Estrogen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-2016304450-A1
Application number	US-201514972333-A
Country	US
Kind code	A1
Filing date	Dec 17, 2015
Priority date	Dec 18, 2014
Publication date	Oct 20, 2016
Grant date	—

Abstract

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.

First claim

What is claimed is:

1 . A compound that has the following structure of Formula (I):

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

is a selective estrogen receptor modulator fragment;
Z 1 and Z 2 are independently selected from —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 )— or —(CH 2 CH 2 )—; and
R 1 is selected from 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 , and —C(O)N(CH 3 ) 2 ;
where carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from 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 , having the structure of Formula (II):

wherein:
indicates a single or double bond where one is a double bond and one is a single bond;
Y 1 is CR 6 and Y 2 is N; Y 1 is S and Y 2 is C; or Y 1 is NR 7 and Y 2 is C;
each R 2 and each R 3 are independently selected from 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 , and —SO 2 NHR 12 ;
R 6 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 12 carbocyclyl, —(C 1 -C 6 alkyl)-(C 3 -C 12 carbocyclyl), C 2 -C 20 heterocyclyl, —(C 1 -C 6 alkyl)-(C 2 -C 20 heterocyclyl), —SO 2 R 11 , —(C 1 -C 6 alkyl)-(C 1 -C 20 heteroaryl), C 1 -C 20 heteroaryl, and C 6 -C 20 aryl;
R 7 is selected from H and C 1 -C 4 alkyl;
each R 10 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 11 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl;
each R 12 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 13 and each R 14 are independently selected from H and C 1 -C 4 alkyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

3 . The compound of claim 2 , having the structure of Formula (IIa):

4 . The compound of claim 3 , wherein R 6 is C 1 -C 6 alkyl.

5 . The compound of claim 4 , wherein R 6 is —CH 3 .

6 . The compound of claim 2 , having the structure of Formula (IIb):

7 . The compound of claim 6 , wherein Z 1 is —O— or —C(O)—.

8 . The compound of claim 2 , having the structure of Formula (IIc):

9 . The compound of claim 8 , wherein R 7 is C 1 -C 4 alkyl.

10 . The compound of claim 9 , wherein R 7 is —CH 3 .

11 . The compound of claim 8 , wherein Z 1 is —C(O)—.

12 . The compound of claim 1 , having the structure of Formula (III):

wherein:
indicates a single or double bond;
each R 2 and each R 3 are independently selected from 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 , and —SO 2 NHR 12 ;
each R 10 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 11 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl;
each R 12 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 13 and each R 14 are independently selected from H and C 1 -C 4 alkyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

13 . The compound of claim 12 , having the structure of Formula (IIIa):

14 . The compound of claim 13 , wherein Z 1 is —O—.

15 . The compound of claim 12 , having the structure of Formula (IIIb):

16 . The compound of claim 15 , wherein Z 1 is —C(O)—.

17 . The compound of claim 12 , having the structure of Formula (IIIc):

18 . The compound of claim 17 , wherein Z 1 is a bond.

19 . The compound of claim 1 , having the structure of Formula (IV):

wherein:
each R 2 is independently selected from 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 , and —SO 2 NHR 12 ; or two R 2 together with the carbon atoms to which they are attached are combined to form a C 2 -C 9 heterocyclyl, or C 1 -C 12 heteroaryl;
R 4 is

and R 5 is C 1 -C 4 alkyl or C 3 -C 8 carbocyclyl; or R 4 and R 5 together with the carbon atom to which they are attached are combined to form a C 3 -C 12 carbocyclyl;
each R 10 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 11 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl;
each R 12 is independently selected from H, C 1 -C 4 alkyl, and C 1 -C 4 fluoroalkyl;
each R 13 and each R 14 are independently selected from H and C 1 -C 4 alkyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

20 . The compound of claim 19 , having the structure of Formula (IVa):

wherein each R 3 is independently selected from 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 f

Assignees

• Genentech Inc

Inventors

• Liang Jun
• Ortwine Daniel Fred
• Wang Xiaojing
• Govek Steven P
• Kahraman Mehmet
• Nagasawa Johnny Y
• Smith Nicholas D
• Goodacre Simon Charles
• Ray Nicholas Charles

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/32

  Antioestrogens · CPC title

• A61P43/00

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

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title