Heterocyclic compounds that inhibit the kinase activity of Mnk useful for treating various cancers
The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula IA or Formula IB, as well as stereoisomers, tautomers or pharmaceutically acceptable salts thereof. For Formula IA and Formula IB compounds A 1 , A 2 , A 3 , A 4 , W 1 , W 2 , Y, X, R 1 , R 2 , R 3 , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 , R 9 , R 9a , R 9b , R 10 and subscript n are as defined in the specification. The inventive Formula IA and Formula IB compounds are inhibitors of Mnk and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
1. A compound according to Formula IA,
or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof wherein:
W 1 and W 2 each are O;
Y is —NR 8 ;
n is 1;
R 1 and R 2 independently are H, (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 is hydrogen or lower alkyl;
R 4a is hydrogen, halogen, or (C 1 -C 8 )alkyl;
R 4b is hydrogen;
R 8 is —H;
X is selected from the following table:
wherein * indicates the point of attachment of variable “X” to variable “Y”; and
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 , oxo, —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.
2. The compound according to claim 1 wherein at least one of R 1 or R 2 is a halogen substituted (C 1 -C 8 )alkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkylene, cycloalkylalkylene, heterocyclylalkylene or heteroaryl alkyl ene.
3. The compound according to claim 1 wherein R 1 and R 2 together with the respective carbon atom to which they are attached form a cycloalkyl that is selected from cyclobutyl, cyclopentyl, cyclohexyl, 2,2-dimethylcyclobutyl, 4-aminocyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 2,2-difluoroethyl-4-cyclohexyl, 4,4-difluorocyclohexyl, 4-cyano-cyclohexyl, 4-trifluoromethylcyclohexyl, 4-hydroxycyclohexyl, 3-hydroxycyclopentyl, 3-aminocyclopentyl and 3-methylcyclopentyl.
4. The compound according to claim 1 selected from
5. 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.