Linkers for antibody-drug conjugates and related compounds, compositions, and methods of use

An antibody-drug conjugate of the following formula (III):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• A is an antibody selected from the group consisting of alemtuzumab, anitumumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, glembatumumab, inotuzumab, ipilimumab, lovortumumab, milatuzumab, ofatumumab, rituximab, tositumomab, and trastuzumab;
• the two depicted cysteine residues are from an opened cysteine-cysteine disulfide bond in A;
• each X and X′ is O;
• W is —NH—;
• CTX is a releasable cytotoxin that is toxic to a cancer cell when released in the cancer cell and is selected from the group consisting of Actinomycin-D, Amonafide, an auristatin, benzophenone, benzothiazole, a calicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin, Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide, Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid, Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1), Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin, Bortezomib, and Vincristine;
• wherein CTX is bonded to (L1)a-(L2)b-(L3)c via an amide, an N—(C1-6alkyl)amide, a carbamate, an N—(C1-6 alkyl)carbamate, an amine, an N—(C1-6alkyl)amine, an ether, a thioether, an urea, an N—(C1-6alkyl)urea, or an N,N-di(C1-6alkyl)urea bond;
• R is absent;
• L1 is selected from the group consisting of —O—, —C(O)—, —(CH2)q—, —(CH2CH2O)p,
• L2 is selected from the group consisting of —O—, —(CH2)q—, —(CH2CH2O)p, and —NH(CH2)2;
• L3 is selected from the group consisting of —OC(O)—, —NHC(O)—, and —NCH3C(O)—;
• a, b and c are each independently 0, 1, or 2, provided that at least one of a, b or c is 1;
• k is 1 and k′ is 0;
• each p is independently an integer of 1 to 14;
• each q is independently an integer or 1 to 12;
• m is an integer of 1 to 4;
• n is an integer of 1 to 4;
• and
• the bond represents a single bond.