COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR

• US 20180099940A1
• Filed: 10/11/2017
• Published: 04/12/2018
• Est. Priority Date: 10/11/2016
• Status: Active Grant

• Current Assignee: Arvinas Operations, Inc. (Arvinas, Inc.)
• Original Assignee: Arvinas, Inc.
• Inventors: Crew, Andrew P., Hornberger, Keith R., Snyder, Lawrence B., Zimmermann, Kurt, Wang, Jing, Berlin, Michael, Crews, Craig M., Dong, Hanqing
• Granted Patent: US 10,584,101 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/02 Halogenated hydrocarbons
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 213/72 Nitrogen atoms nitro radicals C07D213/61
• CPC Class Codes: C07D 221/20 Spiro-condensed ring systems
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/42 Sulfur atoms
• CPC Class Codes: C07D 237/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/24 having three or more double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings

Abstract

The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

Claims

1. A compound having the structure:

ABM-L-CLM,

wherein ABM is an androgen receptor (AR) binding moiety, L is a chemical linker moiety, CLM is a cereblon E3 ubiquintin ligase binding moiety, wherein the ABM comprises a structure selected from the group consisting of;

2. The compound of claim 1, wherein W¹ is selected from the group consisting of:

3. The compound of claim 2, wherein W² is selected from the group consisting of:

4. The compound of claim 1, wherein the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide that binds to the cereblon E3 ubiquitin ligase.

5. The compound of claim 4, wherein the chemical group is a phthalimido group, or an analog or derivative thereof.

6. The compound of claim 1, wherein the CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

7. The compound of claim 1, wherein the CLM has a chemical structure represented by:

8. The compound of claim 1, wherein the CLM or ULM has a chemical structure represented by:

9. A bifunctional compound comprising the chemical structure:

ABM-L-CLM, wherein ABM is an androgen receptor (AR) binding moiety, L is absent (a bond) or a chemical linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety is a chemical group derived from an imide, a thioimide, an amide, or a thioamide, wherein the ABM comprises a structure selected from the group consisting of;

10. The bifunctional compound of claim 9, wherein W¹ is selected from the group consisting of:

11. The bifunctional compound of claim 9, wherein W² is selected from the group consisting of:

12. The bifunctional compound of claim 9, wherein CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide that binds cereblon E3 ubiquitin ligase.

13. The bifunctional compound of claim 12, wherein the chemical group is a phthalimido group, or an analog or derivative thereof.

14. The bifunctional compound of claim 9, wherein the CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.

15. The bifunctional compound of claim 9, wherein the CLM has a chemical structure represented by:

16. The bifunctional compound of claim 9, wherein the CLM or ULM has a chemical structure represented by:

17. The bifunctional compound of claim 9, wherein the linker group L is a group comprises a chemical structural unit represented by the formula:

-A_q-

wherein A_q is a group coupled to at least one of CLM, ABM, or both; and

q is an integer greater than or equal to 1,

wherein Aq is selected from the group consisting of, a bond, CR^L1R^L2, O, S, SO, SO₂, NR^L3, SO₂NR^L3, SONR^L3, CONR^L3, NR^L3CONR^L4, NR^L3SO₂NR^L4, CO, CR^L1═

CR^L2, C≡

C, SiR^L1R^L2, P(O)R^L1, P(O)OR^L1, NR^L3C(═

NCN)NR^L4, NR^L3C(═

NCN), NR^L3C(═

CNO₂)NR^L4, C3-11cycloalkyl optionally substituted with 0-6 RL1 and/or RL2 groups, C5-13 spirocycloalkyl optionally substituted with 0-9 R^L1 and/or R^L2 groups, C3-11heterocyclyl optionally substituted with 0-6 R^L1 and/or R^L2 groups, C_5-13 spiroheterocycloalkyl optionally substituted with 0-8 R^L1 and/or R^L2 groups, aryl optionally substituted with 0-6 R^L1 and/or R^L2 groups, heteroaryl optionally substituted with 0-6 R^L1 and/or R^L2 groups, where R^L1 or R^L2 each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R^L5 groups;

R^L1, R^L2, R^L3, R^L4 and R^L5 are, each independently, H, halo, C_1-8alkyl, OC_1-8alkyl, SC_1-8alkyl, NHC_1-8alkyl, N(C_1-8alkyl)₂, C_3-11cycloalkyl, aryl, heteroaryl, C_3-11heterocyclyl, OC_1-8cycloalkyl, SC_1-8cycloalkyl, NHC_1-8cycloalkyl, N(C_1-8cycloalkyl)₂, N(C_1-8cycloalkyl)(C_1-8alkyl), OH, NH₂, SH, SO₂C_1-8alkyl, P(O)(OC_1-8alkyl)(C_1-8alkyl), P(O)(OC_1-8alkyl)₂, CC—

C_1-8alkyl, CCH, CH═

CH(C_1-8alkyl), C(C_1-8alkyl)═

CH(C_1-8alkyl), C(C_1-8alkyl)═

C(C_1-8alkyl)₂, Si(OH)₃, Si(C_1-8alkyl)₃, Si(OH)(C_1-8alkyl)₂, COC_1-8alkyl, CO₂H, halogen, CN, CF₃, CHF₂, CH₂F, NO₂, SF₅, SO₂NHC_1-8alkyl, SO₂N(C_1-8alkyl)₂, SONHC_1-8alkyl, SON(C_1-8alkyl)₂, CONHC_1-8alkyl, CON(C_1-8alkyl)₂, N(C_1-8alkyl)CONH(C_1-8alkyl), N(C_1-8alkyl)CON(C_1-8alkyl)₂, NHCONH(C_1-8alkyl), NHCON(C_1-8alkyl)₂, NHCONH₂, N(C_1-8alkyl)SO₂NH(C_1-8alkyl), N(C_1-8alkyl) SO₂N(C_1-8alkyl)₂, NH SO₂NH(C_1-8alkyl), NH SO₂N(C_1-8alkyl)₂, NH SO₂NH₂.

18. The bifunctional compound according to claim 9, wherein linker (L) comprises a group represented by a general structure selected from the group consisting of:

—

N(R)—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

OCH2—

,

—

O—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

OCH2—

,

—

O—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

O—

;

—

N(R)—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

O—

;

—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

O—

;

—

(CH2)_m—

O(CH2)_n—

O(CH2)_o—

O(CH2)_p—

O(CH2)_q—

O(CH2)_r—

OCH2—

;

19. The bifunctional compound according to claim 9, wherein linker (L) is selected from the group consisting of:

20. The bifunctional compound according to claim 9, wherein the linker (L) comprises a group represented by a general structure:

21. The bifunctional compound according to claim 9, wherein L is a polyethylene group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.

22. The bifunctional compound according to claim 9, wherein the compound comprises multiple LCMs, multiple ABMs, multiple linkers or any combinations thereof.

23. The bifunctional compound according to claim 9, wherein the compound is a member selected from the group consisting of Examples 1-452 and 528-625 (Tables 2-7), a salt, a polymorph, isotopic derivative, and a prodrug thereof.

25. The bifunctional compound according to claim 9, wherein the ABM is selected from the group consisting of:

26. The bifunctional compound according to claim 9, wherein the ABM is selected from the group consisting of:

27. A composition comprising an effective amount of a bifuctional compound of claim 9, and a pharmaceutically acceptable carrier.

28. The composition of claim 27, wherein the composition further comprises at least one additional bioactive agent.

29. The composition of claim 28, wherein the bioactive agent is an anti-cancer agent.

30. A therapeutic composition comprising an effective amount of at least two different compounds according to claim 9.

31. A method of treating a disease or disorder in a subject comprising the steps of administering a composition comprising a pharmaceutically acceptable carrier and an effective amount of a bifunctional compound according to claim 9 to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

32. The method according to claim 31, wherein the disease or disorder is cancer or Kennedy'"'"'s Disease or both.

33. The method according to claim 32, wherein the cancer is prostate cancer.

34. The method according to claim 31, wherein the composition further comprises an effective amount of at least one additional anti-cancer agent.

24. (canceled)