Androgen receptor modulators and uses thereof

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient and a compound of Formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof, said composition formulated in a dosage form suitable for delivering a therapeutically effective amount of the compound when administered in a single dosage form or in a divided dosage form multiple times over the span of one day:

wherein,

ring A is pyridinyl;

m is 1, 2, 3 or 4;

each R A is independently halogen, —CN, —NO 2 , —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , —N(R 11 )S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —OC(═O)R 10 , —CO 2 R 9 , —N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkoxy, or C 1 -C 6 heteroalkyl;

both R 1 are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;

X is S or O;

ring B is phenyl;

n is 1, or 2;

each R 4 is independently hydrogen, halogen, —CN, —NO 2 , —OH, —OR 9 , —SR 9 , —S(═O)R 10 , —S(═O) 2 R 10 , —N(R 11 )S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —OC(═O)R 10 , —CO 2 R 9 , —OCO 2 R 10 , —N(R 9 ) 2 , —C(═O)N(R 9 ) 2 , —OC(═O)N(R 9 ) 2 , —NR 11 C(═O)N(R 9 ) 2 , —NR 11 C(═O)R 10 , —NR 11 C(═O)OR 10 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;

R 5 is -L 1 -L 2 -R 6 ; and

(i) L 1 is —O—, —S—, —OC(═O)—, or —OC(═O)O—; and

(ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;

or

R 5 is L 1 -R 7 ; and L 1 is —O—, —S—, —OC(═O)—, or —OC(═O)O—;

R 6 and R 7 are independently optionally substituted piperidinyl;

said optional substituents including at least one of alkyl, fluoroalkyl, —CN, halo, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , alkoxy, fluoroalkoxy, -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)-(alkyl);

each R 9 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;

R 10 is C 1 -C 6 alkyl; and

R 11 is independently H or C 1 -C 4 alkyl.

2. The pharmaceutical composition of claim 1 , wherein

both R 1 are taken together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

X is S; and

each R A is independently halogen, —CN, —NO 2 , —OH, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy; and

R 6 and R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)(C 1-6 alkyl.

3. The pharmaceutical composition of claim 2 , wherein:

each R 4 is independently hydrogen, halogen, —CN, —NO 2 , —OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy;

R 5 is -L 1 -L 2 -R 6 ; and

(i) L 1 is —O— or —S—; and

(ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;

or R 5 is -L 1 -R 7 ; and L 1 is —O— or —S.

4. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (II):

wherein,

m is 2;

one R A is —CN, —NO 2 , —S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —CO 2 R 9 , or —C(═O)N(R 9 ) 2 ; and the other R A is halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;

n is 1;

each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;

R 5 is -L 1 -L 2 -R 6 ; and (i) L 1 is —O—; and (ii) L 2 is C 1 -C 6 alkylene, C 1 -C 6 fluoroalkylene or C 1 -C 6 heteroalkylene;

or

R 5 is L 1 -R 7 ; and L 1 is —O—;

or is a pharmaceutically acceptable salt, or N-oxide thereof.

5. The pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has the structure of Formula (VI):

wherein,

one R A is —CN, —NO 2 , —S(═O) 2 R 10 , —S(═O) 2 N(R 9 ) 2 , —C(═O)R 10 , —CO 2 R 9 , or —C(═O)N(R 9 ) 2 ;

and the other R A is H, halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 fluoroalkoxy, or C 1 -C 6 alkoxy;

both R 1 are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;

R 4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, or C 1 -C 4 alkoxy,

R 6 and R 7 are piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , -(alkyl)sulfonyl, -(alkylene)-OH, or —C(O)—(C 1-6 alkyl;

or is a pharmaceutically acceptable salt, or N-oxide thereof.

6. A pharmaceutical composition of claim 1 , wherein the compound of Formula (Ia) has a structure of Formula (VIIIa):

wherein,

R A is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl.

7. The pharmaceutical composition of claim 1 , wherein:

X is S;

R 4 is hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 fluoroalkoxy, or C 1 -C 3 alkoxy; and

R 6 and R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O—(C 1-6 alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), -(alkyl)sulfonyl, -(alkylene)-OH, —C(O)—(C 1-6 alkyl), or carbamoyl.

8. The pharmaceutical composition of claim 7 , wherein the compound of Formula (VIIIa) has the structure of Formula (IXa):

or is a pharmaceutically acceptable salt, or N-oxide thereof.

9. The pharmaceutical composition of claim 8 , wherein:

L 2 is C 1 -C 6 alkylene;

R 6 or R 7 are independently piperidinyl optionally substituted with at least one alkyl, —C(O)—O-(alkyl), —CH 2 —C(O)—O—(C 1-6 alkyl), -(alkyl)sulfonyl, -(alkylene)-OH, —CH 2 —C(O)—(C 1-6 alkyl), or carbamoyl.

10. The pharmaceutical composition of claim 9 , wherein: R A is —CH 3 or CF 3 .

11. The pharmaceutical composition of claim 1 , wherein the compound is

3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile;

5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(3-Fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(2-Fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

3-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile;

5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(8-Oxo-5-(4-((1-propionylpiperidin-4-yl)oxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(4-((1-isobutyrylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

Ethyl 4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxylate;

5-(5-(4-((1-Acetylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile;

5-(5-(4-((1-Ethylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile;

5-(5-(4-((1-(2-Hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methylpicolinonitrile;

5-(5-(4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(4-((1-(Methylsulfonyl)piperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

5-(5-(4-((1-Isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

Ethyl 2-(4-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidin-1-yl)acetate;

4-(4-(7-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)piperidine-1-carboxamide; or

a pharmaceutically acceptable salt, or N-oxide thereof.

12. The pharmaceutical composition of claim 1 , wherein the compound is:

5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile;

5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile;

3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl) picolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile;

3-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile;

5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile;

or a pharmaceutically acceptable salt or N-oxide thereof.

13. The pharmaceutical composition of claim 1 , wherein the compound is 5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

14. The pharmaceutical composition of claim 1 , wherein the compound is 5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

15. The pharmaceutical composition of claim 1 , wherein the compound is 3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl) picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

16. The pharmaceutical composition of claim 1 , wherein the compound is 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

17. The pharmaceutical composition of claim 1 , wherein the compound is 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

18. The pharmaceutical composition of claim 1 , wherein the compound is 3-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

19. The pharmaceutical composition of claim 1 , wherein the compound is 5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

20. The pharmaceutical composition of claim 1 , formulated in a dosage form suitable for delivering a therapeutically effective amount of the compound when administered in a single dosage form.

21. The pharmaceutical composition of claim 12 , formulated in a dosage form suitable for delivering a therapeutically effective amount of the compound when administered in a single dosage form.

22. The pharmaceutical composition of claim 1 , formulated in a divided dosage form suitable for delivering a therapeutically effective amount of the compound when administered multiple times over the span of one day.

23. The pharmaceutical composition of claim 12 , formulated in a divided dosage form suitable for delivering a therapeutically effective amount of the compound when administered multiple times over the span of one day.

24. The pharmaceutical composition of claim 1 , formulated in an oral dosage form and containing the compound in an amount in a range of from about 1 mg to about 500 mg.

25. The pharmaceutical composition of claim 12 , formulated in an oral dosage form and containing the compound in an amount in a range of from about 1 mg to about 500 mg.

26. A method of treating a patient with prostate cancer comprising administering to the patient a therapeutically effective amount of a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof or N-oxide thereof, wherein the therapeutically effective amount of the compound or pharmaceutically acceptable salt or N-oxide thereof is administered in a single dosage form or in a divided dosage form multiple times over the span of one day:

and wherein the compound of Formula (Ia) is:

5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile;

5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-trifluoromethyl) picolinonitrile;

3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)ox)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl) picolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile;

5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile;

3-Methyl-S-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile; or

5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile.

27. The method of claim 26 , wherein the compound is 5-(5-(4-((1-Methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-trifluoromethyl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

28. The method of claim 26 , wherein the compound is 5-(5-(2-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

29. The method of claim 26 , wherein the compound is 3-Methyl-5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl) picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

30. The method of claim 26 , wherein the compound is 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-methyl-picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

31. The method of claim 26 , wherein the compound is 5-(5-(3-Fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)-picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

32. The method of claim 26 , wherein the compound is 3-Methyl-5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

33. The method of claim 26 , wherein the compound is 5-(8-Oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.

34. The method of claim 26 , wherein the therapeutically effective amount of the compound is administered in a single dosage form.

35. The method of claim 26 , wherein the therapeutically effective amount of the compound is administered in a single dosage form.

36. The method of claim 26 , wherein the therapeutically effective amount of the compound is administered in a divided dosage form multiple times over the span of one day.

37. The method of claim 26 , wherein the therapeutically effective amount of the compound is administered in a divided dosage form multiple times over the span of one day.

38. The method of claim 26 , wherein the compound is administered to the patient in a range from about 0.01 to about 10 mg compound per kg per body weight per day.

39. The method of claim 26 , wherein the compound is administered to the patient in an amount ranging from about 1 mg per day to about 1000 mg per day.

40. The method of claim 26 , wherein the compound is administered to the patient in a range from about 0.01 to about 10 mg compound per kg per body weight per day.

41. The method of claim 26 , wherein the compound is administered to the patient in an amount ranging from about 1 mg per day to about 1000 mg per day.

42. The method of claim 26 , wherein the prostate cancer is a hormone dependent cancer.