Method of treating androgen receptor (AR)-positive breast cancers with selective androgen receptor modulator (SARMs)

1. A method of treating, reducing, suppressing the severity of or inhibiting AR-positive breast cancer in a subject with AR-positive breast cancer, comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by a structure of formula I:

X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

R is alkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, alkenyl or OH;

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

R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;

R 3 is H, F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , or Sn(R) 3 ;

Z is NO 2 , CN, COR, COOH, or CONHR;

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

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

n is an integer of 1-4; and

m is an integer of 1-3,

wherein said treating does not include preventing.

2. The method of claim 1 , wherein said SARM compound is represented by a structure of formula XIII:

or formula XIV:

3. The method of claim 1 , wherein said SARM compound is represented by a structure of formula II:

wherein X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COR, COOH or CONHR;

Y is I, CF 3 , Br, Cl, or Sn(R) 3 ;

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

R is a C 1 -C 4 alkyl, aryl, alkenyl, or hydroxyl; and

R 1 is CH 3 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .

4. The method of claim 3 , wherein said SARM compound is represented by a structure of formula:

5. The method of claim 1 , wherein said breast cancer is a breast cancer that has failed selective estrogen receptor modulator (tamoxifen, toremifene), aromatase inhibitor, trastuzumab, ado-trastuzumab emtansine, pertuzumab, lapatinib, exemestane, bevacizumab, and/or fulvestrant treatments.

6. A method of treating, reducing, suppressing the severity of or inhibiting metastatic or advanced AR-positive breast cancer in a subject with metastatic AR-positive breast cancer or advanced AR-positive breast cancer, comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by a structure of formula I:

X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

R is alkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, alkenyl or OH;

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

R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;

R 3 is H, F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , or Sn(R) 3 ;

Z is NO 2 , CN, COR, COOH, or CONHR;

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

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

n is an integer of 1-4; and

m is an integer of 1-3,

wherein said treating does not include preventing.

7. The method of claim 6 , wherein said SARM compound is represented by a structure of formula XIII.

or formula XIV:

8. The method of claim 6 , wherein said SARM compound is represented by a structure of formula II:

wherein X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COR, COOH or CONHR;

Y is I, CF 3 , Br, Cl, or Sn(R) 3 ;

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

R is a C 1 -C 4 alkyl, aryl, phenyl, alkenyl, or hydroxyl; and

R 1 is CH 3 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .

9. The method of claim 8 , wherein said SARM compound is represented by a structure of formula:

10. The method of claim 6 , wherein said metastatic or advanced breast cancer is AR-positive ER-positive metastatic or advanced breast cancer.

11. A method of treating, reducing, suppressing the severity of, or inhibiting refractory AR-positive breast cancer in a subject with refractory AR-positive breast cancer, comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by a structure of formula I:

X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

R is alkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, alkenyl or OH;

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

R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, NO 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;

R 3 is H, F, Cl, Br, I, CN, NO 2 , COR, COOH, CONHR, CF 3 , or Sn(R) 3 ,

Z is NO 2 , CN, COR, COOH, or CONHR;

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

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

n is an integer of 1-4; and

m is an integer of 1-3,

wherein said treating does not include preventing.

12. The method of claim 11 , wherein said SARM compound is represented by a structure of formula XIII:

or formula XIV:

13. The method of claim 11 , wherein said SARM compound is represented by a structure of formula II:

wherein X is O;

G is O;

T is OH, OR, —NHCOCH 3 , or NHCOR;

Z is NO 2 , CN, COR, COOH or CONHR;

Y is I, CF 3 , Br, Cl, or Sn(R) 3 ;

Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO 2 R, SO 2 R or SR;

R is a C 1 -C 4 alkyl, aryl, phenyl, alkenyl, or hydroxyl; and

R 1 is CH 3 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 .

14. The method of claim 13 , wherein said SARM compound is represented by a structure of formula:

15. The method of claim 11 , wherein said refractory AR-positive breast cancer is AR-positive ER-positive refractory breast cancer.

16. The method of claim 1 , wherein said AR-positive breast cancer is AR-positive ER-positive breast cancer.

17. The method of claim 1 , wherein said AR-positive breast cancer is ER-negative PR-negative and HER2-negative.

18. The method of claim 1 , wherein said AR-positive breast cancer is ER-negative PR-negative and HER2-positive.

19. The method of claim 1 , wherein said AR-positive breast cancer is ER-negative PR-positive and HER2-negative.

20. The method of claim 1 , wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-positive.

21. The method of claim 1 , wherein said AR-positive breast cancer is ER-positive, PR-negative and HER2-positive.

22. The method of claim 1 , wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-negative.

23. The method of claim 6 , wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-negative.

24. The method of claim 11 , wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-negative.

25. The method of claim 1 , comprising administering a racemic mixture of said SARM compound, or an isomer, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor modulator, or any combination thereof.

26. The method of claim 25 , wherein said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical product in liquid form; subcutaneously implanting in said subject a pellet containing said pharmaceutical product; orally administering to said subject said pharmaceutical product in a liquid or solid form; or topically applying to said subject said pharmaceutical product.

27. The method of claim 26 , wherein said pharmaceutical product is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.

28. The method of claim 6 , comprising administering a racemic mixture of said SARM compound, or an isomer, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor modulator, or any combination thereof.

29. The method of claim 11 , comprising administering a racemic mixture of said SARM compound, or an isomer, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or crystal of said selective androgen receptor modulator, or any combination thereof.