Combination therapy comprising a mat2a inhibitor and a type ii prmt inhibitor

A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a methionine adenosyltransferase II alpha (MAT2A) inhibitor and administering to the subject an effective amount of PRMT5 inhibitor, wherein the PRMT5 inhibitor is a compound of Formula III:

• or a pharmaceutically acceptable salt thereof;
• wherein
• R1 is hydrogen, halogen, hydroxyalkyl, -L-CN, —Y—C1-C5alkyl, —Y-cycloalkyl, —Y-heterocyclyl, —Y-aryl, —Y-arC1-C3alkyl or —Y-heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl portions are each optionally substituted with one or more R2;
• each Y is independently a bond or —NR4—;
• each R2 is independently hydroxy, halogen, cyano, cyanomethyl, —(NR4)2, hydroxyalkyl, alkoxy, —SO2C1-C3alkyl, —X-arC1-C3alkyl, heteroalkyl, C2-C4 alkynyl, —X-haloalkyl, —X—C1-C5 alkyl, —Z—C1-C5 alkyl, heterocyclyl, —X-L-cycloalkyl, —Z-cycloalkyl, —X-aryl, —Z-aryl, or —X-heteroaryl, wherein the heterocyclyl, the cycloalkyl, the aryl and the heteroaryl are optionally substituted with one or more R5;
• each X is independently a bond, O, S, —NR4— or —NR4C(O)—
• each Z is independently a bond, —SO—, —SO2—, —CH(OH)— or —C(O)—;
• each L is independently a bond or C1-C3 alkylene;
• R3a and R3b are each independently hydrogen or deuterium, or R3a and R3b together are oxo;
• each R4 is independently hydrogen or C1-C3 alkyl;
• each R5 is independently cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, —X-haloalkyl, —Z-cycloalkyl, —X-arC1-C3alkyl, X-ar C1-C3alkyl substituted with cyano —X-L-cycloalkyl, —X-L-heteroaryl optionally substituted with one or more C1-C3alkyl or oxo, or —X-aryl;
• and
• R6 is hydrogen, halogen, C1-C3 alkyl, haloalkyl or alkoxy.