Heterocyclic acyl hydrazone linkers, methods and uses thereof

A compound of Formula (II) or a pharmaceutically acceptable salt or solvate thereof:

• wherein:
• R2 is selected from H, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• R3 and R4 are independently selected from H, CN, NO2, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• X is selected from O, S and NR19;
• W is selected from O, NR11, S, and S(O)2;
• R6, R7, R8, R9, R10, and R11 are independently selected from H, C1-6alkyl and C1-6fluoroalkyl;
• L1 and L2 are independently a linker moiety selected from Ra, Z—Ra, Ra—Z, Ra—Z—Rb and Z—Ra—Za, wherein Z and Za are independently selected from O, S, S(O), SO2, NH, N(C1-6alkyl), C(Q), C(Q)Y, YC(Q), YC(Q)Ya, (YC1-6alkylene)p, (C1-6alkyleneY)p and Y—(C1-6alkyleneY)p, wherein Ra and Rb are independently selected from C1-10alkylene, C2-10alkenylene and C2-10alkynylene;
• Q, Y and Ya are independently selected from O, S, NH and N(C1-6alkyl);
• and p is selected from 1, 2, 3, 4, 5 and 6;
• n is 0, 1, 2 or 3;
• and
• R12 and R13 are different and are independently selected from a fluorescent dye, drug, antibody, nucleic acid, peptide, radiolabel, PET label, nanoparticle, metal complex.

A compound of Formula IV or a pharmaceutically acceptable salt or solvate thereof:

• wherein
• R2 is selected from H, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• R3 and R4 are independently selected from H, CN, NO2, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• X is selected from O, S and NR10;
• W is selected from O, NR11, S, and S(O)2;
• R6, R7, R8, R9, R10, and R11 are independently selected from H, C1-6alkyl and C1-6fluoroalkyl;
• L1 and L2 are independently a linker moiety selected from Z, Ra, Z—Ra, Ra—Z, Ra—Z—Rb and Z—Ra—Za, wherein Z and Za are independently selected from O, S, S(O), SO2, NH, N(C1-6alkyl), C(Q), C(Q)Y, YC(Q), YC(Q)Ya, (YC1-6alkylene)p, (C1-6alkyleneY)p and Y—(C1-6alkyleneY)p, wherein Ra and Rb are independently selected from C1-10alkylene, C1-10alkenylene and C2-10alkynylene;
• Q, Y and Ya are independently selected from O, S, NH and N(C1-6alkyl);
• and p is selected from 1, 2, 3, 4, 5 and 6;
• n is 0, 1, 2 or 3;
• and
• one of R16 and R17 is a reactive functional group selected a Michael addition acceptor, C2-6alkenyl, C2-6alkynyl, OH,
• OC1-6alkyl, halo, C(O)H, C(O)C1-6alkyl, COOH, COOC1-6alkyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, SH, SC1-6alkyl, C(O)NH2, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)2, OCN, NCO, SCN, NCS, NHNH2, C═NNH2, C(O)NHNH2, C═N2, NO2, CN, S—S(C1-6alkyl), S(O)C1-6alkyl, SO2C1-6alkyl, SO2H, S(O)OH, C(O)OC(O)C1-6alkyl, S(O)H, N≡C, C(O)NHC(O)C1-6alkyl, C(NH)OC1-6alkyl, NHOH, C═(NOH)H, C(NOH)alkyl, C(O)NHOH, C(S)NHOH, C(OC1-6alkyl)3,
• NHC(O)NH2, NHC(O)NHNH2, OC(O)NH2, OC(O)NHC1-6alkyl, OC(O)N(C1-6alkyl)2, C(NH)C1-6alkyl, N3, and N═NC1-6alkyl, and the other of R16 and R17 is selected from a fluorescent dye, drug, antibody, nucleic acid, peptide, radiolabel, PET label, nanoparticle, and metal complex.

An antibody-drug conjugate comprising an antibody covalently attached by a linker to one or more drugs, the conjugate having a Formula (III):

• or a pharmaceutically acceptable salt or solvate thereof, wherein
• R14 is an antibody;
• R15 is a drug;
• L1 and L2 are independently a linker moiety selected from Ra, Z—Ra, Ra—Z, Ra—Z—Rb and Z—Ra—Za, wherein Z and Za are independently selected from O, S, S(O), SO2, NH, N(C1-6alkyl), C(Q), C(Q)Y, YC(Q), YC(Q)Ya, (YC1-6alkylene)p, (C1-6alkyleneY)p and Y—(C1-6alkyleneY)p, wherein Ra and Rb are independently selected from C1-10alkylene, C2-10alkenylene and C2-10alkynylene;
• Q, Y and Ya are independently selected from O, S, NH and N(C1-6alkyl);
• and p is selected from 1, 2, 3, 4, 5 and 6;
• R2 is selected from H, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• R3 and R4 are independently selected from H, CN, NO2, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR7 and NR8R9;
• W is selected from O, NR11, S, and S(O)2;
• R6, R7, R8, R9, and R11 are independently selected from H, C1-6alkyl and C1-6fluoroalkyl;
• n is 0, 1, 2 or 3;
• and
• m is an integer from 1 to 20.

A method of preparing an ADC of Formula (III) of claim comprising:

• (a) reacting a compound of Formula (I):
• wherein:
• R1 and R5 are independently a reactive functional group selected from a Michael addition acceptor, C2-6alkenyl, C2-6alkynyl, OH,
• OC1-6alkyl, halo, C(O)H, C(O)C1-6alkyl, COOH, COOC1-6alkyl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, SH, SC1-6alkyl, C(O)NH2, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)2, OCN, NCO, SCN, NCS, NHNH2, C═NNH2, C(O)NHNH2, C═N2, NO2, CN, S—S(C1-6alkyl), S(O)C1-6alkyl, SO2C1-6alkyl, SO2H, S(O)OH, C(O)OC(O)C1-6alkyl, S(O)H, N≡C, C(O)NHC(O)C1-6alkyl, C(NH)OC1-6alkyl, NHOH, C═(NOH)H, C(NOH)alkyl, C(O)NHOH, C(S)NHOH, C(OC1-6alkyl)3,
• NHC(O)NH2, NHC(O)NHNH2, OC(O)NH2, OC(O)NHC1-6alkyl, OC(O)N(C1-6alkyl)2, C(NH)C1-6alkyl, N3, and N═NC1-6alkyl,
• R2 is selected from H, halo, C1-6alkyl, C1-6fluoroalkyl, OR6, SR6 and NR6R7;
• R3 and R4 are independently selected from H, CN, NO2, halo, C1-6alkyl, C1-6fluoroalkyl, OR8, SR8 and NR8R9;
• X is selected from 0, S and NR19;
• W is selected from O, NR11, S, and S(O)2;
• R6, R7, R8, R9, R19, and R11 are independently selected from H, C1-6alkyl and C1-6fluoroalkyl;
• L1 and L2 are independently a linker moiety selected from Z, Ra, Z—Ra, Ra—Z, Ra—Z—Rb and Z—Ra—Za, wherein Z and Za are independently selected from O, S, S(O), SO2, NH, N(C1-6alkyl), C(Q), C(Q)Y, YC(Q), YC(Q)Ya, (YC1-6alkylene)p, (C1-6alkyleneY)p and Y—(C1-6alkyleneY)p, wherein Ra and Rb are independently selected from C1-10alkylene, C2-10alkenylene and C2-10alkynylene;
• Q, Y and Ya are independently selected from O, S, NH and N(C1-6alkyl);
• and p is selected from 1, 2, 3, 4, 5 and 6;
• and
• n is 0, 1, 2 or 3,
• with a drug to provide a Formula (I)-drug conjugate;
• (b) reacting the Formula (I)-drug conjugate with an antibody to provide the ADC of Formula (III);
• and optionally
• (c) purifying the ADC of Formula (III).