EIF4E-inhibiting compounds and methods
The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Q, L 1 , L 2 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and rings A, B and C are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4e and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
1. A compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
L 1 is —(CH 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH((C 1 -C 8 )alkyl)(CH 2 )—, —CH((C 1 -C 8 )alkyl)(CH 2 ) 2 —, —(CH 2 ) 2 —O—, —CH 2 CH═CH—, —CH 2 C≡C— or —CH 2 (cyclopropyl)-;
L 2 is —C(R 6 )(R 6 )—, —C(R 6 )(R 6 )C(R 6 )(R 6 )—, —C(R 6 )═C(R 6 )—, —N(R 5 )C(R 6 )(R 6 )—, —OC(R 6 )(R 6 )—, —C(═O)—, —C(═O)N(R 5 )C(R 6 )(R 6 )— or a bond;
Ring C is a heteroaryl;
R 1 is H, OH, halo, CN, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 3 -C 6 )cycloalkyl or NR 5 R 5 ;
R 2 is independently H, halo, CN, NO, NO 2 , C≡CH, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, CH 2 SR 5 , OR 5 , NHR 5 ,NR 5 R 5 , [(C 1 -C 8 )alkylene]heterocyclyl, [(C 1 -C 8 )alkylene]heteroaryl, [(C 1 -C 8 )alkylene]NHR 5 , [(C 1 -C 8 )alkylene]NR 5 R 5 , C(O)R 5 , C(O)OR 5 , C(O)NHR 5 , C(O)NR 5 R 5 , SR 5 , S(O)R 5 , SO 2 R 5 , SO 2 NHR 5 , SO 2 NR 5 R 5 , NH(CO)R 6 , NR 5 (CO)R 6 , aryl, heteroaryl, cycloalkyl or heterocyclyl;
R 3 is independently OH, halo, CN, NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, C≡CH, NHR 7 , NR 7 R 7 , CO 2 H, CO 2 R 7 , [(C 1 -C 3 )alkylene] (C 1 -C 3 )alkoxy, [(C 1 -C 3 )alkylene]CO 2 H, (C 3 -C 5 )cycloalkyl, ═O, ═S, SR 7 , SO 2 R 7 , NH(CO)R 7 or NR 7 (CO)R 7 ;
R 5 is independently H, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 3 -C 5 )cycloalkyl or heterocyclyl;
R 6 is independently H, OH, halo, CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, NHR 7 , NR 7 R 7 , CO 2 H, [(C 1 -C 3 )alkylene]CO 2 H, (C 3 -C 5 )cycloalkyl, SR 7 , NH(CO)R 7 or NR 7 (CO)R 7 ;
R 7 is independently H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 8 is H, OH, CO 2 H, CO 2 R 7 , CF 2 C(R 6 ) 2 OH, C(R 6 ) 2 OH, C(CF 3 ) 2 OH, SO 2 H, SO 3 H, CF 2 SO 2 C(R 6 ) 3 , CF 2 SO 2 N(H)R 5 , SO 2 N(H)R 5 , SO 2 N(H)C(O)R 6 , C(O)N(H)SO 2 R 5 , C(O)haloalkyl, C(O)N(H)OR 5 , C(O)N(R 5 )OH, C(O)N(H)R 5 , C(O)NR 5 C(O)N(R 5 ) 2 , P(O)(OR 5 )OH, P(O)(C(R 6 ) 3 )C(R 6 ) 3 , B(OH) 2 , heterocyclyl or heteroaryl;
R 9 is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl or heterocyclyl;
m is 0, 1, or 2;
n is 0, 1, 2 or 3;
p is 0, 1,2 or 3;
wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH 3 , SO 2 CH 3 , SO 2 NH 2 , SO 2 NH(C 1 -C 4 )alkyl, halogen, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , NH(aryl), C(O)NH 2 , C(O)NH(alkyl), CH 2 C(O)NH(alkyl), COOH, COOMe, acetyl, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 5 )alkenyl, (C 2 -C 5 )alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH 2 , alkylene-C(O)—NH(Me), NHC(O)alkyl, CH 2 —C(O)—(C 1 -C 8 )alkyl, C(O)—(C 1 -C 8 )alkyl, and alkylcarbonylaminyl.
2. The compound or the salt of claim 1 , wherein L 2 is a bond.
3. The compound or the salt of claim 1 , wherein Ring C is heteroaryl.
4. The compound or the salt of claim 1 , wherein Ring C is
5. The compound or the salt of claim 1 , wherein R 1 is H, (C 1 -C 8 )alkyl or (C 1 -C 8 )haloalkyl.
6. The compound or the salt of claim 1 , wherein R 2 is halo, CN, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl or OR 5 .
7. The compound or the salt of claim 1 , wherein R 2 is halo, CN or (C 1 -C 8 )haloalkyl.
8. The compound or the salt of claim 1 , wherein R 5 is H, (C 1 -C 3 )alkyl or (C 1 -C 3 )haloalkyl.
9. The compound or the salt of claim 1 , wherein R 8 is CO 2 H or C(O)N(H)SO 2 R 5 .
10. The compound or the salt of claim 1 , wherein R 9 is cycloalkyl or heterocyclyl.
11. The compound or the salt of claim 1 , wherein p=0 or 1.
12. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
13. A compound having the formula:
14. A pharmaceutically acceptable salt of a compound having the formula:
15. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
16. A compound having the formula:
17. A pharmaceutically acceptable salt of a compound having the formula:
18. A compound having the formula:
or a pharmaceutically acceptable salt thereof.
19. A compound having the formula:
20. A pharmaceutically acceptable salt of a compound having the formula:
21. A pharmaceutical composition comprising:
(a) a compound or a salt of claim 1 ; and
(b) a pharmaceutically acceptable carrier, diluent, or excipient.
22. The pharmaceutical composition of claim 21 , wherein the compound has the formula
23. A method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound or a salt of claim 1 , wherein the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, pancreatic cancer, melanoma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, or breast cancer.
24. The method of claim 23 , wherein the compound has the formula
25. The method of claim 23 , wherein the cancer is a metastatic cancer.
26. The method of claim 23 , wherein the cancer is breast cancer, prostate cancer, or lung cancer.
27. The method of claim 26 , wherein the cancer is breast cancer.
28. The method of claim 27 , wherein the breast cancer is hormone receptor positive breast cancer.