Anticancer combination therapy with N-(1-acryloyl-azetidin-3-yl)-2-((1H-indazol-3-yl)amino)methyl)-1H-imidazole-5-carboxamide inhibitor of KRAS-G12C

A method of treating cancer comprising administering:

• (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof;
• and
• (b) an additional anti-cancer agent,
• to a subject in need of such treatment, the compound of Formula (I) being:
• wherein
• X is nitrogen or CH,
• R1 is selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C4-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 5- to 10-membered saturated heterocyclic group, and a 5- to 10-membered unsaturated heterocyclic group,
• R2 is selected from the group consisting of hydrogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 5- to 10-membered saturated heterocyclic group, and a 5- to 10-membered unsaturated heterocyclic group,
• L1 is —NH—C(Ra)2—, wherein Ras are identical or different, and each is a hydrogen atom, a deuterium atom, or C1-C6 alkyl,
• ring A is a substituted or unsubstituted 5-membered unsaturated heterocyclic group,
• one of A1, A2, and A3 is substituted or unsubstituted nitrogen or sulfur, and the rest of A1, A2, and A3 are identical or different, and are substituted or unsubstituted carbon, substituted or unsubstituted nitrogen, sulfur, or oxygen,
• when A1 is substituted carbon or substituted nitrogen, the substituent is at least one member selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl that may be substituted with Rb, C2-C6 alkenyl that may be substituted with Rb, C2-C6 alkynyl that may be substituted with Rb, C3-C10 cycloalkyl that may be substituted with Rc, C4-C10 cycloalkenyl that may be substituted with Rc, C6-C10 aromatic hydrocarbon that may be substituted with Rc, a 4- to 10-membered saturated heterocyclic group that may be substituted with Rc, and a 5- to 10-membered unsaturated heterocyclic group that may be substituted with Rc,
• Rb is selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, and a substituted or unsubstituted 5- to 10-membered saturated heterocyclic group,
• Rc is selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C20 aralkyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, C6-C10 aromatic hydrocarbon, a 5- to 10-membered saturated heterocyclic group, and a 5- to 10-membered unsaturated heterocyclic group,
• when two or more Rbs are present, the plurality of Rbs may be identical or different,
• when two or more Rcs are present, the plurality of Rcs may be identical or different,
• when A2 is substituted carbon or substituted nitrogen, the substituent is at least one member selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl,
• when A3 represents substituted carbon or substituted nitrogen, the substituent is at least one member selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl,
• L2 is
• is a 4- to 8-membered saturated heterocyclic group that contains at least one nitrogen atom, and that may contain 1 or 2 heteroatoms selected from sulfur and oxygen, in which N represents nitrogen,
• R3 is hydrogen or C1-C6 alkyl,
• R4 is selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, and C1-C6 hydroxyalkyl,
• when two or more R4s are present, the plurality of R4s may be identical or different,
• when two R4s are attached to the same carbon atom, and these two R4s each represent C1-C6 alkyl, then these two R4s, taken together with the carbon atom to which these two R4s are attached, may form a ring, and
• n is 0, 1, 2, or 3,
• L3 is —C(—O)— or —S(═O)2—, and
• R5 is substituted or unsubstituted C2-C6 alkenyl or substituted or unsubstituted C2-C6 alkynyl.