Selective androgen receptor degrader (SARD) ligands and methods of use thereof

1. A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein

T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;

Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;

A is R 2 or R 3 ;

R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;

R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO2NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and

R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;

wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

2. The method according to claim 1 , wherein the prostate cancer is at least one of advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.

3. The method according to claim 1 further comprising administering androgen deprivation therapy (ADT).

4. The method according to claim 1 , wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist(s).

5. The method according to claim 4 , wherein the androgen receptor antagonist is at least one of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

6. A method of treating enzalutamide resistant prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein

T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;

Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;

A is R 2 or R 3 ;

R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;

R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and

R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;

wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

7. A method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of formula I:

wherein

T is OH, OR, OCOR, CH 3 , —NHCOCH 3 , or NHCOR;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;

or T and R 1 form a 3-8 carbocyclic or heterocyclic ring;

Y is H, CF 3 , F, I, Br, Cl, CN, or C(R) 3 ;

Z is H, NO 2 , CN, halide, COOH, COR, NHCOR, CONHR,

or Y and Z form a 5 to 8 membered fused ring;

X is CH or N;

R is H, alkyl, alkenyl, haloalkyl, alcohol, CH 2 CH 2 OH, CF 3 , CH 2 Cl, CH 2 CH 2 Cl, aryl, F, Cl, Br, I, or OH;

A is R 2 or R 3 ;

R 2 is a five-membered saturated or five or six-membered unsaturated ring having at least one nitrogen atom and 0, 1, or 2 double bonds, optionally substituted with at least one of Q 1 , Q 2 , Q 3 or Q 4 , each independently selected from hydrogen, keto, substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, haloalkyl, CF 3 , substituted or unsubstituted aryl, substituted or unsubstituted phenyl, F, Cl, Br, I, CN, NO 2 , hydroxyl, alkoxy, OR, benzyl, NCS, maleimide, NHCOOR, N(R) 2 , NHCOR, CONHR, COOR or COR;

R 3 is halide, N 3 , CF 3 , COR 4 , COCl, COOCOR 4 , COOR 4 , OCOR 4 , OCONHR 4 , NHCOOR 4 , NHCONHR 4 , OCOOR 4 , CN, CONH 2 , CONH(R 4 ), CON(R 4 ) 2 , SO 3 H, SO 2 NH 2 , SO 2 NH(R 4 ), SO 2 N(R 4 ) 2 , NH 2 , CO(N-heterocycle), NO 2 , cyanate, isocyanate, thiocyanate, isothiocyanate, mesylate, tosylate, triflate, PO(OH) 2 or OPO(OH) 2 ; and

R 4 is H, alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl groups are optionally substituted;

wherein if A is Br or I, R 1 is CH 3 , and T is OH, then X is N or the aniline ring forms a fused heterocyclic ring,

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

8. The method of claim 1 , wherein the SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

9. The method of claim 6 , wherein the SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

10. The method of claim 7 , wherein the SARD compound is represented by the structure of formula IA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

11. The method of claim 1 , wherein the SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

12. The method of claim 6 , wherein the SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

13. The method of claim 7 , wherein the SARD compound is represented by the structure of formula IB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

14. The method of claim 1 , wherein the SARD compound is represented by the structure of formula II:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

15. The method of claim 14 , wherein the SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

16. The method of claim 6 , wherein the SARD compound is represented by the structure of formula II:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

17. The method of claim 16 , wherein the SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

18. The method of claim 7 , wherein the SARD compound is represented by the structure of formula II:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

19. The method of claim 18 , wherein the SARD compound is represented by the structure of formula IIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula IIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

20. The method of claim 1 , wherein the SARD compound is represented by the structure of formula VII:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

21. The method of claim 20 , wherein the SARD compound is represented by the structure of formula VIIA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

22. The method of claim 6 , wherein the SARD compound is represented by the structure of formula VII:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

23. The method of claim 22 , wherein the SARD compound is represented by the structure of formula VITA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

24. The method of claim 7 , wherein the SARD compound is represented by the structure of formula VII:

or its optical isomer, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

25. The method of claim 24 , wherein the SARD compound is represented by the structure of formula VITA:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof;

or by the structure of formula VIIB:

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

26. The method of claim 1 , wherein Q 1 , Q 2 , Q 3 or Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, or substituted or unsubstituted phenyl.

27. The method of claim 6 , wherein Q 1 , Q 2 , Q 3 or Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, or substituted or unsubstituted phenyl.

28. The method of claim 7 , wherein Q 1 , Q 2 , Q 3 or Q 4 is hydrogen, CN, NO 2 , CF 3 , F, Cl, Br, I, NHCOOR, N(R) 2 , NHCOR, COR, or substituted or unsubstituted phenyl.

29. The method of claim 1 , wherein the SARD compound is represented by the structure of any one of the following compounds:

30. The method of claim 6 , wherein the SARD compound is represented by the structure of any one of the following compounds:

31. The method of claim 7 , wherein the SARD compound is represented by the structure of any one of the following compounds:

32. A method of treating prostate cancer (PCa) or increasing the survival of a male subject suffering from prostate cancer comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of any one of compounds 1026, 1029, 1024, and 1040

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

33. The method according to claim 32 , wherein the prostate cancer is at least one of advanced prostate cancer, refractory prostate cancer, castration resistant prostate cancer (CRPC), metastatic CRPC (mCRPC), non-metastatic CRPC (nmCRPC), or high-risk nmCRPC.

34. The method according to claim 32 further comprising administering androgen deprivation therapy (ADT).

35. The method according to claim 32 , wherein the prostate cancer is resistant to treatment with an androgen receptor antagonist(s).

36. The method according to claim 35 , wherein the androgen receptor antagonist is at least one of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

37. A method of treating enzalutamide resistant prostate cancer in a subject comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of any one of compounds 1026, 1029, 1024, and 1040

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.

38. A method of treating abiraterone resistant prostate cancer comprising administering to the subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by the structure of any one of compounds 1026, 1029, 1024, and 1040

or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof.