Compounds and methods for the targeted degradation of androgen receptor

1. A compound having the structure:

wherein:

W 1 is 6-membered aryl or heteroaryl substituted by 1 or more member selected from the group of halogen and CN;

Y 3 , Y 4 , and Y 5 are each independently O, NR Y2 , CR Y1 R Y2 , or C═O;

Q is a 3-6 membered alicyclic ring, optionally substituted with 1-6 R Q groups, each R Q is independently OH, or C 1-6 alkyl;

R Y1 , and R Y2 are each independently H, OH, or linear or branched C 1-6 alkyl;

W 2 is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 R W2 ;

each R W2 is independently halogen, C 1-6 alkyl optionally substituted by 1 or more F, or OC 1-3 alkyl optionally substituted by 1 or more F;

L is a chemical linker group selected from:

wherein the of the chemical linker group indicates the site of attachment with the W 2 or the VLM;

VLM is a hydroxyl prolyl moiety that binds Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which is represented by the chemical structure:

wherein:

W 3 is

R 9 is H;

R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;

R 11 is optionally substituted heteroaryl or;

R 12 is H;

R 13 is H, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, or optionally substituted (heterocyclyl)carbonyl;

R 14a and R 14b are each independently H, or linear or branched C 1 -C 6 alkyl optionally substituted with 1 or more halogen, hydroxyl, nitro, or CN;

W 5 is a phenyl;

R 15 is

wherein R 17 is H, halogen, or optionally substituted C 1-6 alkyl; and

Xa is S or O;

R 16 is absent;

o is 0; and

the of the VLM indicates attachment with the chemical linker group (L).

2. The compound of claim 1 , wherein W 1 is a 6-membered aryl substituted with a CN and a C 1 .

3. The compound of claim 1 , wherein Q is a 4-membered alicyclic group substituted with 4 methyl groups.

4. The compound of claim 1 , wherein at least one of: Y 3 is O, Y 4 is —NH—, and Y 5 is C═O.

5. The compound of claim 1 , wherein W 2 is 6-membered aryl or 6-membered heteroaryl.

6. The compound of claim 1 , wherein R 14a and R 14b are independently selected from H, methyl or ethyl, wherein the ethyl or methyl is optionally substituted by a hydroxyl.

7. The compound of claim 1 , wherein R 11 is

and R 13 is an unsubstituted alkylcarbonyl.

8. The compound of claim 1 , wherein R 10 is tert-butyl, R 11 is

R 3 and R 13 is an unsubstituted alkylcarbonyl.

9. The compound of claim 1 , wherein R 10 is isopropyl and R 11 is an optionally substituted heteroaryl.

10. The compound of claim 1 , wherein R 17 is a methyl group and Xa is S.

11. The compound of claim 1 , wherein the compound has a chemical structure selected from the group consisting of:

12. A compound that has a chemical structure selected from the group consisting of:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug thereof.

13. A composition comprising an effective amount of a compound of claim 1 , and a pharmaceutically acceptable carrier.

14. A composition comprising an effective amount of a compound of claim 11 , and a pharmaceutically acceptable carrier.

15. A method of treating prostate cancer in a subject having prostate cancer, the method comprising administering a therapeutic composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound as described in claim 1 to the subject having prostate cancer, wherein the compound is effective in treating or ameliorating at least one symptom of prostate cancer.