Aryl pladienolides for the treatment of neoplastic disorders

A method for treating a subject having a neoplastic disorder or a subject suspected of having a neoplastic disorder, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of the following formula:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is:
• wherein R1 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C1-C6alkyl group, a C1-C6alkoxy group, a C3-C8 cycloalkyl group, a hydroxy-C1-C6alkyl group, N(CH3)2, and a methoxy-C1-C6 alkyl group;
• R2 is hydrogen, a C1-C6alkyl group, or an OR10 group;
• R3 is hydrogen, a C1-C6alkyl group, or an OR10 group;
• R4 is hydrogen, a C1-C6alkyl group, or an OR10 group;
• R5 is hydrogen, a C1-C6 alkyl group, or an OR10 group;
• R6 is hydrogen, a C1-C6 alkyl group, or an OR10 group;
• R7 is hydrogen, a C1-C6 alkyl group, or an OR10 group;
• V is —CH2— or —NR9—;
• W is a 3- to 8-membered carbocyclyl group or a 3- to 10-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 10-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, NR8R9, a C1-C6 alkyl group, a C1-C6 alkoxy group, a methoxy-C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, and a C3-C5 cycloalkyl group;
• each R8 is independently hydrogen or a C1-C6 alkyl group;
• each R9 is independently hydrogen or a C1-C6 alkyl group;
• each R10 is independently hydrogen, a C1-C6 alkyl group, a C1-C6 aminoalkyl group, a C1-C6 alkylamino group, a C1-C6 alkylcarboxylic acid group, a C3-C8 cycloalkyl group, a benzyl group, a C3-C8 heterocyclyl group, a CH2—C3-C8 heterocyclyl group, a C(O)—C3-C8 heterocyclyl group, an acyl group, a hydroxy-C1-C6 alkyl group, a methoxy-C1-C6 alkyl group, CD3, or C(O)—NR11R12;
• each R11 is independently hydrogen, a C1-C6 alkyl group, a C1-C6 aminoalkyl group, a C1-C6 alkylamino group, a C3-C8 cycloalkyl group, or a C3-C8 heterocyclyl group;
• each R12 is independently hydrogen, a C1-C6 alkyl group, a C1-C6 aminoalkyl group, a C1-C6 alkylamino group, a C3-C8 cycloalkyl group, or a C3-C8 heterocyclyl group;
• L1 is a bond, —O—, —C(O)—, —C(O)—O—, —NR13—C(O)—, —C(O)—NR13—, —NR13—S(O)2—, —S(O)2—NR13—, —S(O)2—, or —NR13—;
• X is a bond, a 3- to 8-membered carbocyclyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 8-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a methoxy-C1-C6 alkyl group, an S(O)2—C1-C6 alkyl group, and NR14R15;
• L2 is a bond, —O—, —C(O)—, —C(O)—O—, —NR13—C(O)—, —C(O)—NR13—, —NR13—S(O)2—, —S(O)2—NR13—, —S(O)2—, or —NR13—;
• Y is hydrogen, a 3- to 8-membered carbocyclyl group, or a 3- to 8-membered heterocyclyl group, wherein the 3- to 8-membered carbocyclyl group or the 3- to 8-membered heterocyclyl group is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, OH, a C1-C6 alkyl group, a hydroxy-C1-C6 alkyl group, a C1-C6 alkoxy group, a methoxy-C1-C6 alkyl group, a S(O)2—C1-C6 alkyl group, and NR14R15;
• each R13 is independently hydrogen or a C1-C6 alkyl group;
• each R14 is independently hydrogen or a C1-C6 alkyl group;
• each R15 is independently hydrogen or a C1-C6 alkyl group;
• n1 is 0, 1, 2, 3, or 4;
• n2 is 0, 1, 2, 3, or 4;
• n3 is 0, 1, 2, 3, or 4;
• and
• n4 is 0, 1, 2, 3, or 4;
• wherein administration of the therapeutically effective amount of the at least one compound or pharmaceutically acceptable salt thereof to the subject in need thereof:
• (i) induces at least one neoantigen;
• or
• (ii) induces a T-cell response;
• or
• (iii) induces at least one neoantigen and a T-cell response.