Conjugates of quaternized tubulysin compounds

A Ligand Drug Conjugate compound of Formula 1A:

• wherein
• L is an antibody Ligand Unit;
• LB is a Ligand Covalent Binding Unit;
• LP is a Parallel Connector Unit;
• PEG is a Polyethylene Glycol Unit;
• subscript a is 0 or 1;
• subscript b is 0 or 1;
• A is a first optional Stretcher Unit so that subscript a is 0 when A is absent or A is present so that subscript a is 1 and optionally comprises two, three or four independently selected subunits (A1, A2, A3, A4);
• B is a Branching Unit or a second optional Stretcher Unit (AO) so that subscript b is 0 when B is absent or B is present so that subscript b is 1 and optionally comprises two, three or four subunits independently of A;
• subscript n is 1, 2, 3 or 4, provided that subscript b is 1 and B is a Branching Unit when subscript n is 2, 3 or 4 and provided that B is AO or is absent when subscript n is 1;
• Su is a carbohydrate moiety;
• —O′— represents an oxygen atom of an O-glycosidic bond cleavable by a glycosidase;
• -J′- represents a heteroatom, optionally substituted when nitrogen, from a functional group of B, when B is present, or LB, when B is absent;
• wherein two of V, Z1, Z2 and Z3 are each ═C(R24)—, wherein one R24 is C(R8)(R9)-D+ so that the indicated C(R8)(R9)-D+ moiety is bonded to one of V, Z1, Z2, Z3 and the other R24 is —O′-Su so that the indicated —O′-Su moiety is bonded to another one of V, Z1, Z2, Z3,
• provided the —O′Su and —C(R8)(R9)-D+ moieties are ortho or para to each other;
• and
• wherein the remainder of V, Z1, Z2 and Z3 are each ═C(R24)—, wherein each R24 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, and halogen, —NO2, —CN and other electron withdrawing groups;
• one of R8 and R9 is hydrogen and the other is hydrogen, alkyl, alkenyl or alkynyl, optionally substituted, or aryl or heteroaryl, optionally substituted;
• R′ is hydrogen or is halogen, —NO2, —CN or other electron withdrawing group;
• D+ is a quaternized tubulysin Drug Unit having the structure of:
• wherein the circle represents a 5-membered nitrogen-containing heteroarylene and wherein the indicated required substituents to that heteroarylene are in a 1,3-relationship with each other with optional substitution at the remaining positions;
• subscript m is 1;
• R2A is hydrogen or optionally substituted alkyl, or R2A along with the oxygen atom to which it is attached defines an O-linked substituent;
• R3 is hydrogen or optionally substituted alkyl;
• R4, R5 and R6 are independently optionally substituted alkyl;
• one R7 is an optionally substituted alkyl, an optionally substituted arylalkyl, or an optionally substituted heteroarylalkyl, and the other R7 is hydrogen or an optionally substituted alkyl;
• and
• subscript p′ is an integer ranging from 1 to 24;
• and
• wherein the wavy line indicates covalent bonding of D+ to the remainder of the Ligand Drug Conjugate compound structure and wherein each optionally substituted alkyl is independently selected, and
• wherein cleavage of said O-glycosidase bond results in release of a tubulysin compound (D) from the Ligand Drug Conjugate compound, wherein the tubulysin compound so released is a tubulin disrupting agent.