Inhibitors of immune checkpoint modulators and related methods

A method of inducing or enhancing an immune response, comprising administering a therapeutically effective amount of a MNK-specific inhibitor and an inhibitor of an immunosuppression component to a subject in need thereof, thereby inducing or enhancing an immune response, wherein the inhibitor of an immunosuppression component is an antibody specific for PD-1, PD-L1, CLA4, or a combination thereof, wherein

• a) the antibody specific for PD-1 is pidilizumab, nivolumab, pembrolizumab, MK-3475, or any combination thereof,
• b) the antibody specific for PD-L1 is MDX-1105, BMS-936559, durvalumab (MEDI4736), atezolizumab (MPDL3280A), MSB0010718C, or any combination thereof;
• and
• c) the antibody specific for CTLA4 is tremelimumab, ipilimumab, or both,
• wherein, wherein the MNK-specific inhibitor has the following Formula (I):
• or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
• W1 and W2 are independently O, S or N—OR′, where R′ is lower alkyl;
• Y is N(R5), —O—, —S—, —C(O)—, —S═O, —S(O)2—, or —CHR9—;
• R1 is hydrogen, lower alkyl, cycloalkyl or heterocyclyl wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;
• n is 1, 2 or 3;
• R2 and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionally substituted with 1, 2 or 3 J groups;
• or R2 and R3 taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;
• R4a and R4b are each independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl;
• R5 is hydrogen, cyano, or lower alkyl;
• or R5 and R8 taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups;
• R6, R7 and R8 are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;
• or R7 and R8 taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups;
• J is —SH, —SR9, —S(O)R9, —S(O)2R9, —S(O)NH2, —S(O)NR9R9, —NH2, —NR9R9, —COOH, —C(O)OR9, —C(O)R9, —C(O)—NH2, —C(O)—NR9R9, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH2—C(O)-alkylene, NR9R9—C(O)-alkylene, —CHR9—C(O)-lower alkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkyl alkylene, cycloalkylalkenylene, cycloalkylcarbonyl aminyl, cycloalkyl aminyl, —CHR9—C(O)-cycl ° alkyl, —C(O)— cycloalkyl, —CHR9—C(O)-aryl, —CHR9-aryl, —C(O)-aryl, —CHR9—C(O)-heterocycloalkyl, —C(O)— heterocycloalkyl, heterocyclylaminyl, or heterocyclyl;
• or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo;
• and
• R9 is hydrogen, lower alkyl or —OH.