1 , wherein R 5 is independently phenyl substituted with halogen, substituted or unsubstituted (C 1 -C 8 ) alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted (C 3 -C 6 ) cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

13. The compound of claim 1 , wherein L 4 is a substituted or unsubstituted monocyclic heterocycloalkylene, substituted or unsubstituted fused ring heterocycloalkylene, substituted or unsubstituted spirocyclic heterocycloalkylene, or substituted or unsubstituted bridged ring heterocycloalkylene.

14. The compound of claim 1 , wherein L 4 is a

15. The compound of claim 1 , wherein E is —C(O)CH═CH 2 , —C(O)CH═CHCH 2 N(CH 3 ) 2 , —C(O)C(═CH 2 )CH 2 N(CH 3 ) 2 , —C(O)C≡CCH 3 , or —C(O)C(═CH 2 )CH 3 .

16. The compound of claim 1 , wherein L 4 is a substituted or unsubstituted 5 to 8 membered monocyclic heterocycloalkylene, substituted or unsubstituted 7 to 8 membered fused ring heterocycloalkylene, substituted or unsubstituted 7 to 8 membered spirocyclic heterocycloalkylene, or substituted or unsubstituted 7 to 8 membered bridged ring heterocycloalkylene.

17. The compound of claim 1 , having the formula:

18. The compound of claim 17 having the structure:

19. The compound of claim 17 having the structure:

20. The compound of claim 17 having the structure:

21. The compound of claim 17 having the structure:

22. The compound of claim 17 having the structure:

23. The compound of claim 17 having the structure:

24. The compound of claim 17 having the structure:

25. The compound of claim 17 having the structure:

26. The compound of claim 17 having the structure:

27. The compound of claim 17 having the structure:

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

29. A method of treating T-cell lymphoma, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

30. The method of claim 29 , wherein the T-cell lymphoma is cutaneous T-cell lymphoma or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).