Diglycidic ether derivative therapeutics and methods for their use

1. A method for modulating androgen receptor (AR) activity for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration;

wherein, the method comprises administering to a mammalian cell a compound having a structure of Formula II:

wherein:

J and J′ are each independently H or a moiety selected from:

L is O, S, NH, NG, N + H 2 , or N + HG;

X is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 I, CHI 2 , CI 3 , CH 2 OJ′″, CH 2 OG, CH 2 OGOG′, GOG′, GOG′OG″, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 ;

Q is G, O, CH 2 , CHG, CG 2 , S, NH or NG;

each Z is independently N, CH, COH, C—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), C—(C 1 -C 10 substituted or unsubstituted unsaturated), CO—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), CO—(C 1 -C 10 substituted or unsubstituted unsaturated),CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;

R 1 and R 2 are each independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl or together form a substituted or unsubstituted, saturated, aromatic cyclic or non-aromatic cyclic C 3 -C 10 alkyl;

each G, G′ and G″ is independently a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C 10 alkyl;

J′″ is H or a moiety selected from:

L′ is O, S, NH, NG, N + H 2 , or N + HG;

each Z′ is independently N, CH, C—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), C—(C 1 -C 10 substituted or unsubstituted unsaturated), CO—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), CO—(C 1 -C 10 substituted or unsubstituted unsaturated),CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;

Q′ is G, O, CH 2 , CHG, CG 2 , S, NH or NG;

X′ is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 I, CHI 2 , CI 3 , G, CH 2 OG, or CH 2 OGOG′;

wherein the optional substituent is selected from the group consisting of: oxo, OJ′″, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 wherein R is an unsubstituted C 1 -C 10 alkyl.

2. The method of claim 1 , wherein X is CH 2 F, CH 2 Br, CH 2 I, CH 2 OG, CH 2 OGOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 ; and

each Z is independently N, CH, or COH and each Z′ is independently N or CH.

3. The method of claim 1 , wherein each Z and Z′ is CH.

4. The method of claim 1 , wherein each of Q and Q′ are O.

5. The method of claim 1 , wherein each of R 1 and R 2 are independently H, or a branched or unbranched, substituted or unsubstituted, C 1 -C 10 alkyl.

6. The method of claim 1 , wherein each R 1 and R 2 is CH 3 .

7. The method of claim 1 , wherein X is H, CH 3 , CH 2 F, CH 2 Br, CH 2 I, CH 2 OJ′″, CH 2 OG, or CH 2 OGOG′.

8. The method of claim 1 , wherein X is CH 2 F, CH 2 I, CH 2 Br, CH 2 OH, CH 2 OCH 3 , or CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

9. The method of claim 1 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OG, CH 2 OGOG′, GOG′, GOG′OG″, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 .

10. The method of claim 1 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OG, or CH 2 OGOG′.

11. The method of claim 1 , wherein X′ is CH 2 Cl, CH 2 F, CH 2 I, CH 2 Br, CH 2 OCH 3 , CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

12. The method of claim 1 , wherein each J, J′, and J′″, when present is

13. The method of claim 1 , wherein each J, J′ J′″, when present, is H.

14. The method of claim 1 , wherein each L and L′, when present, is independently O, or S.

15. The method of claim 1 , wherein each L and L′, when present, is O.

16. The method of claim 1 , wherein the compound is selected from one or more of the following:

17. The method of claim 1 , wherein the mammalian cell is a human cell.

18. The method of claim 1 , wherein the modulating AR activity is for inhibiting AR N-terminal domain activity.

19. The method of claim 1 , wherein the modulating is in vivo.

20. The method of claim 1 , wherein the indication is prostate cancer.

21. The method of claim 20 , wherein the prostate cancer is androgen-independent prostate cancer.

22. The method of claim 20 , wherein the prostate cancer is androgen-dependent prostate cancer.

23. The method of claim 1 , wherein:

L is O, NH, NG, N + H 2 , or N + HG; and

L′ is O, NH, NG, N + H 2 , or N + HG.

24. The method of claim 1 , wherein X′ is CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OCH 3 , CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

25. The method of claim 1 , wherein each L and L′, when present, is independently O, NH or N+H 2 .

26. A compound having a structure of Formula II

wherein

each J and J′ is independently H or a moiety selected from:

each L and L′ is independently O, NH, NG, N + H 2 or N + HG;

each Q and Q′ is independently G, O, CH 2 , CHG, CG 2 , S, NH or NG;

each Z and Z′ is independently N, CH, COH, CF, CCl, CBr, CI, CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;

R 1 and R 2 are each independently H; or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl or together form a substituted or unsubstituted, saturated, aromatic cyclic or non-aromatic cyclic C 3 -C 10 alkyl;

X is CH 2 O(isopropyl), CH 2 OC 2 H 4 OC 4 H 9 , CH 2 SG, CH 2 NH 2 , CH 2 NHG, CH 2 I, CH 2 Br, CH 2 F, or CH 2 NG 2 ;

X′ is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CHI 2 , CI 3 , CH 2 F, CHF 2 , CF 3 , CH 2 OJ′″, CH 2 OG, GOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG or CH 2 NG 2 ;

J′″ is independently H or a moiety selected from:

each G and G′ is independently, a branched or unbranched, non-aromatic cyclic, substituted or unsubstituted, saturated C 1 -C 10 alkyl;

wherein the optional substituent is selected from the group consisting of: oxo, OJ′″, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 wherein R is an unsubstituted C 1 -C 10 alkyl; and

wherein X′ is not —CH 2 O(CH 2 ) 2 —O—(CH 2 ) 3 CH 3 , —CH 2 O(CH 2 ) 2 CH 3 , —CH 2 O(CH 2 ) 3 CH 3 or —CH 2 O(CH 2 ) 3 —O—CH 3 ; and

wherein X is not —CH 2 O(CH 2 ) 2 —O—(CH 2 ) 3 CH 3 when X′ is CH 2 OH.

27. The compound of claim 26 wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 OG, GOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG or CH 2 NG 2 ; and

each Z and Z′ is independently N, CH or COH.

28. The compound of claim 26 , wherein each Z and Z′ is CH.

29. The compound of claim 26 , wherein each of Q and Q′ are O.

30. The compound of claim 26 , wherein each of R 1 and R 2 are independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl.

31. The compound of claim 26 , wherein each R 1 and R 2 is CH 3 .

32. The compound of claim 26 , wherein X is CH 2 I, CH 2 Br, CH 2 F, or CH 2 O(isopropyl).

33. The compound of claim 26 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 OG, GOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 .

34. The compound of claim 26 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, or CH 2 OG.

35. The compound of claim 26 , wherein X′ is CH 2 F, CH 2 Cl or CH 2 OG.

36. The compound of claim 26 , wherein X′ is CH 2 F, CH 2 Cl, CH 2 OCH 3 or CH 2 O(isopropyl).

37. The compound of claim 26 , wherein each J, J′ and J′″, when present, is H.

38. The compound of claim 26 , wherein each L and L′, when present, is independently O, NH or N + H 2 .

39. The compound of claim 26 , wherein each L and L′, when present, is O.

40. The compound of claim 26 wherein the compound is selected from one or more of the following:

41. A pharmaceutical composition comprising a compound according to claim 26 and a pharmaceutically acceptable excipient.

42. A pharmaceutical composition comprising a compound having a structure of Formula II

wherein

J and J′ are each independently H or a moiety selected from:

L is O, S, NH, NG, N + H 2 , or N + HG;

X is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 I, CHI 2 , CI 3 , CH 2 OJ′″, CH 2 OG, CH 2 OGOG′, GOG′, GOG′OG″, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 ;

Q is G, O, CH 2 , CHG, CG 2 , S, NH or NG;

each Z is independently N, CH, COH, CF, CCl, CBr, CI, CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;

R 1 and R 2 are each independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl or together form a substituted or unsubstituted, saturated, aromatic cyclic or non-aromatic cyclic C 3 -C 10 alkyl;

each G, G′, and G″ is independently a branched or unbranched, aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C 10 alkyl;

is H or a moiety selected from:

L′ is O, S, NH, NG, N + H 2 , or N + HG;

each Z′ is independently N, CH, COH, C—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), C—(C 1 -C 10 substituted or unsubstituted unsaturated), CO—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), CO—(C 1 -C 10 substituted or unsubstituted unsaturated),CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;

Q′ is G, O, CH 2 , CHG, CG 2 , S, NH or NG;

X′ is CH 2 Cl, or CH 2 Br,

wherein the optional substituent is selected from the group consisting of: oxo, OJ′″, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 wherein R is an unsubstituted C 1 -C 10 alkyl;

and a pharmaceutically acceptable excipient.

43. A compound selected from one the following:

44. A pharmaceutical composition comprising a compound according to claim 43 and a pharmaceutically acceptable excipient.

45. A method for modulating androgen receptor (AR) activity, the method comprising administering to a mammalian cell a compound of claim 43 .