Estrogen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-2016175284-A1
Application number	US-201514972336-A
Country	US
Kind code	A1
Filing date	Dec 17, 2015
Priority date	Dec 18, 2014
Publication date	Jun 23, 2016
Grant date	—

Abstract

Described herein are compounds that are estrogen receptor modulators of Formula I:

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, 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.

First claim

What is claimed is:

1 . A compound selected from Formula I:

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
X is —CH 2 — or —CH 2 CH 2 —;
each R 1 is independently selected from halogen, —CN, —OR 3 , C 1 -C 4 alkyl, —C 1 -C 4 alkyl-OH, C 1 -C 4 fluoroalkyl, —C(═O)OR 7 , —NHC(═O)R 4 , —C(═O)NHR 7 , —SO 2 R 4 , —NHSO 2 R 4 , and —SO 2 NHR 7 ; or two R 1 together with the carbon atoms to which they are attached form a C 2 -C 7 heterocycloalkyl ring;
R 2 is H, halogen, —CN, C 1 -C 4 alkyl, —OC 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl or C 3 -C 6 cycloalkyl;
each R 3 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 4 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl;
each R 5 is independently H, halogen, —CN, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;
R 6 is H or CH 3 ;
each R 7 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
m is 0, 1, or 2; and
n is 0, 1, 2, or 3.

2 . The compound of claim 1 wherein:
each R 1 is independently selected from the group consisting of F, Cl, —CN, —OH, —OCH 3 , —OCF 3 , —CH 3 , —CH 2 OH, —CF 3 , —C(═O)OH, —C(═O)OCH 3 , —C(═O)OCH 2 CH 3 , —NHC(═O)CH 3 , —C(═O)NH 2 , —SO 2 CH 3 , —NHSO 2 CH 3 , and —SO 2 NH 2 ;
R 2 is H, F, Cl, —CN, —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —CF 3 , cyclopropyl, or cyclobutyl; and
R 5 is H, F, Cl, —CN, —CH 3 , or —CF 3 .

3 . The compound of claim 1 selected from the structures:

4 . The compound of claim 3 wherein n is 1.

5 . The compound of claim 4 wherein R 1 is F, Cl, —CN, or —OH.

6 . The compound of claim 1 wherein R 2 is —CH 3 .

7 . The compound of claim 1 wherein R 6 is H or —CH 3 .

8 . The compound of claim 1 wherein m is 0 or 1, and R 5 is F, Cl, —CN, or —CH 3 .

9 . The compound of claim 1 wherein X is —CH 2 —.

10 . The compound of claim 1 wherein X is —CH 2 CH 2 —.

11 . The compound of claim 1 having Formula (Ia):

12 . The compound of claim 11 having Formula (Ib or Formula (Ic):

13 . The compound of claim 12 selected from the structures:

14 . The compound of claim 13 wherein R 1 is F or —OH.

15 . The compound of claim 1 selected from Table 1a.

16 . The compound of claim 1 selected from Table 1b.

17 . A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

18 . A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

19 . A method of treating an ER-related disease or disorder in a patient comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 17 to a patient with an ER-related disease or condition.

20 . The method of claim 19 wherein the ER-related disease or disorder is cancer selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

21 . The method of claim 20 wherein the cancer is breast cancer.

22 . The method of claim 20 further comprising administering an additional therapeutic agent selected from 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, and an agent for treating immunodeficiency disorders.

23 . A kit for treating a condition mediated by an estrogen receptor, comprising:
a) a pharmaceutical composition of claim 17 ; and b) instructions for use.

Assignees

• Genentech Inc

Inventors

• Labadie Sharada
• Li Jun
• Liang Jun
• Ortwine Daniel Fred
• Wang Xiaojing
• Zbieg Jason
• Govek Steven P
• Kahraman Mehmet
• Nagasawa Johnny Y
• Smith Nicholas D

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P5/30

  Oestrogens · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title