Bi-functional compounds and methods for targeted ubiquitination of androgen receptor

1. A compound having a chemical structure ARB-L-E3LB, wherein ARB is an AR binding moiety that does not bind to a ligand binding domain, E3LB is an E3 ligase binding moiety, and L is a linker coupling the AR binding moiety to the E3 ligase binding moiety, and wherein:

the E3LB moiety is a pyrrolo[3,2-b]pyridine cIAP-class ubiquitin ligase binding moiety having the following structure:

and

wherein the AR binding moiety is selected from:

wherein:

A is 3-10 membered heterocycloalkyl ring with 1-4 heteroatoms, optionally substituted by one or more groups selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

B is phenyl or imidazolyl, each optionally substituted by one or more groups selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl; and

each R 1 is independently selected from H, halo, and hydroxy.

2. The compound of claim 1 , wherein the AR binding moiety is:

wherein:

A is morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, or pyrrolidinyl, optionally substituted by one or more groups selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl;

B is phenyl, optionally substituted by one or more groups selected from halo, hydroxy, nitro, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl; and

R 1 is H, halo, hydroxy, or C 1-6 alkyl.

3. The compound according to claim 2 , wherein A is:

wherein R 1 is H, halo, or C 1-6 alkyl; and

wherein B is:

wherein R 1 is H, halo, or C 1-6 alkyl.

4. The compound according to claim 1 , wherein the AR binding moiety is selected from:

5. The compound according to claim 1 , wherein the linker (“L”) consists of a chemical structural unit represented by the formula -A q -, in which q is an integer greater than 1, and each A is independently selected from the group consisting of: a bond, CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SO 2 R L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 (═NCN)NR L4 , NR L3 C(═NCN), and NR 13 C(C═NO 2 )NR L4 ; and wherein:

R L1 , R L2 , R L3 , R L4 and R L5 are each independently selected from the group consisting of H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, 3-6 membered heterocycloalkyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , SiC( 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, CN, haloC 1-8 alkyl (e.g., CF 3 , CHF 2 , CH 2 F), NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 and NHSO 2 NH 2 ; and wherein R L1 and R L2 each, independently may be linked to another A group to form a cycloalkyl and or heterocycloalkyl moiety that can be further substituted with 0-4 R L5 groups.

6. The compound of claim 5 , wherein q is an integer from 1 to 30.

7. The compound of claim 5 , wherein the linker L is a flexible linker.

8. The compound of claim 5 , wherein the units A are selected from CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , and CO.

9. The compound of claim 8 , wherein the units A are selected from CR L1 R L2 , O, NR L3 , CONR L3 , and CO.

10. The compound of claim 9 , wherein the linker L is selected from:

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-12;

wherein m is from 0-12;

wherein m is from 0-12;

wherein m is from 2-4;

wherein m is from 0-12;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-10;

wherein m is from 0-10;

wherein m is from 0-10;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 1-12;

wherein m is from 1-12;

wherein m is from 1-12; and

wherein m is from 0-10.

11. The compound according to claim 1 , wherein the compound comprises:

the AR binding moiety

the E3 ligase binding moiety

and

a linker selected from:

wherein n is from 1-5;

wherein n is from 1-5;

wherein m is from 0-12;

wherein m is from 2-4;

wherein m is from 0-12;

wherein m is from 0-10;

wherein n is from 1-5; and

wherein m is from 1-12.

12. The compound according to claim 11 , wherein the linker L is selected from:

wherein m is from 0-8; and

wherein n is from 1-3.

13. A compound selected from the group consisting of:

14. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, additive and/or excipient.

15. A method of treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for said disease or condition, wherein the disease or condition is a cancer identified as having a mutation resulting, or expected to result in, overexpression of the androgen receptor, said method comprising administering an effective amount of a compound according to claim 1 , to a patient in need thereof.

16. A method of degrading an androgen receptor in a cell, said method comprising administering an effective amount of a compound according to claim 1 , to such cell.

17. A method of inducing apoptosis in a cell, said method comprising administering an effective amount of a compound according to claim 1 , to such cell.

18. The method according to claim 16 , wherein the cell is a cancer cell, and wherein the androgen receptor is a mutated androgen receptor selected from AR-V1 to AR-V15 splice variants.

19. The method according to claim 17 , wherein the cell is a cancer cell.