Compound comprising self-immolative group and ligand-drug conjugate comprising same

A ligand-drug conjugate represented by Formula 2 below, or a pharmaceutically acceptable salt thereof:

• in Formula 2,
• E is an antibody;
• A′ is a divalent linking group derived from the binding functional group of A;
• the E-A′ binding structure in Formula 2 includes
• wherein * is the remaining moiety of the antibody;
• n is a real number from 1 to 10;
• and
• wherein:
• L1 is a divalent or multivalent linking group, wherein (i) L1 is —(CH2)na—;
• —(CH2CH2O)ma—;
• —(CH2OCH2)mb—;
• —(OCH2CH2)mc—;
• —C(═O)—;
• or a combination thereof, and Rd is H or C1-8 alkyl, and na, ma, mb and me are each independently an integer from 0 to 10 or (ii) L is a C1-20 alkylene optionally substituted with a divalent or multivalent functional group selected from the group consisting of amide, sulfonamide, amino, ether, carbonyl, triazole, tetrazole, and sulfo ester in the middle of the C1-200 alkylene chain;
• k is 0 or 1, and j is 1 to 10;
• A is absent, H or a binding functional group, wherein the binding functional group is selected from the group consisting of OH C1-8 alkoxy, carboxy, C1-8 alkoxycarbonyl, amino, mono-C1-8 alkylamino, N3, maleimidyl,
• and C2-8 alkynyl;
• and
• U is a moiety represented by Formula A below:
• in Formula A,
• R1 and R2 are each independently H or C1-8 saturated or unsaturated hydrocarbyl;
• PL is an active agent linked to L2 or the carbon atom to which R1 and R2 are bound by a heteroatom selected from N, O and S;
• L2 is a self-eliminating linker selected such that cleavage of the bond between L2 and the carbon atom to which R1 and R2 are bound promotes cleavage of the bond between L2 and PL, wherein L2 is selected from the group consisting of —OC(═O)—, —S(═O)2—, and
• and
• R11 and R12 are each independently H, C1-8 alkyl, amino-C1-8 alkyl, C1-8 alkyl substituted with mono- or di-(C1-8 alkyl)amino, or —(CH2CH2O)gR13, wherein
• R13 is H or C1-4 alkyl, and g is an integer from 1 to 10;
• one of Z1 and Z3 is selected from the group consisting of N, NR3, O, S and Se, and the other one of Z1 and Z3 and Z2 are each independently CH or N, and -(L1)k-A, and if present -(V)h, each independently replace H of NH or CH;
• represents a bond with A-(L1)k-;
• R3 is H or C1-8 hydrocarbyl;
• V is an electron withdrawing group or an electron donating group;
• T is a triggering group capable of initiating the release of PL, and if present L2, by a 1,6-elimination reaction upon cleavage;
• L3 is an optional self-immolative spacer group that is cleaved sequentially upon cleavage of T, if present;
• and
• h, i, 1, x and y are each independently 0 or 1;
• -(Y)y-T is selected from the group consisting of moieties represented by
• wherein
• may include a form in which the —OH group is protected by a protecting group or substituted with a substituent;
• R5 is OH, mono-C1-8 alkylamino, di-C1-8 alkylamino or —NH(CH2CH2O)fRt6, wherein Rt6 is H or C1-4 alkyl;
• and
• f is an integer from 1 to 10, and r and s are each an integer from 1 to 5;
• and
• -(X)x-L3- is
• or —O—CH2—, and
• R8 and R9 are each independently selected from the group consisting of H, halogen, C1-8 alkyl, CN and NO2, and o is an integer from 0 to 2.