Macrocyclic EGFR Inhibitor, and Preparation Method Therefor and Pharmaceutical Use Thereof

A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:

• wherein
• X1 is CRa or N;
• X2 is CRb or N;
• X3 is CRc or N;
• X4 is CRd or N;
• L1 is CR5aR5b;
• L2 is (CR5cR5d)p, NR6a, O, S, S(O), S(O)2, or C(O);
• L3 is a bond, CR5eR5f, NR6b, O, S, S(O), S(O)2, or C(O);
• L2 and L3 together form a C4-12 cycloalkyl, 4-12 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, and the C4-12 cycloalkyl, 4-12 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl is independently optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• L4 is CR5gR5h, O, S, S(O), S(O)2, NR6c, or C(O);
• ring A is C4-12 cycloalkyl, 4-12 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl;
• R1 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R3)—C(O)R12, the above R1 groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C1-10 alkyl substituted by C3-12 cycloalkyl, C1-10 alkyl substituted by 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-N(R13)—S(O)2R10, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12, the above one or more substituents each optionally further substituted by one or more substitutents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-N(R1)—S(O)2R10, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• each R2 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R3)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14 and —C0-8 alkyl-N(R13)—C(O)R12, the above R2 groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)R10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R3)—C(O)R12;
• each R3, each Ra, and each Rb are independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• R4 and Rc are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• Rd is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)R10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• R5a and R5b are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R1)—C(O)R12, or, R5a and R5b, together with the carbon atom to which R5a and R5b are directly attached, form a C(O), C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, the above R5a and R5b groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R4, and —C0-8 alkyl-N(R13)—C(O)R12;
• each R5c and each R5d are independently selected form the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12, or, R5c and R5d, together with the carbon atom to which R5c and R5d are directly attached, form a C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, the above R5c and R5d groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R1)—C(O)R12, provided that when R5c or R5d is H or C1-4 alkyl, R1 is optionally substituted C2-10 alkynyl, or, L3 is O, S, S(O), or S(O)2;
• R5e and R5f are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)R10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12, or, R5e and R5f, together with the carbon atom to which R5e and R5f are directly attached, form a C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, the above R5e and R5f groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R2)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• R5g and R5h are each independently selected form the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12, or, R5g and R5h, together with the carbon atom to which R5g and R5h are directly attached, form a C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, or 5-10 membered heteroaryl, the above R5g and R5h groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-S(O)(═N—R7)R8, —C0-8 alkyl-N═S(O)R8R9, —C0-8 alkyl-N═SR8R9, —C0-8 alkyl-O—S(O)2R10, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)SR11, —C0-8 alkyl-S—C(O)R12, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-P(O)(R12)2, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• R6a is selected from the group consisting of hydrogen, deuterium, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, and —O—R11, above R6a groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, ═O, C1-4 alkyl, C1-4 haloalkyl, C1-4 deuteroalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, and —NR13R14;
• R6b is selected from the group consisting of hydrogen, deuterium, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl, 3-6 membered heterocyclyl, and —O—R11, the above R6b groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, ═O, C1-4 alkyl, C1-4 haloalkyl, C1-4 deuteroalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, and —NR13R14;
• R6c is selected from the group consisting of hydrogen, deuterium, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, and —O—R11, above R6c groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, ═O, C1-4 alkyl, C1-4 haloalkyl, C1-4 deuteroalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, and —NR13R14;
• each R7 is independently selected from the group consisting of hydrogen, deuterium, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)R12, or —C0-8 alkyl-C(O)NR13R14, the above R7 groups optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-S(O)R10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-(—C(O)R12, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R13)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, or —C0-8 alkyl-N(R13)—C(O)R12;
• each R8 and each R9 are independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or, R8 and R9, together with the sulfur atom to which R8 and R9 are directly attached, form a 3-10 membered heterocyclyl, the above R8 and R9 groups optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-S(O)rR10, —C0-8 alkyl-O—R11, —C0-8 alkyl-C(O)OR11, —C0-8 alkyl-C(O)R12, —C0-8 alkyl-O—C(O)R12, —C0-8 alkyl-NR13R14, —C0-8 alkyl-C(═NR13)R12, —C0-8 alkyl-N(R3)—C(═NR14)R12, —C0-8 alkyl-C(O)NR13R14, and —C0-8 alkyl-N(R13)—C(O)R12;
• each R10 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and —NR13R14, the above R10 groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and —NR13R14;
• each R11 is independently selected from the group consisting of hydrogen, deuterium, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, and the above R11 groups are each independently optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, ═O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and —NR13R14;
• each R12 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 member heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and —NR13R14, the above R12 groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, ═O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and —NR13R14;
• each R13 and each R14 are independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, and C1-10 alkanoyl, the above R13 and R14 groups each optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoC1-10 alkylamino, diC1-10 alkylamino, and C1-10 alkanoyl;
• or
• R13 and R14, together with the nitrogen atom to which they are directly attached, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, the 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally further substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuteroalkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, methanesulfonylmethyl, amino, monoC1-10 alkylamino, diC1-10 alkylamino, and C1-10 alkanoyl;
• m is 0, 1, 2, 3 or 4;
• n is 0, 1, or 2;
• p is 1 or 2;
• and
• each r is independently 0, 1, or 2.