Estrogen receptor modulators and uses thereof
Described herein are compounds that are estrogen receptor modulators of Formula (I): and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein SERMF is a selective estrogen receptor modulator fragment and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
1. A compound that has the following structure of Formula (IIa):
stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
Z 1 and Z 2 are independently —O—, —(CH 2 )—, —C(O)—, or a bond;
Cy is C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, or C 1 -C 20 heteroaryl;
X is —(CH 2 )—;
R 1 is H, F, Cl, —CN, —CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —CH(CF 3 )OH, —CH 2 F, —CHF 2 , —CH 2 CHF 2 , —CF 3 , —CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , or —C(O)N(CH 3 ) 2 ;
each R 2 and each R 3 are independently halogen, —CN, —OR 10 , —NR 13 R 14 , C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, —OC 2 -C 4 alkyl-OH, C 1 -C 4 fluoroalkyl, —C(═O)OR 12 , —NHC(═O)R 11 , —C(═O)NHR 12 , —SO 2 R 11 , —NHSO 2 R 11 , or —SO 2 NHR 12 ;
R 6 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
each R 10 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;
each R 11 is independently C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl;
each R 12 is independently H, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;
each R 13 and each R 14 are independently H or C 1 -C 4 alkyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3;
where carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently comprising F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OCF 3 , —OCHF 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, pyrrolidin-1-yl, and morpholino.
2. The compound of claim 1 , wherein R 6 is C 1 -C 6 alkyl.
3. The compound of claim 2 , wherein R 6 is —CH 3 .
4. The compound of claim 1 , wherein Cy is phenyl or C 2 -C 9 heteroaryl.
5. The compound of claim 1 , wherein Z 1 is —(CH 2 )—.
6. The compound of claim 1 , wherein Z 2 is —O—.
7. The compound of claim 1 , wherein R 1 is H or —CH 3 .
8. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
9. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 , with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
10. A method of treating an ER mediated disease or disorder in a patient having the ER-mediated disease or disorder, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 8 to the patient, wherein the ER-mediated disease or disorder comprises breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer.
11. The method of claim 10 wherein the cancer is breast cancer.
12. The method of claim 10 further comprising administering an additional therapeutic agent comprising an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
13. A kit for treating a condition mediated by an estrogen receptor, wherein the condition comprises breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the kit comprising:
a) a pharmaceutical composition of claim 8 ; and
b) instructions for use.
14. The compound of claim 1 selected from:
1-(4-(2-(3-(Fluoromethyl)azetidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol;
1-(4-(2-(3-(Fluoromethyl)azetidin-1-yl)ethoxy)benzyl)-2-(4-fluorophenyl)-3-methyl-1H-indol-5-ol;
1-(4-(2-(3-(Fluoromethyl)azetidin-1-yl)ethoxy)benzyl)-3-methyl-2-phenyl-1H-indole;
4-(1-(4-(2-(3-(Fluoromethyl)azetidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indol-2-yl)phenol;
1-[[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]methyl]-2-(4-hydroxy-3-methyl-phenyl)-3-methyl-indol-5-ol;
2-(3-chloro-4-hydroxy-phenyl)-1-[[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]methyl]-3-methyl-indol-5-ol;
2-(2-chloro-4-hydroxy-phenyl)-1-[[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]methyl]-3-methyl-indol-5-ol;
4-fluoro-1-[[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol;
6-fluoro-1-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol; and
1-[[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]methyl]-2-(4-hydroxy-2-methyl-phenyl)-3-methyl-indol-5-ol; or a pharmaceutically acceptable salt thereof.