Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applications

A compound of Formula (III):

• or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
• or
• a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R1 is selected from the group consisting of
• each X is independently CH2 or C(═O);
• RZ is —NR7aR8a or ring A;
• and ring A is C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more RA;
• R2 is H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• R3a, R3b, R3c, R3d, R3e, and R3f are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR11b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R3g is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R4 is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl;
• each R5 is independently H, deuterium, C1-C6 alkyl,
• each R6a, R6b, R6c, R6d, R14, and R15 is independently H, substituted or unsubstituted amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C3-C8 carbocyclyl;
• or R6a and R6b together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• or R6′ and R6d together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• wherein each C3-C8 carbocyclyl is optionally substituted with one or more RB;
• each R7a, R7b, R7c, R7d, R7e, R8a, R8b, R8c, R16, and R17 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C14 aralkyl, or optionally substituted C3-C8 carbocyclyl;
• or R7a and R8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7b and R8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7c and R8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R16 and R17 together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• wherein each of C6-C10 aryl, C7-C14 aralkyl, C3-C8 carbocyclyl, and 3 to 7 membered heterocyclyl is optionally substituted with one or more RB;
• each R9 is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each of R10a, R10b, R12, and R13 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each R11a, R11b, R11c, and R11d is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each RA is independently halogen, cyano, nitro, hydroxyl, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more RB;
• each RB is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, halogen, or cyano;
• or two geminal RB form oxo;
• m is an integer of 0, 1, 2, 3, 4, or 5;
• n1 is an integer of 0, 1, 2, or 3;
• each p is independently an integer of 0, 1, or 2;
• and
• each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

A compound of Formula (IV):

• or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
• or
• a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R1 is selected from the group consisting of
• each X is independently CH2 or C(═O);
• RZ is —NR7aR8a or ring A;
• and ring A is C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more RA;
• R2 is H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• R3a, R3b, R3c, R3d, R3e, and R3f are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR11b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R3g is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R4 is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl;
• each R5 is independently H, deuterium, C1-C6 alkyl,
• each R6a, R6b, R6, R6d, R14, and R15 is independently H, substituted or unsubstituted amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C3-C8 carbocyclyl;
• or R6a and R6b together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• or R6c and R6d together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• wherein each C3-C8 carbocyclyl is optionally substituted with one or more RB;
• each R7a, R7b, R7c, R7d, R7e, R8a, R8b, R8c, R16, and R17 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C14 aralkyl, or optionally substituted C3-C8 carbocyclyl;
• or R7a and R8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7b and R8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7c and R8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R16 and R17 together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• wherein each of C6-C10 aryl, C7-C14 aralkyl, C3-C8 carbocyclyl, and 3 to 7 membered heterocyclyl is optionally substituted with one or more RB;
• each R9 is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each of R10a, R10b, R12, and R13 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each R11a, R11b, R11c, and R11d is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted —C3-C8 carbocyclyl;
• each RA is independently halogen, cyano, nitro, hydroxyl, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more RB;
• each RB is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, halogen, or cyano;
• or two geminal RB form oxo;
• m is an integer of 0, 1, 2, 3, 4, or 5;
• n1 is an integer of 0, 1, 2, or 3;
• each p is independently an integer of 0, 1, or 2;
• and
• each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

A compound of Formula (V):

• or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
• or
• a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;
• wherein:
• R1 is selected from the group consisting of
• each X is independently CH2 or C(═O);
• RZ is —NR7aR8a or ring A;
• and ring A is C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more RA;
• R2 is H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• R3a, R3b, R3c, R3d, R3e, and R3f are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R3g is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;
• each R4 is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl;
• each R5 is independently H, deuterium, C1-C6 alkyl,
• each R6a, R6b, R6, R6d, R14, and R15 is independently H, substituted or unsubstituted amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C3-C8 carbocyclyl;
• or R6a and R6b together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• or R6′ and R6d together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• wherein each C3-C8 carbocyclyl is optionally substituted with one or more RB;
• each R7a, R7b, R7c, R7d, R7e, R8a, R8b, R8c, R16, and R17 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C14 aralkyl, or optionally substituted C3-C8 carbocyclyl;
• or R7a and R8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7b and R8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7c and R8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R16 and R17 together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• wherein each of C6-C10 aryl, C7-C14 aralkyl, C3-C8 carbocyclyl, and 3 to 7 membered heterocyclyl is optionally substituted with one or more RB;
• each R9 is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each of R10a, R10b, R12, and R13 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each R11a, R11b, R11c, and R11d is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each RA is independently halogen, cyano, nitro, hydroxyl, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more RB;
• each RB is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, halogen, or cyano;
• or two geminal RB form oxo;
• m is an integer of 0, 1, 2, 3, 4, or 5;
• n1 is an integer of 0, 1, 2, or 3;
• each p is independently an integer of 0, 1, or 2;
• and
• each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

A compound of Formula (IIa), (IIb), or (IIc):

• or a pharmaceutically acceptable salt thereof, wherein:
• each n is independently an integer of 0, 1, or 2;
• one of R1 and R2 is selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted 3 to 10 membered heterocyclyl, and optionally substituted 5 to 10 membered heteroaryl;
• and the other of R1 and R2 is
• each R3g is independently H, deuterium, C1-C6 alkyl,
• each R4 is independently H, deuterium, halogen, or optionally substituted C1-C6 alkyl;
• L is
• Z1 is C(═O), C(═NH), S(O)2 or (CH2)k;
• Z2 is a bond, S, O, or NH;
• Z3 is C(═O) or S(O)2;
• ring A is C6-C10 aryl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more RA;
• each of Ra1, Ra2, and Ra3 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C14 aralkyl, or optionally substituted C3-C8 carbocyclyl;
• each Rb1, Rb2, Rc1, and Rc2 is independently H, hydroxyl, substituted or unsubstituted amino, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C3-C8 carbocyclyl;
• or Rb1 and Rc1 together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• or Rb2 and Rc2 together with the carbon atom to which they are attached form a C3-C8 carbocyclyl;
• wherein each C3-C8 carbocyclyl is optionally substituted with one or more RB;
• each R5a, R5b, R10a, and R10b is independently H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each of R6a and R6b is independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C3-C8 carbocyclyl;
• each R7a, R7b, R7c, R7d, R7e, R8a, R8b, R8c, R7, and R8 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C14 aralkyl, or optionally substituted C3-C8 carbocyclyl;
• or R7a and R8a together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7b and R8b together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• or R7c and R8c together with the nitrogen atom to which they are attached form optionally substituted 3 to 7 membered heterocyclyl;
• wherein each of C6-C10 aryl, C7-C14 aralkyl, C3-C8 carbocyclyl, or 3 to 7 membered heterocyclyl is optionally substituted with one or more RB;
• each R9 is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each R11a, R11b, R11c, and R11d is independently optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C7-C14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C3-C8 carbocyclyl;
• each RA is independently halogen, cyano, nitro, hydroxyl, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —(CH2)t—NR7aR8a, —O(CH2)t—NR7aR8a, —C(O)NR7bR8b, —S(O)2NR7cR8c, —OR9, —SR10a, —C(O)OR10b, —C(O)R11a, —NR7dC(O)R11b, —S(O)2R11c, —NR7eS(O)2R11d, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5 to 10 membered heteroaryl, C3-C8 carbocyclyl, and 3 to 10 membered heterocyclyl is optionally substituted with one or more RB;
• each RB is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, —O(C1-C6 alkoxy)C1-C6 alkyl, halogen, or cyano;
• or two geminal RB form oxo;
• m1, m2, m3, and m4 are each independently an integer of 0, 1, 2, 3, 4 or 5;
• k is an integer of 1, 2, 3, 4, 5 or 6;
• and
• each t is independently an integer of 0, 1, 2, 3, 4, or 5;
• provided that:
• when, in Formula (IIa), one of R1 or R2 is H, n is 1 or 2, R3 is H, R4 is H, L is —CH2—NH—C(═O)—NH—CH2— or —CH2—NH—C(═O)—NH—*, then ring A is not 3-chloro-4-methylphenyl, wherein the symbol “*” indicates the attachment point to ring A;
• when, in Formula (IIb), R is H, n is 1 or 2, R3 is H, R4 is H, L is —NH—C(═O)—CH2—*, —CH2—NH—C(═O)—CH2—*, or —CH2—NH—C(═S)—NH—*, then ring A is not 3-chloro-4-methylphenyl, wherein the symbol “*” indicates the attachment point to ring A;
• when, in Formula (IIb), R1 is H, n is 1 or 2, R3 is H, R4 is H, L is —NH—C(═O)—NH—, —CH2—NH—C(═O)—NH—CH2—, or —CH2—NH—C(═O)—NH—*, then ring A is not any of 3-chloro-4-methylphenyl, 4-methyl-3-isopropylphenyl, 3-chloro-4-methyl-5-isopropylphenyl, 3-chloro-4,6-dimethylphenyl, 4-methyl-3-trifluoromethylphenyl, 3-chloro-4-trifluoromethylphenyl, 6-chloro-5-methylpyrid-2-yl, and 2-methylpyrid-5-yl, wherein the symbol “*” indicates the attachment point to ring A;
• and
• when, in Formula (ac), R1 is H, n is 1, R3 is H, R4 is H, L is —CH2—NH—C(═O)—NH—*, then ring A is not 3-chloro-4-methylphenyl, wherein the symbol “*” indicates the attachment point to ring A.