Hydrophilic self-immolative linkers and conjugates thereof

A compound of the formula (II):

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• T is a targeting moiety;
• R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• and
• A is an acyl unit.

A method of preparing Compound X:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• and
• A is an acyl unit;
• and
• R1 is NO2 or NH2;
• comprising reacting Compound W:
• A-L4-L3-L2;
• and Compound I:

A method of preparing Compound Z:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• and
• A is an acyl unit
• R1 is NO2 or NH2;
• comprising:
• reacting Compound X:
• and p-nitrophenylchloroformate to form Compound Y:
• reacting Compound Y with a compound comprising L1-D.

A method of preparing Compound X1:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• and
• R1 is NO2 or NH2;
• comprising:
• reacting Compound W1:
• L3-L2;
• and Compound I:

A method of preparing Compound Y1:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• and
• R1 is NO2 or NH2;
• comprising:
• reacting Compound X1:
• and a compound comprising L1-D.

A method of preparing Compound Z:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• A is an acyl unit;
• and
• R1 is NO2 or NH2;
• comprising:
• reacting Compound Y1:
• and a compound comprising A-L4.

A compound of formula:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• and
• A is an acyl unit;
• and
• R1 is NO2 or NH2.

A compound of formula:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• L4 is bond or a spacer;
• and
• A is an acyl unit;
• and
• R1 is NO2 or NH2.

A compound of formula:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• and
• R1 is NO2 or NH2.

A compound of formula:

• or a salt or solvate or stereoisomer thereof;
• wherein:
• D is drug moiety;
• L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
• L2 is a bond or a second self-immolative linker;
• wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
• wherein if L2 is a second self-immolative linker, then L1 is a bond;
• L3 is a peptide linker;
• and
• R1 is NO2 or NH2.