EIF4A-inhibiting compounds and methods related thereto

1. A method for treating an eIF4A dependent condition in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of at least one compound according to Formula (I)

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

X is O, S, S(O) or S(O) 2 ;

Y is a 5-membered heteroaryl or a 6-membered aryl or heteroaryl;

R 1 and R 2 independently are aryl;

R 3a , R 3b , R 4a and R 4b independently are H, halogen, CN, C 1 -C 8 (alkyl), (C 1 -C 8 )haloalkyl, C 2 -C 8 (alkenyl), (C 2 -C 8 )alkynyl, OR 9 , NHR 9 , NR 9 R 9 , [(C 1 -C 8 )alkylene]OR 9 , [(C 1 -C 8 )alkylene]NHR 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)R 8 , C(O)NHR 9 , C(O)NR 9 R 9 , C(O)[(C 1 -C 8 )alkylene]NHR 9 , C(O)[(C 1 -C 8 )alkylene]NR 9 R 9 , CO 2 R 9 , C(S)NHR 9 , C(S)NR 9 R 9 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 2 NHR 9 , SO 2 NR 9 R 9 , NH(CO)R 8 , NR 9 (CO)R 8 , NH(CO)NHR 9 , NH(CO)NR 9 R 9 , NR 9 (CO)NHR 9 , NR 9 (CO)NR 9 R 9 , P(O)(OH)(OR 9 ), P(O)(OR 9 ) (OR 9 ), aryl, heteroaryl, cycloalkyl or heterocyclyl;

R 3a and R 3b , and R 4a and R 4b independently combine to form oxo or alkenyl, or a cycloalkyl or heterocyclyl ring; or

R 3a and R 4a , R 3b and R 4b or R 4a and R 5 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R 5 is H, halogen, OH, CN, N 3 , SR 9 , (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 8 )alkynyl, NHC(O)(C 1 -C 8 )alkyl or heteroaryl;

R 6 and R 7 independently are H, CN, halogen, OR 9 , SR 9 , (C 1 -C 8 )alkyl, NH(R 9 ) or NR 9 R 9 ;

R 8 is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, cycloalkyl, O(cycloalkyl), heterocyclyl, O(heterocyclyl), aryl, O(aryl), heteroaryl or O(heteroaryl);

R 9 is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl, heterocyclyl, [(C 1 -C 8 )alkylene]heterocyclyl, aryl, [(C 1 -C 8 )alkylene] aryl or heteroaryl;

wherein the two R 9 's together with the nitrogen atom to which they are attached of NR 9 R 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)NR 9 R 9 , C(O)[(C 1 -C 8 )alkylene]NR 9 R 9 , C(S)NR 9 R 9 , SO 2 NR 9 R 9 , NH(CO)NR 9 R 9 or NR 9 (CO)NR 9 R 9 , optionally form a heterocyclyl ring;

wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or 3 groups selected from OH, CN, SH, SO 2 NH 2 , SO 2 (C 1 -C 4 )alkyl, SO 2 NH(C 1 -C 4 )alkyl, halogen, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , C(O)NH 2 , COOH, COOMe, acetyl, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, NH 2 —C(O)-alkylene, NH(Me)-C(O)-alkylene, CH 2 —C(O)-lower alkyl, C(O)-lower alkyl, alkylcarbonylaminyl, CH 2 —[CH(OH)] m —(CH 2 ) p —OH, CH 2 —[CH(OH)] m —(CH 2 ) p —NH 2 or CH 2 -aryl-alkoxy;

or wherein any alkyl, cycloalkyl or heterocyclyl is optionally substituted with oxo;

“m” and “p” are 1, 2, 3, 4, 5 or 6; and

wherein when Y is a 6-membered aryl then X is not O,

in combination with at least one other therapeutic agent;

wherein the eIF4A dependent condition is breast cancer.

2. The method according to claim 1 wherein X is O.

3. The method according to claim 1 wherein the 6-membered aryl or heteroaryl is

wherein

A 1 is N or CR 10 ;

A 2 is N or CR 11 ;

A 3 is N or CR 12 ;

A 4 is N or CR 13 ; and

R 10 , R 11 , R 12 and R 13 independently are H, halogen, C 1 -C 8 (alkyl), (C 1 -C 8 )haloalkyl, C(O)O(C 1 -C 8 )alkyl, C(O)(C 1 -C 8 )alkyl, SO 2 (C 1 -C 8 )alkyl, C 1 -C 8 (alkenyl), (C 1 -C 8 )alkynyl, OR 9 , NHR 9 , NR 9 R 9 , CN, [(C 1 -C 8 )alkylene]OR 9 , [(C 1 -C 8 )alkylene]NHR 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)R 8 , C(O)NHR 9 , C(O)NR 9 R 9 , C(O)[(C 1 -C 8 )alkylene]NHR 9 , C(O)[(C 1 -C 8 )alkylene]NR 9 R 9 , CO 2 R 9 , C(S)NHR 9 , C(S)NR 9 R 9 , SR 9 , S(O)R 9 , SO 2 R 9 , SO 2 N(H)(R 9 ), SO 2 NR 9 R 9 , NH(CO)R 8 , NR 9 (CO)R 8 , NH(CO)NHR 9 , NH(CO)NR 9 R 9 , NR 9 (CO)NHR 9 , NR 9 (CO)NR 9 R 9 , P(O)(OH)(OR 9 ), P(O)(OR 9 ) (OR 9 ), aryl, heteroaryl, cycloalkyl, or heterocyclyl.

4. The method according to claim 3 wherein

A 2 and A 4 are N, A 1 is CR 10 and A 3 is CR 12 , wherein R 10 and R 12 independently are H, CN, halogen or OR 9 ;

A 2 is N, A 1 is CR 10 , A 3 is CR 12 and A 4 is CR 13 , wherein R 10 , R 12 and R 13 independently are H, CN, halogen or OR 9 ;

A 3 is N, A 1 is CR 10 , A 2 is CR 11 and A 4 is CR 13 , wherein R 10 , R 11 and R 13 independently are H, CN, halogen or OR 9 ; or

A 4 is N, A 1 is CR 10 , A 2 is CR 11 and A 3 is CR 12 , wherein R 10 , R 11 and R 12 independently are H, CN, halogen or OR 9 .

5. The method according to claim 4 wherein A 2 is N, A 1 is CR 10 , A 3 is CR 12 and A 4 is CR 13 , wherein R 10 , R 12 and R 13 independently are H, CN, halogen or OR 9 ; or

A 3 is N, A 1 is CR 10 , A 2 is CR 11 and A 4 is CR 13 , wherein R 10 , R 11 and R 13 independently are H, CN, halogen or OR 9 .

6. The method according to claim 1 wherein R 3a , R 3b , R 4a and R 4b independently are H, halogen, C 1 -C 8 (alkyl), (C 1 -C 8 )haloalkyl, OH, CN, [(C 1 -C 8 )alkylene]OR 9 , [(C 1 -C 8 )alkylene]NHR 9 , [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)NR 9 R 9 , C(O)R 9 , CO 2 R 9 , C(S)NH 2 , S(O)R 9 , SO 2 R 9 , SO 2 NHR 9 , SO 2 NR 9 R 9 , heteroaryl or cycloalkyl, wherein R 9 is a C 1 -C 8 (alkyl) or (C 1 -C 8 )haloalkyl, or wherein the two R 9 's together with the nitrogen atom to which they are attached of [(C 1 -C 8 )alkylene]NR 9 R 9 , C(O)NR 9 R 9 or SO 2 NR 9 R 9 , optionally form a heterocyclyl ring.

7. The method according to claim 1 wherein R 3b is [(C 1 -C 8 )alkylene]NHR 9 or [(C 1 -C 8 )alkylene]NR 9 R 9 , wherein R 9 is C 1 -C 8 (alkyl) or (C 1 -C 8 )haloalkyl, or wherein the two R 9 's together with the nitrogen atom to which they are attached of [(C 1 -C 8 )alkylene]NR 9 R 9 optionally form a heterocyclyl ring.

8. The method according to claim 7 wherein R 3b is [(C 1 -C 8 )alkylene]NR 9 R 9 and R 9 is C 1 -C 8 (alkyl).

9. The method according to claim 1 wherein R 4b is OH.

10. The method according to claim 1 wherein R 5 is OH.

11. The method according to claim 1 wherein R 6 and R 7 are H or C 1 -C 8 (alkyl).

12. The method according to claim 1 wherein R 9 is H or C 1 -C 8 (alkyl).

13. The method according to claim 1 where the compound is selected from

(5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 147F),

4-((5aR,6S,7S,8R,8aS)-3-Chloro-8,8a-dihydroxy-1-methoxy-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 198aF),

(5aR,6S,7S,8R,8aS)-7-(Azetidin-1-ylmethyl)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 212F),

(5aR,6S,7S,8R,8aS)-5a-(4-Chlorophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 145F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a-(4-(trifluoromethyl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 144F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 143F),

Rac-(5aR,6S,7S,8R,8aS)-3-chloro-5a-(4-chlorophenyl)-7-((dimethylamino)methyl)-1-methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (Cpd. No. 142F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 196F),

(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 139F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 207bF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 152F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 157bF),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 158bF),

4-((5aR,6S,7S,8R,8aS)-7-((Dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 231F),

Rac-4-((5aR,6S,7S,8R,8aS)-3-chloro-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 159bF),

4-((5aR,6S,7S,8R,8aS)-3-Chloro-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (Cpd. No. 140F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(difluoromethyl)phenyl)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 146F),

(5aR,6S,7S,8R,8aS)-5a-(4-Cyanophenyl)-8,8a-dihydroxy-1-methoxy-7-(morpholinomethyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 151F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-(((2,2-difluoroethyl)amino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 197F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 207aF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 157cF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((3,3-difluoropyrrolidin-1-yl)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 153F),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((diethylamino)methyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 159cF),

Rac-(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylmethyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile (Cpd. No. 158cF),

Rac-4-((4bR,5R,6R,7S,7aR)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-5-(morpholino-methyl)-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 180F),

Rac-4-((4bR,5R,6R,7S,7aR)-5-((dimethylamino)methyl)-4b-hydroxy-6-(hydroxymethyl)-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 206F),

4-((4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4b,5-dihydroxy-4-methoxy-7-phenyl-4b,5,6,7-tetrahydro-7aH-cyclopenta[4,5]furo[2,3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 66F),

(4bS,5R,6S,7S,7aR)-7a-(4-Chlorophenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 272F),

(4bS,5R,6S,7S,7aR)-7a-(4-(Difluoromethyl)phenyl)-6-((dimethylamino)methyl)-4-methoxy-7-phenyl-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 106F), and

(4bS,5R,6S,7S,7aR)-6-((Dimethylamino)methyl)-4-methoxy-7-phenyl-7a-(4-(trifluoromethyl)phenyl)-5,6,7,7a-tetrahydro-4bH-cyclopenta[4,5]furo[2,3-c]pyridine-4b,5-diol (Cpd. No. 107F),

or pharmaceutically acceptable salts thereof.

14. The method of claim 1 wherein the at least one additional therapeutic agent is an anti-cancer agent.

15. The method of claim 14 , wherein the anti-cancer agent is a chemotherapeutic drug.

16. The method of claim 15 , wherein the chemotherapeutic drug is selected from the group consisting of an inhibitor of chromatin function, a topoisomerase inhibitor, a microtubule inhibiting drug, a DNA damaging agent, an antimetabolite, a DNA synthesis inhibitor, a DNA interactive agent, and a DNA repair inhibitor.

17. The method of claim 16 , wherein the chemotherapeutic drug is selected from the group consisting of pyrimidine analogs, purine analogs, folate antagonists, antiproliferative/antimitotic agents, vinca alkaloids, epidipodophyllotoxins, antibiotics, anthracyclines, enzymes, antiplatelet agents, antiproliferative/antimitotic alkylating agents, nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates-busulfan, nitrosoureas, trazenes, antimetabolites, platinum coordination complexes, hormones, hormone analogs, aromatase inhibitors, anticoagulants, fibrinolytic agents, antisecretory agents, immunosuppressives, anti-angiogenic compounds, growth factor inhibitors, angiotensin receptor blocker, nitric oxide donors, anti-sense oligonucleotides, antibodies, chimeric antigen receptors, cell cycle inhibitors, differentiation inducers, mTOR inhibitors, topoisomerase inhibitors, corticosteroids, growth factor signal transduction kinase inhibitors, mitochondrial dysfunction inducers, toxins, caspase activators, and chromatin disruptors.

18. The method of claim 15 , wherein the chemotherapeutic drug is selected from the group consisting of 5-fluorouracil, floxuridine, capecitabine, gemcitabine, cytarabine, mercaptopurine, thioguanine, pentostatin, cladribine, vinblastine, vincristine, vinorelbine, taxane, paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilones, navelbine, etoposide, teniposide, actinomycin, amsacrine, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, temozolamide, triethylenethiophosphoramide, dactinomycin, daunorubicin, doxorubicin, adriamycin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin, mitomycin, L-asparaginase, mechlorethamine, cyclophosphamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, carmustine, dacarbazinine, methotrexate, cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane, aminoglutethimide, estrogen, tamoxifen, goserelin, bicalutamide, nilutamide, letrozole, anastrozole, heparin, synthetic heparin salts, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, breveldin, cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil, TNP470, genistein, trastuzumab, rituximab, tretinoin, doxorubicin (adriamycin), amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, irinotecan, cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, prednisolone, Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, and diphtheria toxin.

19. The method of claim 18 , wherein the chemotherapeutic drug is an antibody.