Antifolate linker-drugs and antibody-drug conjugates

An antibody-drug conjugate of formula (III),

• Ab-(L-D)y (III),
• wherein Ab is an antibody or an antigen-binding fragment thereof,
• L-D represents the residue of a conjugated linker-drug compound according to formula (I)
• wherein
• R1 is O, NH2 or OH;
• R2 and R2′ are independently N, CH, CMe, C-Et, C-ethyn, C-vinyl, C—CN, C—OH, C—OMe, C—SH, C—SMe, C-halogen, C—CHal3, C—CHHal2, or C—CH2Hal, wherein Hal is halogen;
• R3 is O, S, NH, N(C1-5 alkyl), N(C2-4 alkenyl), N(C2-4 alkynyl), N—CH2CN, N—CH2CH2Hal, CH2, CH(C1-5 alkyl), CH(C2-4 alkenyl), CH(C2-4 alkynyl), CH(C1-4 alkoxyl), CH—CH2CN, or CH—CH2CH2Hal, wherein Hal is halogen;
• R4 is H, halogen, —COOH, OH, NH2, —CONH2, —CONHR, —CONR2, C1-4 alkyl, C1-4 alkoxyl, benzyloxy, tetrazole, —SO3H, —NSO3H, —OSO3H, —PO3H2, —NPO3H2, —OPO3H2, —CN, or azido, wherein R is selected from H and C1-5 alkyl, or R4 is a carboxylic acid bioisostere selected from the group consisting of
• wherein Ra′ is selected from H, CH2F, CHF2, CF3, and C1-6 alkyl, each Ra is independently selected from H, F, CH2F, CHF2, CF3, and C1-6 alkyl, and two Ra substituents can optionally be joined forming a ring;
• R5 is H, halogen, NH2, OH, SH, CF3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyl, or C1-4 alkylthio, or R3 and R5 are optionally being joined by one or more bonds to form an optionally substituted carbocycle or heterocycle;
• R6 is H, C1-4 alkyl, C2-4 alkenyl, C3-6 cycloalkyl;
• R7 is H or F;
• n is 1, 2, 3, or 4;
• Q is either absent, —N(R8)—(C═O)—, —(C═O)—N(R8)—, —CH2N(R8)—, —N(R8)CH2—, —N(R8)SO2—, or —SO2N(R8)—, wherein R8 is H, C1-4 alkyl, C1-4 alkenyl, or C1-4 alkynyl, or
• Q is an amide bond bioisostere selected from the group consisting of
• wherein Rb is selected from H and C1-5 alkyl, T1, T1′ and T1″ are independently selected from CH and N, and W1, W1′ and W1″ are independently selected from C, CH, S, N, NH, N(C1-5 alkyl) and O;
• V is an aryl, heteroaryl, heterocycle, or cycloalkane that is optionally substituted with one or more R4-groups and is independently selected from
• wherein U1, U1′, U1″, U2, U2′, U2″ and U2″′ are independently selected from C, CH, S, N, NH, N(C1-5 alkyl) and O, or V is selected from the group consisting of
• wherein Z is 0, S, NH or NRc, and Rc is selected from H and C1-5 alkyl;
• s is 0 or 1;
• W is an aryl or heteroaryl that is optionally substituted with one or more R5-groups;
• X is a connecting group selected from O, NH, S, C1-5 alkylene, C1-5 alkenylene and C1-5 alkynylene;
• k is 1, 2, 3 or 4;
• L is a linker moiety;
• means that the indicated bond may be a single bond or a non-cumulated, optionally delocalized, double bond;
• and
• y represents an average drug-to-antibody ratio of from 1 to 16.