Estrogen receptor modulators
Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
A 1 is an optionally substituted aryl;
R 1 is an optionally substituted cycloalkyl;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 2 and R 3 together with the carbon to which R 2 and R 3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 4 and R 5 together with the carbon to which R 4 and R 5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine;
R 10 is hydrogen, deuterium, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl;
R 11 is hydrogen or an optionally substituted C 1-6 alkyl; and
R 12 is hydrogen or C 1-3 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an optionally substituted phenyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein A 1 is a substituted phenyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein A 1 is a 3,5-difluorophenyl.
6. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an unsubstituted phenyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a substituted cycloalkyl.
9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is an unsubstituted bicyclopentyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 1 is an unsubstituted bicyclo[1.1.1]pentyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl and difluoromethyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein any one or more of each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is hydrogen.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydroxy.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of halogen, hydroxy, and unsubstituted alkoxy.
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 7 is fluoro or methoxy.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy.
17. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
18. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
19. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
20. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
21. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
22. A method of making a compound of Formula 11A: comprising:
reacting a compound of Formula 11-1 with benzaldehyde to form a compound of Formula 11-2:
reacting the compound of Formula 11-2 with tricyclo[1.1.1.0 1,3 ]pentane of Formula 11-3 to form a compound of Formula 11-4:
hydrogenating the compound of Formula 11-4 to form a compound of Formula 11-5:
reacting the compound of Formula 11-5 with (E)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate to form a compound of Formula 11-6:
hydrolyzing the compound of Formula 11-6 to form the compound of Formula 11A.
23. The compound of claim 1 of the Formula 11A:
or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising an effective amount of the compound of claim 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.