EIF4E inhibitors and uses thereof
The present invention provides compounds inhibiting eIF4E activity, and compositions and methods of using thereof.
1. A compound of formula V:
or a pharmacutically salt thereof, wherein:
each R‘ 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‘ 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)-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; 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 compound 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 compound of claim 2 , wherein at least one of R 12 is not hydrogen.
4. The compound of claim 1 , wherein L 1 is a bond.
5. The compound of claim 1 , wherein R 2 is not hydrogen.
6. The compound of claim 5 , wherein R 2 is optionally substituted —C 1-6 aliphatic.
7. The compound of claim 1 , wherein R 2 is H,
8. The compound of claim 1 , wherein R 3 is —COOH, —CN,
9. The compound 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 compound of claim 1 , wherein the compound is of Formulae V-a to 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 compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
12. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
13. The compound of claim 1 , wherein R 1 is optionally substituted —C 1-6 alkyl.
14. The compound of claim 1 , wherein
15. The compound of claim 1 , wherein R 3 is —C(O)OR.
16. The compound 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.
17. The compound 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.
18. The compound 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.
19. The compound 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.
20. The compound 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.
21. The compound of claim 15 , wherein R is hydrogen or optionally substituted —C 1-6 aliphatic.