Methionine adenosyltransferase 2a (mat2a) inhibitor combinations and uses thereof

A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:

• (a) a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof:
• wherein:
• Â is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-10heteroaryl;
• Z1 is CR7 or N;
• Z2 is CR9 or N;
• Z3 is CR6 or N;
• Z4 is CR6a or N;
• X is selected from —N(R4)—, —O—, and —C(R5)(R5a)—;
• Y is selected from —N(R4a)—, —O—, and —C(R5)(R5a)—;
• R1 is selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R3, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(=NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15a;
• R1a and R1b are independently selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15a;
• each R2 and each R3 are each independently selected from hydrogen, halogen, oxo, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9 heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(=NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15b;
• or R2 and R3, together with the carbon to which they are attached, form a C3-6cycloalkyl or C2-9heterocycloalkyl;
• R4 is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• or R4 and an R3 are combined to form a C2-9heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• R4a is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9 heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• or R4a and an R3 are combined to form a C2-9heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• R5 and R5a are independently selected from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• or R5 and an R3 are combined to form a C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C2-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• R6, R7, R1, and R9 are independently selected from hydrogen, halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15c;
• R6a is selected from hydrogen, halogen, —CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R3, —S(O)2N(R10)(R11)—, —N═S(═O)(R3)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-10alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15c;
• each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• each R11 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
• or R10 and R11, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl;
• each R12 is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;
• each R13 is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, —CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;
• each R14 is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(RI), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from R15d;
• each R15a, R15b, R15c, and R15d are each independently selected from halogen, oxo, —CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, —CH2—C3-6cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, C1-9heteroaryl, —CH2—C1-9heteroaryl, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR11, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R11), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(R11), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11), —Si(C1-6alkyl)3, and —P(O)(R10)2, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, —CH2—C3-10cycloalkyl, C2-9heterocycloalkyl, —CH2—C2-9heterocycloalkyl, C6-10aryl, —CH2—C6-10aryl, —CH2—C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, —CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, —OR10, —SR10, —SF5, —N(R10)(R11), —C(O)OR10, —OC(O)N(R10)(R11), —N(R12)C(O)N(R10)(R1 l), —N(R12)C(O)OR13, —N(R12)S(O)2R13, —C(O)R13, —S(O)R13, —OC(O)R13, —C(O)N(R10)(R11), —C(O)C(O)N(R10)(R11), —N(R12)C(O)R13, —S(O)2R13, —S(O)2N(R10)(R11I)—, —N═S(═O)(R13)2, —S(═O)(═NH)N(R10)(R11), —S(═O)(═NH)C(R10)(RI), —S(═O)(═NR13)R13, —CH2C(O)N(R10)(R11), —CH2N(R12)C(O)R13, —CH2S(O)2R13, —CH2S(O)2N(R10)(R11) and —P(O)(R10)2;
• m is 0, 1, 2, 3, 4, or 5;
• and
• n is 0, 1, 2, 3, 4, 5, or 6;
• and
• (b) an additional agent,
• wherein the combined amount of the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.