Compounds and methods for the enhanced degradation of targeted proteins

A bifunctional compound comprising a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (ULM), and a protein targeting moiety (PTM) connected directly or through a chemical linker (L);

• wherein ULM is a group according to the chemical structure:
• wherein, each R5 and R6 is independently —OH, —SH, or optionally substituted alkyl or R5, R6, and the carbon atom to which they are attached form a carbonyl;
• R7 is H or optionally substituted alkyl;
• E is a bond, C═O, or C═S;
• G is a bond, optionally substituted alkyl, —COOH or C=J;
• J is O or N—R8;
• R8 is H, CN, optionally substituted alkyl or optionally substituted alkoxy;
• M is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic or
• each R9 and R10 is independently H;
• optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulphide linked ULM, optionally substituted heteroaryl, or haloalkyl;
• or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
• R11 is optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl, or
• R12 is H or optionally substituted alkyl;
• R13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
• optionally substituted (oxoalkyl)carbamate,
• each R14 is independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl or optionally substituted heterocycloalkyl;
• R15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
• each R16 is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
• each R25 is independently H or optionally substituted alkyl;
• or both R25 groups can be taken together to form an oxo or optionally substituted cycloalkyl group;
• R23 is H or OH;
• Z1, Z2, Z3, and Z4 are independently C or N;
• and
• o is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.