EIF4E inhibitors and uses thereof

1. A method for treating a cancer in a patient comprising administering to the patient a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R;

n is 0, 1, 2, 3, 4, or 5;

L 1 is a bond, or an optionally substituted C 1-8 bivalent straight or branched hydrocarbon chain, wherein 1, 2, 3, or 4 methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —N(R)—, or —S(O) 2 —;

R 2 is halogen, R, —OR, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, or —S(O) 2 N(R) 2 ;

R 3 is —CN, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —N(R)—C(O)—, —N(R)—C(O)—OR, —S(O) 2 —N(R) 2 , —S(O) 2 —N(R)—C(O)R, —C(O)—N(R)—S(O) 2 R, —C(═NR)—N(R) 2 , —N(R)—C(═NR)—N(R) 2 , or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

R is hydrogen, optionally substituted —C 1-6 aliphatic, or an optionally substituted ring selected from phenyl, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-6 membered monocyclic, saturated or partially unsaturated, carbocyclic ring, or a 3-6 membered monocyclic, saturated or partially unsaturated, heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The method of claim 1 , wherein

is

wherein each of R 11 and R 12 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R.

3. The method of claim 2 , wherein at least one of R 12 is not hydrogen.

4. The method of claim 1 , wherein L 1 is a bond.

5. The method of claim 1 , wherein R 2 is not hydrogen.

6. The method of claim 5 , wherein R 2 is optionally substituted —C 1-6 aliphatic.

7. The method of claim 1 , wherein R 2 is H,

8. The method of claim 1 , wherein R 3 is —COOH, —CN,

9. The method of claim 1 , wherein L 1 is a bond, or an optionally substituted C 1-8 bivalent straight or branched hydrocarbon chain, wherein 1, 2, 3, or 4 methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —N(R)—, or —S(O) 2 —, wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

10. The method of claim 1 , wherein the compound is of Formulae V-a, V-b, V-c, or V-d:

or a pharmaceutically acceptable salt thereof, wherein each of R 11 and R 12 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R.

11. The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein R 2 is optionally substituted —C 1-6 alkyl.

13. The method of claim 1 , wherein

14. The method of claim 1 , wherein R 3 is —C(O)OR.

15. The method of claim 1 , wherein each R 1 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R, wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

16. The method of claim 1 , wherein R 2 is halogen, R, —OR, —SR, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, or —S(O) 2 N(R) 2 , wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

17. The method of claim 1 , wherein R 3 is —CN, —C(O)R, —C(O)OR, —C(O)N(R) 2 , —N(R)—C(O)—R, —N(R)—C(O)—OR, —S(O) 2 —N(R) 2 , —S(O) 2 —N(R)—C(O)R, —C(O)—N(R)—S(O) 2 R, —C(═NR)—N(R) 2 , —N(R)—C(═NR)—N(R) 2 , or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

18. The method of claim 2 , wherein each of R 11 and R 12 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R, wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

19. The method of claim 10 , wherein each of R 11 and R 12 is independently halogen, R, —N(R) 2 , —OR, —SR, —C(O)OR, or —S(O) 2 R, wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

20. The method of claim 14 , wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.

21. The method of claim 1 , wherein the cancer is multiple myeloma, breast cancer, colorectal cancer, lung cancer, glioblastoma, sarcomas, melanoma, prostate cancer, or lymphomas.