Trimethyl lock based tetrapartate prodrugs

A compound of Formula (I):

• wherein:
• R1 is a mono- or bivalent polymer residue,
• L1 is a bifunctional linking group;
• Y1 and Y2 are independently O, S or NR7;
• R2-7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• D is a moiety that is a leaving group or a residue of a compound to be delivered into a cell;
• Z is selected from the group consisting of:
• a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
• Ar is selected from the group consisting of
• wherein
• R2, R9, R10 and R11 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• Z1 and Z2 are independently CR23 or NR24;
• and Z3 is O, S or NR25 where R23-25 are selected from the same group as that which defines R2 or a cyano, intro, carboxyl, acyl, substituted acyl or carboxyalkyl;
• and (y) is a positive integer greater than or equal to 1.

A method of preparing a tetrapartate prodrug comprising reacting a compound of formula:

• with a compound of formula:
• III Lx-Z—[D]y;
• wherein
• B is a leaving group for Formula II;
• Lx is a leaving group for Formula III;
• Z is covalently linked to [D]y, wherein Z is selected from the group consisting of:
• a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
• R1 is a polymeric residue;
• L1 is a bifunctional linking group;
• Y1 and Y2 are independently O, S or NR7;
• R2-7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• D is a moiety that is a leaving group or a residue of a compound to be delivered into a cell;
• Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
• and
• (y) is 1 or 2.

A method of preparing a tetrapartate prodrug comprising reacting a compound of formula

• with at least one biologically active material;
• wherein
• R1 is a polymeric residue;
• L1 is a bifunctional linking group;
• Y1 and Y2 are independently O, S or NR7;
• R2-7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
• Z is covalently linked to La and wherein Z is selected from the group consisting of:
• a moiety that is actively transported into a target cell, a hydrophobic moiety and combinations thereof;
• Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
• and
• La is a leaving group for Formula IV wherein Z is covalently linked thereto.