eIF4A-inhibiting compounds and methods related thereto

1. A compound according to Formula (I):

or stereoisomers, tautomers, or pharmaceutically acceptable salts 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 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; or

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.

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

3. The compound 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 compound 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 compound 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 1 and R 13 independently are H, CN, halogen or OR 9 .

6. The compound 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 compound 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 compound 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 compound according to claim 1 wherein R 4b is OH.

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

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

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

13. A compound 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. A pharmaceutical composition comprising (i) a therapeutically effective amount of at least one compound according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof; (ii) in combination with a pharmaceutically acceptable carrier, diluent or excipient.