Compositions and methods for treating cancer

1. A human K-Ras protein having a cysteine at residue 12, wherein said cysteine is covalently bonded to a compound, wherein said compound has the formula

R 1 -L 1 -L 2 -L 3 -E,

wherein

R 1 is a substituted phenyl having the formula

 wherein

e5 is an integer from 1 to 4;

each R 3 is independently halogen, —CX 3 , —CN, —SO 2 NR 7 R 8 , —N(O) 2 , —NR 7 C(═O)R 9 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein

two adjacent R 3 substituents are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R 7 , R 8 , R 9 , R 10 is independently hydrogen, or substituted or unsubstituted alkyl; R 7 and R 8 are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X is —F;

L 1 is substituted or unsubstituted heteroarylene;

L 2 is a bond;

L 3 is

 wherein

f8 is an integer from 0 to 8;

each R 2C is independently oxo, halogen, —CX c 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7 CR 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)—OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCX c 3 , —OCHX c 2 , 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; wherein

two adjacent R 2C substituents are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each R 7c , R 8c , R 9c and R 10c is independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , 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 7c and R 8c are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

m1, m3, v1, and v3 are independently an integer from 1 to 2;

n1 and n3 are independently an integer from 0 to 4;

X c is independently —Cl, —Br, —I, or —F; and,

prior to covalently bonding to the cysteine 12,

E is

wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl is independently substituted with a substituent group.

2. The human K-Ras protein of claim 1 , wherein

each R 3 is independently halogen, —CX 3 , —CN, —SO 2 NR 7 R 8 , —N(O) 2 , —NR 7 C(═O)R 9 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , substituted or unsubstituted alkyl, unsubstituted aryl, or unsubstituted heteroaryl, wherein

two adjacent R 3 substituents are optionally joined to form a substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R 7 , R 8 , R 9 , R 10 are independently hydrogen or substituted or unsubstituted alkyl;

R 7 and R 8 are optionally joined to form a substituted or unsubstituted heterocycloalkyl or unsubstituted heteroaryl; and

X is —F.

3. The human K-Ras protein of claim 1 , wherein each R 3 is independently —Cl, —Br, —I, —F, —CF 3 , —OH, —OCH 3 , —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 OH, —OCH 2 CCH, —CH 3 , —CH 2 CH 3 , —CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CHCH 3 OH, —C(OH)(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 N(CH 3 ) 2 , —CCH, —CN, —C(O)H, —C(O)CH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OH, —C(O)N(CH 3 ) 2 , —CH 2 NHC(O)CH 3 , —C(O)NHCH 2 CH 2 OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)OC(CH 3 ) 3 , —S(O) 2 NH 2 , phenyl, pyrrolidinyl, tetrazolyl, imidazolyl, isoxazolyl, or

and when two adjacent R 3 substituents are joined, the two adjacent R 3 substituents form 2,2-dimethyl-1,3-dioxolane, 1,2,5-thiadiazole, 1,2,5-oxadiazolyl, or pyridyl.

4. The human K-Ras protein of claim 1 , wherein the substituted phenyl ring of R 1 is substituted with at least one halogen atom.

5. The human K-Ras protein of claim 4 , wherein the substituted phenyl ring of R 1 is additionally substituted with at least one hydroxyl group.

6. The human K-Ras protein of claim 5 , wherein

f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or

f8 is 2 and R 2C is methyl.

7. The human K-Ras protein of claim 5 , wherein f8 is 1 and R 2C is methyl.

8. The human K-Ras protein of claim 3 , wherein each R 3 is independently a halogen or —OH.

9. The human K-Ras protein of claim 8 , wherein exactly one R 3 group is a halogen.

10. The human K-Ras protein of claim 8 , wherein exactly one R 3 group is a fluorine.

11. The human K-Ras protein of claim 9 , wherein exactly one R 3 group is —OH.

12. The human K-Ras protein of claim 10 , wherein exactly one R 3 group is —OH.

13. The human K-Ras protein of claim 11 , wherein

f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or

f8 is 2 and R 2C is methyl.

14. The human K-Ras protein of claim 12 , wherein

f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or

f8 is 2 and R 2C is methyl.

15. The human K-Ras protein of claim 11 , wherein f8 is 1 and R 2C is methyl.

16. The human K-Ras protein of claim 12 , wherein f8 is 1 and R 2C is methyl.

17. The human K-Ras protein of claim 6 , wherein L 1 is fused ring heteroarylene substituted with at least one substituent group.

18. The human K-Ras protein of claim 6 , wherein L 1 is 6,6-fused ring heteroarylene substituted with at least one substituent group.

19. The human K-Ras protein of claim 17 , wherein L 1 is substituted with at least one substituent group independently selected from the group consisting of oxo, halogen, and heteroaryl substituted with at least one unsubstituted alkyl.

20. The human K-Ras protein of claim 18 , wherein L 1 is substituted with at least one substituent group independently selected from the group consisting of oxo, halogen, and heteroaryl substituted with at least one unsubstituted alkyl.

21. The human K-Ras protein of claim 19 , wherein R 1 comprises a substituted phenyl ring, wherein the substituted phenyl ring is substituted with exactly one fluoro and exactly one hydroxyl group.

22. The human K-Ras protein of claim 15 , wherein L 1 is fused ring heteroarylene substituted with at least one substituent group.

23. The human K-Ras protein of claim 15 , wherein L 1 is 6,6-fused ring heteroarylene substituted at least one substituent group.

24. The human K-Ras protein of claim 21 , wherein L 1 is substituted with at least one substituent group independently selected from the group consisting of oxo, halogen, and heteroaryl substituted with at least one unsubstituted alkyl.

25. The human K-Ras protein of claim 22 , wherein L 1 is substituted with at least one substituent group independently selected from the group consisting of oxo, halogen, and heteroaryl substituted with at least one unsubstituted alkyl.