Pyrrolo-, pyrazolo-, imidazo-pyrimidine and pyridine compounds that inhibit MNK1 and MNK2

1. A compound according to Formula (I):

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

A 1 is —N—;

A 2 is —CR 5a ;

A 3 is —CR 6 ;

A 4 is —N— or —CR 5b ;

A 5 is —NR 7 ;

A 6 and A 7 are CR 8a when ------ represents a bond, otherwise A 6 and A 7 are CR 8a R 8b ;

W 1 is O;

m is 1;

n is 1;

R 1 and R 2 independently are —H, —NHR 10 , NHR 10 -alkylene, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene or heteroarylalkylene; or

R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl ring;

R 3 and R 4 independently are —H, —OH, —CN, —SR 10 , S(O) 2 (C 1 -C 8 ) alkyl, —C(O)NHR 10 , —C(O)NR 10 R 10 , —NHR 10 , —NR 10 R 10 , NHR 10 -alkylene, NR 10 R 10 -alkylene, (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 10 , —O(C 1 -C 8 )alkyleneNR 10 R 10 , cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, heteroarylalkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, or heterocyclylaminyl;

R 5a 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, —NHR 10 , —NR 10 R 10 , —NHR 10 -alkylene, NR 10 R 10 -alkylene, or —O(C 1 -C 8 )haloalkyl;

R 5b and R 6 is —H, —OH, —SH, —CN, —S(O) 2 R 10 , halogen, —S(C 1 -C 8 )alkyl, —NHR 10 , —NR 10 R 10 , (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 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkyleneNHR 10 , —O(C 1 -C 8 )alkyleneNR 10 R 10 —(C 1 -C 8 )alkyleneNHR 10 , —(C 1 -C 8 )alkyleneNR 10 R 10 , —S(C 1 -C 8 )alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl;

R 7 is —H;

R 8a and R 8b independently are —H, —OH, —CN, acetyl, —SH, —S(O) 2 R 10 , halogen, —S(C 1 -C 8 )alkyl, —NHR 10 , —NR 10 R 10 , (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, —O(C 1 -C 8 )alkyl, —O(C 1 -C 8 )alkylNHR 10 , —O(C 1 -C 8 )alkylNR 10 R 10 , —(C 1 -C 8 )alkylNHR 10 , —(C 1 -C 8 )alkylNR 10 R 10 , cycloalkyl, heterocyclyl, heteroaryl or aryl:

R 10 is —H, —OH, —C(O)O(C 1 -C 8 )alkyl, —C(O)(C 1 -C 8 )alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 8 )alkyl, NH 2 —C(O)-alkylene, —S(C 1 -C 8 )alkyl, acetyl, —(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, alkylcarbonylaminyl, alkylaminyl, —C(O)alkyl, —C(O)cycloalkyl, —C(O)O—(C 1 -C 8 )alkyl, aryl, heteroaryl, heterocyclyl or cycloalkyl;

wherein any alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene, heteroarylalkylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl or heterocyclylaminyl 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, acetyl, —(C 1 -C 8 )alkyl, —O (C 1 -C 8 )alkyl (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, haloalkyl, thioalkyl, cyanomethylene, alkylaminyl, 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, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, —CH 2 —C(O)-cycloalkyl, —C(O)-cycloalkyl, —CH 2 —C(O)-aryl, —CH 2 -aryl, —C(O)-aryl, —CH 2 —C(O)-heterocycloalkyl, —C(O)-heterocycloalkyl, heterocyclylaminyl or heterocyclyl; and

--- represents the option of having a double bond.

2. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 independently are —H, methyl, ethyl, i-propyl, —NH 2 , aminomethylene or —CH 3 O—C(O)NH-methylene.

3. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl ring selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, 1-(2,2-difluoroethyl)piperidine or 1-methylpiperidine.

4. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein A 4 is —CR 5b .

5. The compound according to claim 4 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 5a and R 6 independently are —H, chlorine, fluorine, or methyl and R 5b is —H.

6. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein A 4 is —N and R 5a d R 6 independently are —H, chlorine, fluorine or methyl.

7. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 independently are —NH 2 .

8. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is —H and R 4 is methyl, ethyl or —NH 2 .

9. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein --- represents a bond and R 8a is —H, heteroaryl or aryl.

10. The compound according to claim 9 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein A 6 and A 7 are —CH.

11. The compound according to claim 9 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein A 6 is —CH and A 7 is —C(heteroaryl) or —C(aryl).

12. The compound according to claim 1 , or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from the following table:

13. A pharmaceutical composition comprising (i) 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.

14. A method for attenuating or inhibiting the activity of MnK in at least one cell overexpressing Mnk comprising contacting the at least one cell with a compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein the at least one cell is a colon cancer cell, a gastric cancer cell, a thyroid cancer cell, a lung cancer cell, a leukemia cell, a B-cell lymphoma, a T-cell lymphoma, a hairy cell lymphoma, Hodgkin's lymphoma cell, non-Hodgkin's lymphoma cell, Burkitt's lymphoma cell, a pancreatic cancer cell, a melanoma cell, a multiple melanoma cell, a brain cancer cell, a CNS cancer cell, a renal cancer cell, a prostate cancer cell, an ovarian cancer cell, or a breast cancer cell.

16. A method for treating a tumorMnk dependent condition in a mammal in need thereof comprising administering to the mammal (i) a therapeutically effective amount of at least one compound according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition of claim 13 wherein the mammal is suffering from a tumor.

17. The method of claim 14 , wherein the at least one cell is a cancer cell.