Androgen receptor modulators and methods for their use

1. A compound having the structure (I-A):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:

A and B are each independently aryl or heteroaryl;

X is a bond, —(CR 8 R 9 ) t —, —O—, —C(═O)—, —S(O) p —, —NR 10 —, —CONR 10 —, —SO 2 NR 10 —, or —NR 10 SO 2 —;

Y and Z are each independently a bond, —(CR 8 R 9 ) t —, —O—, —S(O) p —, —NR 10 —, —CONR 10 —, —NR 10 CO—, —SO 2 NR 10 —, or —NR 10 SO 2 —;

V is a bond, optionally substituted —(CR 11 R 12 ) m —, —C(═O)—, —N(R 10 )CO—, —CONR 10 —, or —NSO 2 R 10 —;

R is —(CR 4a R 4b )—(CR 5a R 5b )—W or W;

W is hydrogen, halogen, —CF 3 , —CF 2 R 10 , —CN, —OR 13 , —NR 13 R 14 , optionally substituted —CONR 13 R 14 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

D is —(CR 1a R 1b ) q —, —O—, or —NR 10 —;

L is —(CR 2a R 2b )—R 3 or -E-R 3 ;

E is —(CR 2a R 2b ) g —, —O—, —NR 10 —, or —NR 10 —(CR 2a R 2b ) g —;

R 1a , R 1b , R 2a , and R 2b are each independently hydrogen, halogen, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted —OCO(C 1 -C 6 alkyl), —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-NR 13 R 14 , NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 1a and R 1b taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 2a and R 2b taken together form a CO, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 1a , R 1b , R 2a and R 2b taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 4a , R 4b , R 5a , and R 5b are each independently hydrogen, halogen, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted —OCO(C 1 -C 6 alkyl), —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-NR 13 R 14 , NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 4a and R 4b taken together form a CO, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 4a , R 4b , R 5a and R 5b taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 3 is absent, hydrogen, —CN, —CF 3 , —OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted —OR 15 , optionally substituted C 1 -C 6 alkoxy, —NH 2 , —NR 16 R 17 , —NR 16 COR 18 , NR 16 S(O) p R 18 , —CONR 14 R 15 , —SONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —S(O) p R 18 , —N 3 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 2a , R 2b and R 3 taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 2a and R 10 taken together form an optionally substituted heterocyclyl;

R 6 and R 7 are each independently H, methyl, methoxy, —CN, F, Cl, Br, I, 123 I, —CF 3 , —OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted —(C 1 -C 6 alkyl)-(C 1 -C 6 alkoxy), optionally substituted —(C 1 -C 6 alkyl)-OH, —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl-NR 13 R 14 , —NR 14 SO 2 R 16 , optionally substituted —(C 1 -C 6 alkyl)NR 14 SO 2 R 16 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl)-CONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl)-SO 2 NR 14 R 15 , optionally substituted —SO 2 R 16 , or optionally substituted —(C 1 -C 6 alkyl)-SO 2 R 16 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 8 , R 9 , R 11 and R 12 are each independently hydrogen, —OH, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkylamino, optionally substituted —OCO(C 1 -C 6 alkyl), —NR 13 R 14 , optionally substituted —(C 1 -C 6 alkyl)-NR 13 R 14 , —NR 14 COR 16 , optionally substituted —(C 1 -C 6 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , optionally substituted —(C 1 -C 6 alkyl-CONR 14 R 15 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 8 and R 9 taken together form an optionally substituted carbocyclyl or optionally substituted heterocyclyl;

or alternatively, R 11 and R 12 , on a same carbon atom or a different carbon atom, taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 10 is hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, —CO(C 1 -C 6 alkyl), optionally substituted C 1 -C 6 alkylamino, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

or alternatively, R 14 and R 15 are taken together to form an optionally substituted heterocyclyl, or optionally substituted heteroaryl;

or alternatively, R 16 and R 17 are taken together to form an optionally substituted heterocyclyl, or optionally substituted heteroaryl;

m is 0, 1, 2, 3, or 4;

each n is independently 0, 1 or 2;

each p is independently 0, 1 or 2;

q is 0, 1 or 2;

each g is independently 0, 1, 2, 3, or 4; and

each t is independently 1 or 2.

2. The compound of claim 1 , wherein R is W.

3. The compound of claim 1 , wherein W is hydrogen, halogen, —CF 3 , or —NR 13 R 14 .

4. The compound of claim 1 , wherein L is -E-R 3 .

5. The compound of claim 1 , wherein R 3 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted —OR 15 , optionally substituted —SR 18 , optionally substituted C 1 -C 6 alkoxy, —NR 16 R 17 , —NR 16 SR 18 , —NR 16 SOR 18 , —NR 16 SO 2 R 18 , —NR 16 COR 18 , —CONR 14 R 15 , —SONR 14 R 15 , —SO 2 NR 14 R 15 , optionally substituted —SOR 18 , or optionally substituted —SO 2 R 18 .

6. The compound of claim 1 , wherein R 3 is selected from hydrogen, —C 1 -C 3 alkyl, —NR 16 SO(C 1 -C 3 alkyl), —NR 16 SO 2 (C 1 -C 3 alkyl), —SONR 14 R 15 , —SO 2 NR 14 R 15 , —SOR 18 , or —SO 2 R 18 .

7. The compound of claim 1 , having the structure of formula (Ic):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:

X, Y, Z are each independently a bond, —(CR 8 R 9 ) t —, O, S(O) p , NR 10 , CONR 10 , NR 10 CO, SO 2 NR 10 , or NR 10 SO 2 ;

V is a bond or optionally substituted —(CR 11 R 12 ) m —;

W is hydrogen, halogen, —CF 3 , CN, OR 13 or optionally substituted CON(R 13 R 14 );

R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently hydrogen, halogen, hydroxy, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy; or

R 1a and R 1b taken together are optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 2a and R 2b taken together are CO, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 1a , R 1b , R 2a and R 2b taken together are optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 4a and R 4b taken together are CO, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 4a , R 4b , R 5a and R 5b taken together are optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 3 is absent, hydrogen, OH, OR 15 , NH 2 , NR 16 R 17 , NR 16 COR 18 , NR 16 S(O) p R 18 , S(O) p R 18 , N 3 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 2a , R 2b and R 3 taken together are optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R 6 and R 7 is independently H, methyl, methoxy, —CN, F, Cl, Br, I, 123 I or —CF 3 ;

R 8 , R 9 , R 10 , R 11 and R 12 are each independently hydrogen, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkylamino; or

R 8 and R 9 are optionally substituted carbocyclyl or optionally substituted heterocyclyl; or

R 11 and R 12 taken together form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 16 and R 17 are taken together to form an optionally substituted heterocyclyl, or optionally substituted heteroaryl;

m is independently 0, 1 or 2;

each n is independently 0, 1 or 2;

each p is independently 0, 1 or 2; and

each t is independently 1 or 2.

8. The compound of claim 1 , wherein X is bond, —(CR 8 R 9 ) t — or —NR 10 —.

9. The compound of claim 1 , wherein each R 8 and R 9 are hydrogen or methyl.

10. The compound claim 1 , wherein Y is —(CR 8 R 9 ) t —, —O—, or —NR 10 —.

11. The compound of claim 1 , wherein Z is —(CR 8 R 9 ) t —, O, or NR 10 .

12. The compound of claim 1 , wherein V is a bond or an optionally substituted —C(R 11 R 12 ) m —.

13. The compound of claim 1 , having the structure of formula (Id) or (Ie):

14. The compound of claim 1 , wherein R 1a and R 1b are each hydrogen or optionally substituted C 1-6 alkyl.

15. The compound of claim 1 , wherein R 2a and R 2b are each hydrogen or optionally substituted C 1-6 alkyl.

16. The compound of claim 1 , wherein R 3 is —NR 16 R 17 , —NR 16 COR 18 , —NR 16 S(O) p R 18 , —S(O) p R 18 , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

17. The compound of claim 1 , wherein R 3 is —NR 16 S(O) p R 18 or —S(O) p R 18 .

18. The compound of claim 17 , wherein R 16 is hydrogen; R 18 is C 1 -C 6 alkyl; and p is 2.

19. The compound of claim 1 , wherein R 4a , R 4b , R 5a , and R 5b are each independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.

20. The compound claim 1 , wherein W is Cl.

21. The compound of claim 1 , wherein each occurrence of R 6 and R 7 is independently H, methyl, methoxy, CN, F, Cl, Br, or I.

22. The compound of claim 1 , wherein D is —(CH 2 ) 2 —.

23. The compound of claim 1 , wherein the compound has the structure of formula (D):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:

X is a bond, —NR 10 —, or —(CR 8a R 9a ) t —;

Y and Z are each independently a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—;

V is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, —CH 2 CH(OH)CH 2 —, or —CH 2 C(OH)(CH 3 )CH 2 —;

W is halogen, —NH 2 , or —CF 3 ;

D is —NR 10 — and E is —(CR 2a R 2b ) g —, —NR 10 —, or —NR 10 —(CR 2a R 2b ) g —;

or alternatively, E is —NR 10 — or —NR 10 —(CR 2a R 2b ) g —, and D is —(CR 1a R 1b ) q — or —NR 10 —;

R 1a , R 1b , R 2a , and R 2b are each independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —OCO(C 1 -C 3 alkyl), —NR 13 R 14 , —(C 1 -C 3 alkyl)-NR 13 R 14 , —NR 14 COR 16 , —(C 1 -C 3 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , or —(C 1 -C 6 alkyl)-CONR 14 R 15 ; or (R 1a and R 1b ) or (R 2a and R 2b ) taken together form an oxo (═O), an optionally substituted carbocyclyl, or an optionally substituted heterocyclyl;

R 3 is selected from hydrogen, —C 1 -C 6 alkyl, —OR 15 , —SR 18 , —C 1 -C 6 alkoxy, —NR 16 R 17 , —NR 16 SR 18 , —NR 16 SOR 18 , —NR 16 SO 2 R 18 , —NR 16 COR 18 , —CONR 14 R 15 , —SONR 14 R 15 , —SO 2 NR 14 R 15 , SOR 18 , or —SO 2 R 18 ;

R 6 and R 7 are each independently H, halogen, —CN, —CF 3 , —OH, or C 1 -C 3 alkyl;

R 8a and R 9a are each independently hydrogen, halogen, —OH, or C 1 -C 3 alkyl; or R 8a and R 9a taken together form an 3- to 6-membered carbocyclyl or heterocyclyl;

R 10 is each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or —CO(C 1 -C 3 alkyl);

R 13 , R 14 , R 15 , R 16 , R 17 and R 18 a are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form an optionally substituted 5- or 6-membered heterocyclyl;

m is 0, 1, 2, 3, or 4;

each n is independently 0, 1 or 2;

q is 0, 1 or 2;

each g is independently 0, 1, 2, 3, or 4; and

each t is independently 1 or 2.

24. The compound of claim 1 , wherein the compound has the structure of formula (E):

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:

X is a bond, —NR 10 —, or —(CR 8a R 9a ) t —;

Y and Z are each independently a bond, —CH 2 —, —C(CH 3 )H—, —O—, —S—, —NH—, —NCH 3 —, or —N(COCH 3 )—;

V is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, —CH 2 CH(OH)CH 2 —, or —CH 2 C(OH)(CH 3 )CH 2 —;

W is halogen, —NH 2 or —CF 3 ;

D is —O— or —NR 10 — and E is —(CR 2a R 2b ) gg —;

or alternatively, E is —O—, —NR 10 — or —NR 10 —(CR 2a R 2b ) g —, and D is —(CR 1a R 1b ) q —;

R 1a , R 1b , R 2a , and R 2b are each independently hydrogen, halogen, —OH, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, —OCO(C 1 -C 3 alkyl), —(C 1 -C 3 alkyl-NR 13 R 14 , —NR 14 COR 16 , —(C 1 -C 3 alkyl)-NR 14 COR 16 , —CONR 14 R 15 , or —(C 1 -C 6 alkyl)-CONR 14 R 15 ; or (R 1a and R 1b ) or (R 2a and R 2b ) taken together form an oxo (═O), an optionally substituted carbocyclyl, or an optionally substituted heterocyclyl;

R 3 is selected from hydrogen, —C 1 -C 6 alkyl, —OR 15 , —SR 18 , —C 1 -C 6 alkoxy, —NR 16 R 17 , —NR 16 SR 18 , —NR 16 SOR 18 , —NR 16 SO 2 R 18 , —NR 16 COR 18 , —CONR 14 R 15 , —SO 2 NR 14 R 15 , —SOR 18 , or —SO 2 R 18 ;

R 6 and R 7 are each independently H, halogen, —CN, —CF 3 , —OH, or C 1 -C 3 alkyl;

R 8a and R 9a are each independently hydrogen, halogen, —OH, or C 1 -C 3 alkyl; or R 8a and R 9a taken together form an 3- to 6-membered carbocyclyl or heterocyclyl;

R 10 is each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, or —CO(C 1 -C 3 alkyl);

R 13 , R 14 , R 15 , R 16 , R 17 an R 18 are each independently hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, or C 2 -C 3 alkynyl; or R 14 and R 15 taken together form an optionally substituted 5- or 6-membered heterocyclyl;

m is 0, 1, 2, 3, or 4;

each n is independently 0, 1 or 2;

q is 1 or 2;

g is 0, 1, 2, 3, or 4;

gg is 1, 2, 3, or 4; and

t is 1 or 2.

25. The compound of claim 24 , wherein R 3 is selected from —NHSO 2 (C 1 -C 3 alkyl), —NCH 3 SO 2 (C 1 -C 3 alkyl), or —SO 2 (C 1 -C 3 alkyl).

26. A compound selected from

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof.

27. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27 , further comprising one or more additional therapeutic agents.