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

1. 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 (L 1 ) a -(L 2 ) b -(L 3 ) c via an amide, an N—(C 1-6 alkyl)amide, a carbamate, an N—(C 1-6 alkyl)carbamate, an amine, an N—(C 1-6 alkyl)amine, an ether, a thioether, an urea, an N—(C 1-6 alkyl)urea, or an N,N-di(C 1-6 alkyl)urea bond;

R is absent;

L 1 is selected from the group consisting of —O—, —C(O)—, —(CH 2 ) q —, —(CH 2 CH 2 O) p ,

L 2 is selected from the group consisting of —O—, —(CH 2 ) q —, —(CH 2 CH 2 O) p , and —NH(CH 2 ) 2 ;

L 3 is selected from the group consisting of —OC(O)—, —NHC(O)—, and —NCH 3 C(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.

2. The antibody-drug conjugate or pharmaceutically acceptable salt of claim 1 , wherein A is trastuzumab.

3. The antibody-drug conjugate or pharmaceutically acceptable salt of claim 1 , wherein the CTX is an auristatin, a calicheamicin, a maytansinoid, or a tubulysin.

4. The antibody-drug conjugate or pharmaceutically acceptable salt of claim 1 , wherein the CTX is monomethylauristatin E, monomethylauristatin F, calicheamicin γ, a pyrrolobenzodiazepine, mertansine, tubulysin T2, tubulysin T3, or tubulysin T4.

5. The antibody-drug conjugate or pharmaceutically acceptable salt of claim 1 , wherein CTX is bonded to (L 1 ) a -(L 2 ) b -(L 3 ) c via a bond selected from the group consisting of:

wherein each R B is independently branched or unbranched C 1-6 alkyl.