IP Library › Granted Patent US 10,118,910
Granted Patent B2
US 10,118,910 · App. 15/374,966 · Granted Nov 6, 2018

Benzothiophene-based selective estrogen receptor downregulators

Inventors: Gregory R. Thatcher (Urbana, IL); Rui Xiong (Urbana, IL); Jiong Zhao (Urbana, IL); Debra A. Tonetti (Urbana, IL)
Assignee: The Board of Trustees of the University of Illinois
C07D333/64C07D409/06C07D409/12
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,118,910
App. No.
15/374,966
Granted
Nov 6, 2018
Kind
B2
Abstract

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

Claims (84)

1. A compound or a pharmaceutically acceptable salt thereof of the formula:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X A is—O—;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl, 5- or 6-membered monocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclic heterocyclyl;

R 1 is selected from hydroxyl, hydrogen, halogen, —O(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), —OC(O)C 6 H 5 , —OC(O)O(C 1 -C 6 alkyl), —OC(O)OC 6 H 5 and —OSO 2 (C 2 -C 6 alkyl);

R 2 is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH, C 2 -C 6 alkenylene-COOH and C 2 -C 6 alkynylene-COOH;

R 3 is independently selected at each occurrence from hydrogen, halogen, —CN, —NO 2 , C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl; and

R 4 is independently selected at each occurrence from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —O(C 1 -C 6 alkyl), and —O(C 1 -C 6 fluoroalkyl).

2. The compound of claim 1 , wherein R 1 is selected from hydroxyl and —O(C 1 -C 6 alkyl).

3. The compound of claim 2 , wherein R 2 is selected from —COOH, —NH(CO)COOH and —CH═CHCOOH.

4. The compound of claim 3 , wherein Ring B is phenyl, naphthyl or quinolinyl and Ring C is phenyl or thienyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula:

6. The compound of claim 5 , wherein R 3 is independently selected at each occurrence from hydrogen, halogen, and C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula:

8. The compound of claim 7 , wherein R 3 is independently selected at each occurrence from hydrogen, halogen, and C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is methyl.

9. The compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

13. The pharmaceutical composition of claim 12 wherein the compound is of structure:

14. The pharmaceutical composition of claim 12 wherein the compound is of structure:

15. The pharmaceutical composition of claim 12 wherein the compound is of structure:

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

19. The compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 selected from

or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 5 , wherein R 3 is hydrogen.

22. The compound according to claim 21 , wherein n is 1.

23. The compound according to claim 21 , wherein n is 2.

24. The compound according to claim 21 , wherein n is 3.

25. The compound according to claim 24 , wherein at least one R 4 is halogen.

26. The compound according to claim 24 , wherein at least one R 4 is C 1 -C 6 alkyl.

27. The compound according to claim 24 , wherein at least one R 4 is C 1 -C 6 fluoroalkyl.

28. The compound according to claim 24 , wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.

29. The compound according to claim 28 , wherein one R 4 is halogen.

30. The compound according to claim 29 , wherein the remaining two R 4 s are C 1 -C 6 alkyl.

31. The compound according to claim 7 , wherein R 3 is hydrogen.

32. The compound according to claim 31 , wherein n is 1.

33. The compound according to claim 31 , wherein n is 2.

34. The compound according to claim 31 , wherein n is 3.

35. The compound according to claim 34 , wherein at least one R 4 is halogen.

36. The compound according to claim 34 , wherein at least one R 4 is C 1 -C 6 alkyl.

37. The compound according to claim 34 , wherein at least one R 4 is C 1 -C 6 fluoroalkyl.

38. The compound according to claim 34 , wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.

39. The compound according to claim 38 , wherein one R 4 is halogen.

40. The compound according to claim 39 , wherein the remaining two R 4 s are C 1 -C 6 alkyl.

41. The compound according to claim 1 , wherein n is 1.

42. The compound according to claim 1 , wherein n is 2.

43. The compound according to claim 1 , wherein n is 3.

44. The compound according to claim 1 , wherein at least one R 4 is halogen.

45. The compound according to claim 1 , wherein at least one R 4 is C 1 -C 6 alkyl.

46. The compound according to claim 1 , wherein at least one R 4 is C 1 -C 6 fluoroalkyl.

47. The compound according to claim 1 , wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.

48. The compound according to claim 1 , wherein one R 4 is halogen.

49. The compound according to claim 1 , wherein two R 4 s are C 1 -C 6 alkyl.

50. The compound according to claim 1 , wherein m is 0.

51. The compound according to claim 1 , wherein Ring B is phenyl.

52. The compound according to claim 1 , wherein Ring C is phenyl.

53. The compound according to claim 1 , wherein R 1 is hydroxyl.

54. The compound according to claim 1 , wherein R 2 is —CH═CHCOOH.

55. The compound according to claim 1 , wherein R 2 is —CH═CHCOOH or —NH(CO)COOH.

56. The compound according to claim 54 , wherein Ring B is phenyl.

57. The compound according to claim 56 , wherein Ring C is phenyl.

58. The compound according to claim 57 , wherein R 1 is hydroxyl.

59. The compound according to claim 58 , wherein m is 0.

60. The compound according to claim 59 , wherein n is 1.

61. The compound according to claim 59 , wherein n is 2.

62. The compound according to claim 59 , wherein n is 3.

63. The compound according to claim 62 , wherein at least one R 4 is halogen.

64. The compound according to claim 62 , wherein at least one R 4 is C 1 -C 6 alkyl.

65. The compound according to claim 62 , wherein at least one R 4 is C 1 -C 6 fluoroalkyl.

66. The compound according to claim 62 , wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.

67. The compound according to claim 66 , wherein one R 4 is halogen.

68. The compound according to claim 67 , wherein the remaining two R 4 s are C 1 -C 6 alkyl.

69. The compound according to claim 68 , wherein C 1 -C 6 alkyl is methyl.

Assignments (4)
RELEASE OF SECURITY INTEREST IN INTELLECTUAL PROPERTY Recorded Sep 19, 2024
From: HERCULES CAPITAL, INC., AS COLLATERAL AGENT
To: G1 THERAPEUTICS, INC.
Reel/Frame 068996/0001 →
INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded May 29, 2020
From: G1 THERAPEUTICS, INC.
To: HERCULES CAPITAL, INC., AS COLLATERAL AGENT
Reel/Frame 052795/0074 →
CONFIRMATORY LICENSE Recorded Jan 31, 2017
From: UNIVERSITY OF ILLINOIS AT CHICAGO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 041565/0515 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 3, 2017
From: THATCHER, GREGORY R.; XIONG, RUI; ZHAO, JIONG; TONETTI, DEBRA A.
To: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS
Reel/Frame 040824/0720 →
Continuity (3)
Provisional Application 62322878 · Apr 15, 2016
Provisional Application 62264971 · Dec 9, 2015
Related Publication 20170166550A1 · Jun 15, 2017