Polycyclic estrogen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9586952-B2
Application number	US-201414851215-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

Described herein are compounds that are estrogen receptor modulators. 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 of Formula (VII), or a pharmaceutically acceptable salt, or N-oxide thereof:

wherein,
ring A is 3-7 membered monocyclic C 2 -C 6 heterocycloalkyl, 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl;
each R a is independently selected from the group consisting of H, halogen, —NR 7 R 8 , —CN, —OH, —OR 9 , —SR 8 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, and substituted or unsubstituted C 1 -C 6 heteroalkyl;
m is 0, 1, 2, 3, or 4;

ring B is phenyl, indanyl, indenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or 8-, 9- or 10-membered bicyclic heteroaryl;
each R b is independently selected from the group consisting of H, halogen, —NR 7 R 8 , —CN, —OH, —OR 9 , —SR 8 , —S(═O)R 9 , —S(═O) 2 R 9 , —NHS(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 8 , —OCO 2 R 9 , —C(═O)N(R 8 ) 2 , —OC(═O)N(R 8 ) 2 , —NR 7 C(═O)N(R 8 ) 2 , —NR 7 C(═O)R 9 , —NR 7 C(═O)OR 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted phenyl and substituted or unsubstituted monocyclic heteroaryl;
n is 0, 1, 2, 3, or 4;
each R c is independently selected from the group consisting of H, halogen, —CN, —OH, —OR 9 , C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
p is 0, 1, 2, 3 or 4;
R 5 is H, C 1 -C 4 alkyl, or halogen;
R 6 is H, C 1 -C 4 alkyl, or halogen;

R 1 is —C(═O)—Z, a carboxylic acid bioisostere, or a substituted or unsubstituted N-containing C 2 -C 8 heterocycloalkyl;
Z is —OH, —OR 9 , —NR 7 R 8 , —NR 7 S(═O) 2 R 9 , —NHOH or —NR 7 OR 9 ;

R 2 is halogen, —CN, —NO 2 , —SR 9 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 deuteroalkyl, C 3 -C 6 cycloalkyl, —C 1 -C 4 alkylene-W, —C 1 -C 4 fluoroalkylene-W, —C 3 -C 6 cycloalkylene-W;
W is hydroxy, halogen, —CN, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 3 -C 6 cycloalkyl;

each R 3 is independently selected from the group consisting of H, halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and C 1 -C 6 heteroalkyl;
q is 0, 1, 2, 3 or 4;

R 4 is H, halogen, —CN, —OH, —OR 9 , —SR 8 , —S(═O)R 9 , —S(═O) 2 R 9 , —NHS(═O) 2 R 9 , —S(═O) 2 N(R 8 ) 2 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 8 , —C(═O)N(R 8 ) 2 , —OC(═O)N(R 8 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, or C 1 -C 6 heteroalkyl;
each R 7 is independently H or C 1 -C 6 alkyl;
each R 8 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted benzyl;
each R 9 is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted benzyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is 3-7 membered monocyclic N-containing C 2 -C 6 heterocycloalkyl, N-containing 5-membered monocyclic heteroaryl, or N-containing 6-membered monocyclic heteroaryl; and
ring B is phenyl, indanyl, indenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or 8-, 9- or 10-membered bicyclic heteroaryl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is aziridinyl, azetindinyl, pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; and
ring B is phenyl, naphthyl, indanyl, indenyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, inolizinyl, azainolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, azabenzotriazolyl, benzoxazolyl, azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl, or purinyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C(═O)—Z,

Z is —OH, —OR 9 , or —NR 7 R 8 .

6. The compound of claim of 1 , wherein the compound of Formula (VII) has the following structure of Formula (VIII) or Formula (IX):

or is a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is aziridinyl, azetindinyl, pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is C-linked 3-7 membered monocyclic N-containing C 2 -C 6 heterocycloalkyl, C-linked N-containing 5-membered monocyclic heteroaryl, or C-linked N-containing 6-membered monocyclic heteroaryl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is N-linked 3-7 membered monocyclic N-containing C 2 -C 6 heterocycloalkyl, or N-linked N-containing 5-membered monocyclic heteroaryl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Assignees

• Seragon Pharmaceuticals Inc
• Genentech Inc

Inventors

• Smith Nicholas D
• Govek Steven P
• Kahraman Mehmet
• Bonnefous Celine
• Julien Jackaline D

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/30

  Oestrogens · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P37/02

  Immunomodulators · CPC title