Herboxidiene antibody-drug conjugates and methods of use

An antibody-drug conjugate of Formula (I):

• Ab-(L-H)p (I)
• wherein:
• Ab is an antibody or antigen binding fragment which targets a neoplastic cell;
• H is a herboxidiene splicing modulator;
• L is a linker which covalently attaches Ab to H;
• and
• p is an integer from 1 to 15.

A compound comprising:

• or a pharmaceutically acceptable salt thereof, wherein:
• Y is chosen from O, S, NR6, and CR6R7;
• R1, R2, and R3 are each independently chosen from hydrogen, hydroxyl, —O—(C1-C6 alkyl) groups, —O—C(═O)—(C1-C6 alkyl) groups, —C(═O)—O—(C1-C6 alkyl) groups, and C1-C6 alkyl groups;
• R4 is chosen from hydrogen, C1-C6 alkyl groups, —C(═O)—(C1-C6 alkyl) groups, —C(═O)—(C3-C8 carbocyclyl) groups, —C(═O)—(C3-C8 heterocyclyl) groups, and —C(═O)—NR6R7;
• R5 is chosen from hydrogen, hydroxyl, —CH2—OH, —CO2H, —C(═O)—O—(C1-C6 alkyl) groups, —C(═O)—NR6R7, —NR6—C(═O)—R8, —O—C(═O)—NR6R7, —NR6—C(═O)—R8, and —NR6—C(═O)—NR6R7;
• R6 and R7 are each independently chosen from hydrogen, —R8, —C(═O)—R8, and —C(═O)—O—R8;
• and
• R8 is chosen from C1-C6 alkyl groups, C3-C8 carbocyclyl groups, and C3-C8 heterocyclyl groups,
• wherein R1, R2, R3, R4, R5, R6, R7, and R8 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl, C1-C6 alkyl groups, —O—(C1-C6 alkyl) groups, —CO2H, —C(═O)—(C1-C6 alkyl) groups, —C(═O)—(C3-C8 carbocyclyl) groups, —C(═O)—(C3-C8 heterocyclyl) groups, —NR6R7, C3-C8 carbocyclyl groups, C1-C6 alkylhydroxy groups, C1-C6 alkylalkoxy groups, benzyl groups, and C3-C8 heterocyclyl groups, each of which may be independently substituted with 0 or 1 group chosen from halogens, hydroxyl, C1-C3 alkyl groups, C1-C3 alkoxy groups, C1-C3 haloalkyl groups, —NH—C(═O)(C1-C3 alkyl), and —NH—C(═O)—O—(C1-C3 alkyl).