Imide-based modulators of proteolysis and associated methods of use

A compound having a chemical structure that is:

• PTM-L-CLM
• or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein
• PTM is a moiety that binds to an androgen receptor that has a chemical structure represented by:
• designates a site for the L group to covalently attach to the PTM;
• L is a chemical linker moiety covalently attaching the PTM to the CLM, wherein L is:
• -Aq-
• wherein
• q is an integer from 1 to 20;
• and
• A is independently selected from the group consisting of CRL1RL2, O, SO2, NRL3, CONRL3NRL3CONRL4, CO, CRL1═CRL2, C≡C, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C3-11heterocyclyl optionally substituted with 1-6 RL1 and/or RL2 groups, aryl optionally substituted with 1-6 RL1 and/or RL2 groups, heteroaryl optionally substituted with 1-6 RL1 and/or RL2 groups;
• wherein RL1, RL2, RL3, RL4 and RL5 are each, independently, selected from the group consisting of H, halo, C1-8alkyl, OC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SO2C1-8alkyl, CC—C1-8alkyl, CCH, CH═CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl), C(C1-8alkyl)═C(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2;
• and
• wherein when q is greater than 1, RL1 or RL2 each, independently, can be covalently bonded to another A group to form cycloalkyl and/or heterocyclyl moiety that can be further substituted with 0-4 RL5 groups;
• and
• CLM is a cereblon E3 Ubiquitin Ligase binding moiety that has a chemical structure represented by:
• wherein:
• W is CH2 or C═O;
• each X is independently selected from the group consisting of absent and O;
• Z is absent or O;
• G is H, OH, or alkyl;
• Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from H, R, and N;
• A is H, alkyl, Cl, or F
• n is an integer from 1 to 4;
• R is —OR′, —NR′R″, alkyl, —Cl, —F, —CF3, or —CN, wherein one R is modified to be covalently attached to the chemical linker moiety (L);
• R′ and R″ are H or alkyl;
• and
• represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

A compound having a chemical structure that is:

• PTM-L-CLM
• or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein
• PTM is a moiety that binds to an androgen receptor that has a chemical structure represented by:
• designates a site for the L group to covalently attach to the PTM;
• L is a chemical linker moiety covalently attaching the PTM to the CLM, wherein L is an optionally substituted (poly)ethyleneglycol having between 1 and 8 ethylene glycol units, wherein each O is optionally replaced with an optionally substituted N, and wherein the chemical linker moiety substitution is selected from an aryl, phenyl, benzyl, alkyl or heterocycle;
• and
• CLM is a cereblon E3 Ubiquitin Ligase binding moiety that has a chemical structure represented by:
• wherein:
• W is CH2 or C═O;
• each X is independently selected from the group consisting of absent and O;
• Z is absent or O;
• G is H, OH, or alkyl;
• Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from H, R, and N;
• A is H, alkyl, Cl, or F
• n is an integer from 1 to 4;
• R is —OR′, —NR′R″, alkyl, —Cl, —F, —CF3, or —CN, wherein one R is modified to be covalently attached to the chemical linker moiety (L);
• R′ and R″ are H or alkyl;
• and
• represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.

A compound having a chemical structure that is:

• PTM-L-CLM
• or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein
• PTM is a moiety that binds to an androgen receptor that has a chemical structure represented by:
• designates a site for the L group to covalently attach to the PTM;
• L is a chemical linker moiety covalently attaching the PTM to the CLM, wherein L is selected from the group consisting of:
• and
• CLM is a cereblon E3 Ubiquitin Ligase binding moiety that has a chemical structure represented by:
• wherein:
• W is CH2 or C═O;
• each X is independently selected from the group consisting of absent and O;
• Z is absent or O;
• G is H, OH, or alkyl;
• Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from H, R, and N;
• A is H, alkyl, Cl, or F
• n is an integer from 1 to 4;
• R is —OR′, —NR′R″, alkyl, —Cl, —F, —CF3, or —CN, wherein one R is modified to be covalently attached to the chemical linker moiety (L);
• R′ and R″ are H or alkyl;
• and
• represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific.