Benzimidazole-indole inhibitors of Mnk1 and Mnk2

1. A compound according to Formula I or Formula II

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

X 1 is N or CR 5 ;

X 2 is N or CR 6 ;

X 3 is N or CR 7 ;

X 4 and X 5 are independently N or CR 8 ;

Y 1 is H or NR 9 R 10 ;

Y 2 is NR 11 R 12 , alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R 1 is —H, —OH, —SH, —CN, halogen, —(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyleneNHR 9 , —O(C 1 -C 8 )alkyleneY 1 , —(C 1 -C 8 )alkyleneNHR 9 , —(C 1 -C 8 )alkyleneY 1 , cycloalkyl, heterocyclyl, heteroaryl, aryl, —S(C 1 -C 8 )alkyl, —S(O) 2 R 13 , SO 2 NR 9 R 10 , NHR 9 , Y 1 or NR 9 SO 2 R 13 ;

R 2 is —OH, —CN, halogen, —(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyleneNHR 9 , —O(C 1 -C 8 )alkyleneY 1 , —C(O)NHR 9 , —C(O)Y 1 , cycloalkyl, heterocyclyl, heteroaryl, aryl, —SR 13 , —SO 2 (C 1 -C 8 ) alkyl, —SO 2 Y 1 , NHR 9 , Y 1 or NR 9 SO 2 R 13 , or R 2 and Y 2 can combine to form a 5- or 6-membered cycloalkyl or heterocyclyl ring;

R 3 , R 5 , R 6 and R 7 are independently —H, —OH, —CN, halogen, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyleneNHR 9 , —O(C 1 -C 8 )alkyleneY 1 , —C(O)NHR 9 , —C(O)Y 1 , —SR 13 , —SO 2 (C 1 -C 8 ) alkyl, —SO 2 Y 1 , NHR 9 , Y 1 or NR 9 SO 2 R 13 ,

R 4 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;

R 8 is —H, —OH, halogen, —CN, acetyl, —(C 1 -C 8 )alkyl, —S(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —O(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )haloalkyl, NHR 9 or Y 1 ;

R 9 , R 10 , R 11 and R 12 are independently —H, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, —C(O)(C 1 -C 8 )alkyl, —C(O)cycloalkyl, —C(O)O(C 1 -C 8 )alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 8 )alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, wherein R 11 and R′ 2 cannot both be —H;

R 13 is —H, —(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;

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

2. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X 2 is —CH.

3. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X 3 is —CH.

4. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X 4 is N and X 5 is —CH.

5. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 1 is NH 2 .

6. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Y 2 is N((C 1 -C 8 )alkyl)2.

7. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is —H, halogen or —(C 1 -C 8 )alkyl.

8. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen, cycloalkyl or heterocyclyl.

9. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , R 5 and R 6 are —H.

10. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 7 is —H, halogen or —(C 1 -C 8 )alkyl.

11. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are —H.

12. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are independently selected from the group consisting of —(C 1 -C 8 )alkyl, —(C 1 -C 8 )haloalkyl, heterocyclyl and cycloalkyl.

13. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 8 and R 13 are —H or —(C 1 -C 8 )alkyl.

14. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from

(3-(6-aminopyrimidin-4-yl)-5-chloro-1-methyl-7-(1-methylpiperidin-3-yl)-1H-indol-6-yl)(azetidin-1-yl)methanone,

(3-(6-aminopyrimidin-4-yl)-5-chloro-1-methyl-7-(1-methylpiperidin-3-yl)-1H-indazol-6-yl)(azetidin-1-yl)methanone,

(3-(6-aminopyrimidin-4-yl)-5-chloro-1-methyl-7-(1-methylpiperidin-3-yl)-1H-pyrrolo[3,2-b]pyridin-6-yl)(azetidin-1-yl)methanone,

(3-(6-aminopyrimidin-4-yl)-5-chloro-1-methyl-7-(1-methylpiperidin-3-yl)-1H-pyrazolo[4,3-b]pyridin-6-yl)(azetidin-1-yl)methanone, and

3-(6-amino-5-chloropyrimidin-4-yl)-7-isobutyl-1-methyl-1H-indole-6-carboxamide.

15. 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.

16. A compound having the structure:

or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof.