Benzothiophene-based selective estrogen receptor downregulator compounds

Patent metadata

Field	Value
Publication number	US-11072595-B2
Application number	US-201916424240-A
Country	US
Kind code	B2
Filing date	May 28, 2019
Priority date	Dec 9, 2015
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.

First claim

We claim:

1. A compound, or a pharmaceutically acceptable salt thereof of Formula

wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
X D is selected from —O—, —CH 2 —, —S—, —NR 17 —, —CHF—, —CF 2 —, and cycloalkyl;
Y is selected from —C(O)—, —O—, —CF 2 —, or C 3 cycloalkyl, —CH 2 —, —S—, —NH—, and —NMe;
Ring D is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;
Ring E is phenyl, heteroaryl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;
R 19 is selected from R 14 ;
R 18 is hydroxyl;
R 20 is hydrogen;
R 11 is selected from —CH═CHCOOR 17 , —NR 17 (CO)COOR 17 , —COOR 17 , cycloalkyl-COOR 17 , —C 2 -C 6 alkenylene-COOR 17 , —C 2 -C 6 alkynylene-COOR 17 ,—CH═CHC(O)R 16 , —NR 17 (CO)C(O)R 16 , —C(O)R 16 , -cycloalkyl-C(O)R 16 , —C 2 -C 6 alkenylene-C(O)R 16 and —C 2 -C 6 alkynylene-C(O)R 16 ;
R 12 , R 13 , and R 14 are independently selected at each occurrence from —OR 15 , —SR 15 , —N(R 15 ) 2 , aryl, heteroaryl, halogen, —CN, —NO 2 , haloalkyl, cycloalkyl, thiol, C 1 -C 6 alkyl, —O(C 1 -C 6 fluoroalkyl), —C(O)R 16 , —C(S)R 16 , —OSO 2 R 16 , —NHSO 2 R 16 , —N(alkyl)SO 2 R 16 , —OP(O)(R 16 ) 2 , —P(O)(R 16 ) 3 , —P(O)R 16 , —S 2 R 16 , alkyne, alkene, arylalkyl, aryloxy, heteroarylalkyl, and C 1 -C 6 fluoroalkyl;
R 15 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
R 16 is independently selected at each occurrence from —N(R 15 ) 2 , —SR 15 , and —OR 15 ; and
R 17 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)R 15 , —C(S)R 15 , —C(O)R 16 , —C(S)R 16 , and heteroaryl.

2. The compound of claim 1 , wherein X D is —O—.

3. The compound of claim 1 , wherein X D is —S—.

4. The compound of claim 1 , wherein R 11 is selected from COOH, —NH(CO)COOH and —CH═CHCOOH.

5. The compound of claim 4 , wherein Ring D is phenyl, naphthyl or quinolinyl and Ring E is phenyl or thienyl.

6. The compound of claim 1 , wherein R 12 is independently selected at each occurrence from halogen and C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is methyl.

7. The compound of claim 1 , wherein R 12 is independently selected at each occurrence from halogen.

8. A compound, or a pharmaceutically acceptable salt thereof of Formula

wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
R 19 is selected from R 14 ;
R 18 is hydroxyl;
R 20 is hydrogen;
X F is selected from —O—, —C(O), —CH 2 —, —S—, —NR 17 —, —CHF—, —CF 2 —, and cycloalkyl;
Y F is selected from —C(O)—, —O, —S, —NR 17 —, CF 2 —, cycloalkyl, —CH 2 —, and —CHF—;
Ring D is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl, or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;
Ring E is phenyl, heteroaryl, 5- or 6-membered monocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;
R 11F is selected from —CH═CHCOOR 17 , —NR 17 (CO)COOR 17 , cycloalkyl-COOR 17 , —C 2 -C 6 alkenylene-COOR 17 , —C 2 -C 6 alkynylene-COOR 17 , —CH═CHC(O)R 16 , —NR 17 (CO)C(O)R 16 , -cycloalkyl-C(O)R 16 ,—C 2 -C 6 alkenylene-C(O)R 16 and —C 2 -C 6 alkynylene-C(O)R 16 ;

R 12 , R 13 , and R 14 are independently selected at each occurrence from —OR 15 , —SR 15 , —N(R 15 ) 2 , aryl, heteroaryl, halogen, —CN, —NO 2 , haloalkyl, cycloalkyl, thiol, C 1 -C 6 alkyl, —O(C 1 -C 6 fluoroalkyl), —C(O)R 16 , —C(S)R 16 , —OSO 2 R 16 , —NHSO 2 R 16 , —N(alkyl)SO 2 R 16 —OP(O)(R 16 ) 2 , —P(O)(R 16 ) 3 , —P(O)R 16 , —SO 2 R 16 , alkyne, alkene, arylalkyl, aryloxy, heteroarylalkyl, and C 1 -C 6 fluoroalkyl;
R 15 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
R 16 is independently selected at each occurrence from —N(R 15 ) 2 , —SR 15 , and —OR 15 ; and
R 17 is independently selected at each occurrence from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, —C(O)R 15 , —C(S)R 15 , —C(O)R 16 , —C(S)R 16 , and heteroaryl.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

10. A method of treating an estrogen-related disorder in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein the estrogen-related disorder is a cancer.

12. The method of claim 11 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, and lung cancer.

13. The method of claim 11 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.

14. The method of claim 11 , wherein the cancer is breast cancer.

15. The method of claim 14 , wherein the breast cancer is hormone receptor positive metastatic breast cancer.

16. The method of claim 14 , wherein the breast cancer is a tamoxifen resistant breast cancer.

17. The method of claim 14 , wherein the breast cancer is a triple negative breast cancer.

18. The method of claim 10 , wherein the estrogen-related disorder is bone loss.

19. The method of claim 18 , wherein the bone loss is caused by osteoporosis.

20. The method of claim 10 , wherein the estrogen-related disorder is a tumor.

Assignees

• Univ Illinois
• The Board Of Trustees Of Lhe Univ Of Illinois

Inventors

• Thatcher Gregory R
• Xiong Rui
• Zhao Jiong
• Tonetti Debra A

Classifications

• A61K31/381 Primary

  having five-membered rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D333/64 Primary

  Oxygen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title