Enzyme-triggered self-reacting linker having improved physicochemical and pharmacological properties

A Ligand-Drug-Conjugate compound (LDC) having the following formula (I)

• Wherein
• L is a ligand;
• X1 is a connector unit;
• Z is an optional spacer;
• X2 is a connector unit;
• K is an optional hydrophobicity masking entity;
• R1 is selected from the group consisting of H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• D is an active agent;
• each R2 is independently selected from the group consisting electron-withdrawing groups and C1-C4 alkyl;
• n is 0, 1 or 2;
• R4 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• R5 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• T is a sugar cleavable unit or a polypeptide cleavable unit;
• Y is O when T is a sugar cleavable unit, or NR3 when T is a polypeptide cleavable unit;
• R3 is selected from the group consisting of H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• R″ and R′″ being independently selected from H and C1-C6 alkyl;
• and pharmaceutically acceptable salts thereof.

An intermediate compound of formula (II)

• Wherein
• X1′ is a group which can react with a ligand to form a connector unit;
• Z is an optional spacer;
• X2 is a connector unit;
• K is an optional hydrophobicity masking entity;
• R1′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• D is an active agent;
• each R2 is independently selected from the group consisting electron-withdrawing groups and C1-C4 alkyl;
• n is 0, 1 or 2;
• R4 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• R5 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• T is a sugar cleavable unit or a polypeptide cleavable unit;
• Y′ is O when T is a sugar cleavable unit, or NR3′ when T is a polypeptide cleavable unit;
• R3′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• R″ and R″ being independently selected from H and C1-C6 alkyl;
• and pharmaceutically acceptable salts thereof.

An intermediate compound of formula (III)

• Wherein
• R1′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• D is an active agent;
• each R2 is independently selected from the group consisting electron-withdrawing groups and C1-C4 alkyl;
• n is 0, 1 or 2;
• R4 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• R5 is selected from the group consisting H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• T is a sugar cleavable unit or a polypeptide cleavable unit;
• Y′ is O when T is a sugar cleavable unit, or NR3′ when T is a polypeptide cleavable unit;
• R3′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• R″ and R′″ being independently selected from H and C1-C6 alkyl;
• and pharmaceutically acceptable salts thereof.

An intermediate compound of formula (IV)

• Wherein
• R1′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• each R2 is independently selected from the group consisting electron-withdrawing groups and C1-C4 alkyl;
• n is 0, 1 or 2;
• R4 is H;
• R5 is H;
• T is a sugar cleavable unit;
• Y′ is O;
• and pharmaceutically acceptable salts thereof.

An intermediate compound of formula (IV)

• Wherein
• R1′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• each R2 is independently selected from the group consisting electron-withdrawing groups and C1-C4 alkyl;
• n is 0, 1 or 2;
• R4 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatoms or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• R5 is selected from the group consisting of H, C1-C6 alkyl and C2-C6 alkenyl, said alkyl and alkenyl being optionally interrupted by one or more heteroatoms or chemical groups selected from —O—, —S—, —C(O)—, and —NR″—;
• Y′ is NR3′;
• T is a polypeptide cleavable unit;
• R3′ is selected from the group consisting of amino protecting groups, H, C1-C24 alkyl, C2-C6 alkenyl;
• optionally substituted polyether, aryl having 6 to 10 ring atoms, C3-C8 cycloalkyl, heterocycloalkyl having 3 to 10 ring atoms, heteroaryl having 5 to 10 ring atoms, and any combination thereof,
• said alkyl and alkenyl being optionally interrupted by one or more heteroatom or chemical groups selected from —O—, —S—, —C(O)—, —NR″—, —C(O)NR″—, —NR″—C(O)—, —NR″—C(O)—NR′″—, —NR″—C(O)—O—, —O—C(O)NR″— and triazole;
• R″ and R′″ being independently selected from H and C1-C6 alkyl;
• and pharmaceutically acceptable salts thereof.