MNK inhibitors and methods related thereto
The present invention relates to compounds according to Formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , W 1 , W 2 , Y and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula I compounds as well as methods for utilizing the compounds of Formula I and the pharmaceutically acceptable compositions of Formula I compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.
1. A process for preparing a compound according to 5a
comprising:
(a) contacting a compound of 1a
with a cyclohexanone to obtain a compound of 2a
(b) coupling a compound of 2a with a compound of 3a
in the presence of a metal catalyst, an inorganic base, and a phosphine ligand in a non-polar aprotic solvent to obtain compound (4a)
(c) reacting a compound of 4a in an aqueous base and organic solvent to obtain a compound of 5a
wherein:
X is halogen, -OTf, —B(OH) 2 or —B(OR′) 2 ,
R 4a is —H, halogen, —OH, —SH, hydroxyalkylene, —CN, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl; and
R′ is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.
2. The process according to claim 1 , further comprising reacting a compound of 5a with an acid to afford a pharmaceutically acceptable salt.
3. The process according to claim 2 , wherein the acid is HCl, sulfuric or methanesulfonic acid.
4. The process according to claim 1 , step a, wherein compound 1a is contacted with cyclohexanone in a non-polar organic solvent and an acid to obtain compound 2a.
5. The process according to claim 4 , wherein the acid is sulfuric or hydrochloric acid in an amount ranging from about 0.1 to 0.9 molar equivalents with respect to compound 1a.
6. The process according to claim 4 , wherein the non-polar organic solvent is 1,4-dioxane.
7. The process according to claim 4 , wherein the reaction temperature is between 90° C. and 105° C.
8. The process according to claim 1 , step b, wherein the metal catalyst is a palladium catalyst, the inorganic base is Cs 2 CO 3 , and the phosphine ligand is xantphos.
9. The process according to claim 8 , wherein the palladium catalyst is Pd 2 (dba) 3 or Pd(OAc) 2 .
10. The process according to claim 8 , wherein the non-polar aprotic solvent is 1,4-dioxane.
11. The process according to claim 8 , wherein the reaction temperature is between 90° C. and 105° C.
12. The process according to claim 1 , step c, wherein the aqueous base is KOH and the organic solvent is a mixture of ethanol, tetrahydrofuran and water.
13. The process according to claim 1 , wherein R 4a is alkyl.
14. The process according to claim 1 , wherein X is bromine.
15. The process according to claim 1 , wherein R′ is cycloalkyl.
16. Compound 1a or a stereoisomer or tautomer thereof:
wherein,
X is halogen, -OTf, —B(OH) 2 or —B(OR′) 2 , and
R 4a is —H, halogen, —OH, —SH, hydroxyalkylene, —CN, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl.
17. The compound according to claim 16 , wherein R 4a is alkyl and X is Br.
18. Compound 2a or a stereoisomer or tautomer thereof:
wherein:
X is halogen, -OTf, —B(OH) 2 or —B(OR′) 2 , and
R 4a is —H, halogen, —OH, —SH, hydroxyalkylene, —CN, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl.
19. The compound according to claim 18 , wherein R 4a is alkyl and X is Br.
20. The compound according to claim 19 , wherein R 4a is methyl.