Imidazolidine compounds as androgen receptor modulators

1. A method for the treatment of a condition selected from cachexia, osteoporosis, sarcopenia, a decline in libido and/or sexual dysfunction, comprising administering an agonist or mixed agonist/antagonist compound or pharmaceutically acceptable salt thereof,

wherein said compound is according to Formula Ib:

wherein

X is O or S;

R 1 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, and C 1 -C 6 acyl; each of which may optionally be substituted with cyano, one or more halo, hydroxyl, or C 1 -C 6 alkoxy;

R 2a is selected from H, P(O)(OH) 2 , and C(O)(CH 2 ) n1 C(O)OH; or

R 2a is selected from C 1 -C 6 acyl, and C 3 -C 6 alkenyl; each of which may optionally be substituted with amino, or carboxy; n1 is 0, 1, 2, 3, or 4;

each R 2b and R 2c is independently selected from H, and C 1 -C 6 alkyl; or

R 2b and R 2c may join together to form a C 3 -C 7 cycloalkyl;

R 3a is H, halo, cyano, or nitro; or

R 3a is C 1 -C 6 alkyl optionally substituted with halo, cyano, nitro, hydroxyl, or C 1 -C 4 alkoxy; or

R 3a is amido optionally substituted with C 1 -C 6 alkyl;

each R 3b is independently halo, cyano, or nitro; or

each R 3b is independently C 1 -C 6 alkyl optionally substituted with cyano, or halo; or

each R 3b is amido optionally substituted with C 1 -C 6 alkyl;

each R 4a , and R 4b is independently H, halo, cyano, carboxy or nitro; or

each R 4a , and R 4b is selected from C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; each of which may optionally be substituted by one or more halo, or C 1 -C 6 alkoxy; or R 4a and R 4b are joined together to form an 5 or 6-membered cycloalkyl, 5 or 6-membered heterocycloalkyl, 5 or 6-membered aryl, or 5 or 6-membered heteroaryl;

R 4c is halo, cyano, or nitro; and

m1 is 0, 1, or 2.

2. A method according to claim 1 , wherein X is O.

3. A method according to claim 1 wherein R 2b is H.

4. A method according to claim 1 wherein R 2b is Me or Et.

5. A method according to claim 1 wherein R 2c is H or C 1 -C 6 alkyl.

6. A method according to claim 1 wherein R 2c is H, Me or Et.

7. A method according to claim 1 , wherein R 2b and R 2c are joined together to form a cyclopropyl, or cyclobutyl ring.

8. A method according to claim 1 , wherein each of R 2b and R 2c are H.

9. A method according to claim 1 wherein R 2a is H, P(O)(OH) 2 , or C 1 -C 6 acyl.

10. A method according to claim 1 wherein R 2a is C 3 -C 6 alkenyl.

11. A method according to claim 10 wherein R 2a is CH 2 —CH═CH 2 .

12. A method according to claim 9 wherein R 2a is H.

13. A method according to claim 9 wherein R 2a is P(O)(OH) 2 .

14. A method according to of claim 1 wherein R 2a is P(O)(OH) 2 and the salt is a mono or his salt thereof.

15. A method according to claim 14 , wherein R 2a is P(O)(ONa) 2 .

16. A method according to claim 1 wherein R 2a is C(O)(CH 2 ) n1 C(O)OH; and n1 is 0, 1, 2, or 3.

17. A method according to claim 16 wherein R 2a is C(O)—CH 2 CH 2 —C(O)OH.

18. A method according to claim 17 wherein R 2a is a pharmaceutically acceptable salt of C(O)—CH 2 CH 2 —C(O)OH.

19. A pharmaceutically acceptable salt method according to claim 18 wherein R 2a is C(O)—CH 2 CH 2 —C(O)ONa.

20. A method according to claim 1 wherein R 2a is C(O)—CH(iPr)NH 2 .

21. A method according to claim 20 ; wherein R 2a is a pharmaceutically acceptable salt of C(O)—CH(iPr)NH 2 .

22. A method according to claim 21 wherein R 2a is C(O)—CH(iPr)NH 3 Cl.

23. A method according to claim 1 wherein R 1 is H.

24. A method according to claim 1 wherein R 1 is C 1 -C 6 alkyl optionally substituted with halo, cyano or hydroxy.

25. A method according to claim 24 wherein R 1 is C 1 -C 6 alkyl optionally substituted with cyano.

26. A method according to claim 1 wherein R 1 is C 3 -C 6 alkynyl.

27. A method according to claim 26 wherein R 1 is —CH 2 —C≡CH.

28. A method according to claim 24 ; wherein R 1 is Me, Et, i-Pr, or n-Pr.

29. A method according to claim 24 wherein R 1 is Me.

30. A method according to claim 1 , wherein the compound is according to Formula II

wherein R 3a , R 3b , R 4a , R 4b , R 4c , and m1 are as in claim 1 .

31. A method according to claim 1 , wherein R 4c is cyano, halo or nitro.

32. A method according to claim 31 , wherein R 4c is cyano.

33. A method according to claim 1 , wherein R 4b is H, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

34. A method according to claim 33 , wherein R 4b is Cl, F, CN or CF 3 .

35. A method according to claim 34 , wherein R 4b is CF 3 .

36. A method according to claim 1 , wherein R 4a is H, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

37. A method according to claim 36 wherein R 4a is Cl or F.

38. A method according to claim 36 , wherein R 4a is H.

39. A method according to claim 1 , wherein the compound is according to Formulae IIIa or IIIb:

wherein R 3a , R 3b , R 4b , and m1 are as in claim 1 .

40. A method according to claim 39 , wherein R 4b is H, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

41. A method according to claim 40 , wherein R 4b is Cl, F, CN or CF 3 .

42. A method according to claim 41 , wherein R 4b is CF 3 .

43. A method according to claim 1 , wherein the compound is according to Formulae IVa or IVb:

wherein R 3a , R 3b , and m1 are as in claim 1 .

44. A method according to claim 1 , wherein R 3a is H, halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

45. A method according to claim 44 , wherein R 3a is H, Me, Cl, F, CN or CF 3 .

46. A method according to claim 1 , wherein m1 is 1 or 2.

47. A method according to claim 1 , wherein R 3b is halo, cyano, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

48. A method according to claim 47 , wherein R 3b is Me, Cl, F, CN or CF 3 .

49. A method according to claim 1 , wherein m1 is 0.

50. A method according to claim 1 , wherein the compound is according to Formulae Va, Vb, Vc or Vd:

and wherein R 3a is as in claim 1 ; and

R 3c is H, halo, cyano, or nitro; or

R 3c is C 1 -C 6 alkyl optionally substituted with cyano, or halo; or

R 3c is amido optionally substituted with C 1 -C 6 alkyl.

51. A method according to claim 50 , wherein R 3a is H, halo, or cyano; and R 3c is H.

52. A method according to claim 51 , wherein R 3a is H, CN, Cl, or F and R 3c is H.

53. A method according to claim 50 , wherein R 3a is H; and R 3c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cyano.

54. A method according to claim 53 , wherein R 3a is H;

and R 3c is CN, Cl, F, Me or CF 3 .

55. A method according to claim 50 , wherein each R 3a and R 3c is H.

56. A method according to claim 1 , wherein the compound is selected from:

4-[2,5-Dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-(4-fluorophenyl)-4-(hydroxymethyl)-3-methylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[4-(4-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methyl-imidazolidin-1-y-1)-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-(4-fluorophenyl)-4-hydroxymethyl-3-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[4-(3-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methyl-imidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

(S)-4-[2,5-Dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

(R)-4-[2,5-Dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-3-ethyl-4-(hydroxymethyl)-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[4-(4-Cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

4-[4-(3-Cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-(3-trifluoromethylphenyl)imidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

1-(3,4-Dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazolidine-2,5-dione;

4-[2,5-Dioxo-4-(hydroxymethyl)-3-(1-methylethyl)-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[3-Cyanomethyl-2,5-dioxo-4-(hydroxymethyl)-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-(hydroxymethyl)-4-phenyl-3-(1-propynyl)imidazolidin-1-yl-]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-hydroxymethyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile;

4-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-(3-methylphenyl)imidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

4-[4-(2-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methyl-imidazolidin-1-yl)-2-trifluoromethylbenzonitrile;

[1-(4-Cyano-3-trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-phenylimidazolidin-4-yl]methyl dihydrogen phosphate;

(2S)-1-[1-(4-Cyano-3-trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-phenylimidazolidin-4-yl]methoxy-3-methyl-1-oxobutan-2-aminium chloride;

4-[1-(4-Cyano-3-trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-phenylimidazolidin-4-yl]methoxy-4-oxobutanoic acid;

(S)-(1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-4-yl)methyl dihydrogen phosphate;

(S)-4-((1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-4-yl)methoxy)-4-oxobutanoic acid;

(S)—((S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-4-yl)methyl-3-methylbutanoate-2-ammonium chloride;

4-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazolidin-1-yl]-2-methoxybenzonitrile; and

(S)-1-(3,4-Dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazolidine-2,5-dione.