Estrogen receptor-modulating compounds

1. A compound according to formula II′

wherein:

each R a is independently selected from H, C 1 -C 3 alkyl, phenyl (optionally substituted with 1-3 groups selected from fluorine, chlorine, C 1 -C 3 alkyl, CN, OC 1 -C 3 alkyl, OH), OH, OC 1-3 alkyl, CN, fluorine, chlorine, O(CO)R, O(CO)NR 1 R 2 , OPO 3 , OSO 3 ,O(SO 2 )NR 1 R 2 , or two adjacent R a together form:

R is C 1 -C 6 alkyl or aryl;

R 1 and R 2 are each independently hydrogen or C 1 -C 6 alkyl;

each R 3 is independently hydrogen; C 1 -C 12 acyl or C 1 -C 12 acyloxy;

each R 4 is independently hydrogen, C 1 -C 3 alkyl, fluorine or chlorine;

each R e is independently selected from hydrogen, halogen, OH, O(CO)R, O(CO)NR 1 R 2 ,

OPO 3 , OSO 3 ,O(SO 2 )NR 1 R 2 , or wherein two adjacent R e together form:

each R f is independently H, C 1 -C 3 alkyl, OC 1 -C 3 alkyl, fluorine or chlorine;

R g is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, CN, fluorine, chlorine or bromine;

X is CH 2 or a bond;

Y and Z are each independently selected from CR f ;

U and V are each independently selected from CR a ; and

W is CHR′—CHR′—NH—C 1 -C 4 alkyl, —CHR′—CHR′—NH—C 1 -C 4 fluoroalkyl, —CHR′—CHR′—NH—C 3 -C 6 cycloalkyl, —CHR′—CHR′—NH—C 1 -C 4 alkyl-C 3 -C 6 cycloalkyl,

wherein each R′ is independently H or C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein: X is CH 2 ; Y and Z are each CR f ; U and V are each CR a ; R g is F, Cl or CH 3 ; each R a is independently selected from H, OH, CH 3 and Cl; each R f is H; and W is —CH 2 —CH 2 —NH—CH 2 —CH 2 —CH 3 , —CH 2 —CH 2 —NH—CH 2 —CH 2 —CH 2 F,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein each R e is independently selected from hydrogen or OH, or wherein two adjacent R e together form

and wherein R 3 is H and R 4 is H.

4. The compound of claim 1 , having a structure according to formula III′:

wherein: Q is H or F; Rg is F, Cl, or CH 3 ; Ra is CH 3 , Cl or OMe; and Ra′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein Rg is F.

6. The compound of claim 5 , wherein Ra is CH 3 and Ra′ is H.

7. The compound of claim 1 , having a structure according to formula IV′:

wherein: Q is H or F; Rg is F, Cl, or CH 3 ; Ra is CH 3 , Cl or OMe; and Ra′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 , wherein Rg is F.

9. The compound of claim 8 , wherein Ra is CH 3 and Ra′ is H.

10. The compound of claim 1 , having a structure according to formula V′:

wherein: Q is H or F; Rg is F, Cl, or CH 3 ; Ra is CH 3 , Cl or OMe; and Ra′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein Rg is F.

12. The compound of claim 11 , wherein Ra is CH 3 and Ra′ is H.

13. The compound of claim 1 , having a structure according to formula VI′:

wherein: Q is H or F; Rg is F, Cl, or CH 3 ; Ra is CH 3 , Cl or OMe; and Ra′ is H, F or OH; or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein Rg is F.

15. The compound of claim 14 , wherein Ra is CH 3 and Ra′ is H.

16. The compound of claim 1 , wherein the compound selected from:

1-(4-(2-(Ethyl amino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol;

1-(4-(2-(Isopropyl amino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol;

1-(4-(2-(Cyclohexylamino)ethyl)benzyl)-2-(4-methoxyphenyl)-3-methyl-1H-indol-5-ol;

2-(4-Methoxyphenyl)-3-methyl-1-(4-(2-((2,2,2-trifluoroethyl)amino)ethyl)benzyl)-1 H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-5-ol;

1-(4-(2-(Ethyl amino)ethyl)benzyl)-3-fluoro-2-(4-methoxyphenyl)-1H-indol-5-ol;

3-Chloro-1-(4-(2-(ethyl amino)ethyl)benzyl)-2-(4-methoxyphenyl)-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol;

3-Fluoro-2-(2-methoxyphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol;

1-(4-(2-(Cyclobutylamino)ethyl)benzyl)-2-(2,6-dimethylphenyl)-3-fluoro-1H-indol-5-ol;

2-(2,6-Dimethylphenyl)-1-(4-(2-(ethylamino)ethyl)benzyl)-3-fluoro-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-hydroxy-2-methylphenyl)-1H-indol-5-ol;

3-Fluoro-1-(4-(2-((2-fluoroethyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indol-5-ol;

3-Fluoro-1-(4-(2-((3-fluoropropyl)amino)ethyl)benzyl)-2-(4-methoxy-2-methylphenyl)-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(4-fluoro-2-methylphenyl)-1H-indol-5-ol;

3-Fluoro-2-(4-methoxy-2-methylphenyl)-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol; 2-([1,1′-Biphenyl]-2-yl)-3-fluoro-1-(4-(2-(propylamino)ethyl)benzyl)-1H-indol-5-ol;

1-(4-(2-(Ethylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol;

1-(4-(2-(Cyclobutylamino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol;

3-Fluoro-1-(4-(2-(propyl amino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-ol;

1-(4-(2-(Butyl amino)ethyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol;

3-Fluoro-1-(4-(2-((3-fluoropropyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-ol;

3-Fluoro-1-(4-(2-((2-fluoroethyl)amino)ethyl)benzyl)-2-(o-tolyl)-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)propyl)benzyl)-3-fluoro-2-(o-tolyl)-1H-indol-5-ol;

1-(4-(2-((Cyclopropylmethyl)amino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol;

1-(4-(2-(Cyclopropylamino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol;

1-(4-(2-(Ethyl amino)ethyl)benzyl)-3-fluoro-2-(2-(trifluoromethyl)phenyl)-1H-indol-5-ol; 2-(2-Chlorophenyl)-1-(4-(2-(cyclopropylamino)ethyl)benzyl)-3-fluoro-1H-indol-5-ol;

N-Ethyl-2-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine;

N-(Cyclopropylmethyl)-2-(4(2((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenyl)ethan-1-amine;

N-(4((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclobutanamine;

N-(4((8-Fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)cyclopropanamine;

N-(4((8-fluoro-7-(o-tolyl)pyrrol o [3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine;

3-Fluoro-N-(4-O-fluoro-7-(o-tolyl)pyrrol o [3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine; and 3-Fluoro-N-(4-((8-fluoro-7-(o-tolyl)pyrrolo[3,2-e]indazol-6(3H)-yl)methyl)phenethyl)propan-1-amine.

17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

18. A method of treating a disease, syndrome, illness, or symptom associated with insufficient or overabundant estrogen levels in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. A method of treating a cancer selected from the group consisting of prostate cancer, breast cancer, endometrial cancer, lung cancer, hepatocellular cancer, lymphoma, multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroid cancer, testicular cancer, leukemia, and ovarian cancer in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.