Compounds and methods for the targeted degradation of androgen receptor

1. A compound represented by the structure:

ABM-L-CLM,

or a pharmaceutically acceptable salt thereof, wherein:

(a) CLM is

wherein:

W is CH 2 or C═O;

A is H;

n is an integer from 1 to 4;

wherein when n is 1, R is an aryl, heteroaryl, cycloalkyl, or heterocyclyl covalently joined to the linker group (L); and when n is 2, 3, or 4, one R is an aryl, heteroaryl, cycloalkyl, or heterocyclyl covalently joined to the linker group (L) and the remaining R are selected from OR′, —NR′R″, —SR′, —C 1-6 alkyl, —Cl, —F, —Br, —I, —CF 3 , —CN, and —OCF 3 ;

R′ and R″ are each independently selected from H, C 1-6 alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; and

represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific;

(b) L is a chemical linker group that is covalently bound to the ABM and the CLM, and has the chemical structure -(A L ) q -, wherein:

q is an integer greater than or equal to 1;

each A L is selected from CR L1 R L2 , O, S, NR L3 , CO, CR L1 ═CR L2 , C≡C, C 3-11 cycloalkyl optionally substituted with 1-6 R L1 , C 5-13 spirocycloalkyl optionally substituted with 1-9 R L1 , C 3-11 heterocyclyl optionally substituted with 1-6 R L1 , C 5-13 spiroheterocycloalkyl optionally substituted with 1-8 R L1 , aryl optionally substituted with 1-4 R L1 , and heteroaryl optionally substituted with 1-4 R L1 ; and

R L1 , R L2 , and R L3 are each, independently, H, halogen, C 1-8 alkyl, OC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 , N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , COC 1-8 alkyl, CO 2 H, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , CONHC 1-8 alkyl, or CON(C 1-8 alkyl) 2 , or R L1 and R L2 are linked to form a cycloalkyl or a heterocyclyl moiety; and

(c) ABM is:

wherein:

W 1 is aryl optionally substituted by 1 or more halogen; hydroxyl; nitro; CN; C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl; or C 1-6 alkoxyl optionally substituted by 1 or more halogen;

each Y 3 is independently a bond, O, NR Y2 , CR Y1 R Y2 , or C═O;

Q is a 6-membered alicyclic substituted with 0-6 R Q ;

each R Q is independently halogen; C 1-6 alkoxy; or C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl;

R Y1 and R Y2 are each, independently, H, halogen, C 1-6 alkoxy, or C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl;

W 2 is aryl optionally substituted by 1-4 R W2 or heteroaryl optionally substituted by 1-4 R W2 ;

each R W2 is, independently, halogen; C 1-6 alkyl optionally substituted by 1 or more —F; OH; NR Y1 R Y2 ; CN; or OC 1-3 alkyl optionally substituted by 1 or more —F; and

is the point of attachment of the ABM to the chemical linker group (L).

2. The compound of claim 1 , wherein the ABM is:

wherein:

Y 4 and Y 5 are each individually selected from: O, NR Y2 , CR Y1 R Y2 , and C═O; and

is the point of attachment of the ABM to the chemical linker group (L).

3. The compound of claim 1 , wherein W 1 is:

4. The compound of claim 2 , wherein W 2 is:

5. The compound of claim 1 , wherein W 2 is:

6. The compound of claim 1 , wherein the ABM is:

wherein:

R Q2 is H, halogen, CH 3 or CF 3 ;

R Q3 is H, halogen, hydroxyl, nitro, CN, C 1-6 alkyl optionally substituted by 1 or more halogen; or C 1-6 alkoxyl optionally substituted by 1 or more halogen;

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

R Y1 and R Y2 are each, independently, H or C 1-6 alkyl optionally substituted by 1 or more halogen or C 1-6 alkoxyl; and

X ABM is N or CH.

7. The compound of claim 1 , wherein the ABM is:

8. The compound of claim 1 , wherein the chemical linker group (L) is:

9. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

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

11. The pharmaceutical composition of claim 10 , wherein the composition further comprises an anti-cancer agent.

12. The compound of claim 1 , wherein the chemical linker group (L) is:

wherein each m, n, o, p, and r is independently 0, 1, 2, 3, 4, 5, or 6, provided that the chemical linker group does not contain a N—O or O—O bond; and

wherein X L is H or F.

13. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 3 , wherein W 1 is:

15. The compound of claim 14 , wherein W 1 is

16. The compound of claim 4 , wherein W 2 is

17. The compound of claim 5 , wherein W 2 is

18. The compound according to claim 7 , wherein the ABM is

19. The compound of claim 1 , wherein n is 1; and R is a heterocyclyl covalently joined to the linker group (L).

20. The compound of claim 1 , wherein n is 1; and R is a piperazinyl or piperidinyl covalently joined to the linker group (L).

21. The compound of claim 1 , wherein n is 2; one R is a heterocyclyl covalently joined to the linker group (L); and the other R is —F.

22. The compound of claim 1 , wherein n is 2; one R is a piperazinyl covalently joined to the linker group (L); and the other R is —F.

23. The compound of claim 1 , wherein n is 2; one R is a piperidinyl covalently joined to the linker group (L); and the other R is —F.

24. The compound of claim 1 , wherein each A L is selected from CR L1 R L2 and C 3-11 heterocyclyl optionally substituted with 1-6 R L1 .

25. The compound of claim 24 , wherein each A L is selected from CH 2 , piperazinyl, and piperidinyl.

26. The compound of claim 24 , wherein each A L is selected from CH 2 and piperidinyl.