TETRASUBSTITUTED ALKENE COMPOUNDS AND THEIR USE

• US 20180127378A1
• Filed: 09/22/2017
• Published: 05/10/2018
• Est. Priority Date: 05/29/2015
• Status: Active Grant

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Inventors: BOCK, Mark, HAO, Ming-Hong, KORPAL, Manav, NYAVANANDI, Vijay Kumar, PUYANG, Xiaoling, SAMAJDAR, Susanta, SMITH, Peter Gerard, WANG, John, ZHENG, Guo Zhu, ZHU, Ping
• Granted Patent: US 10,851,065 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/14 Ortho-condensed systems

Abstract

Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-α protein.

Claims

1. (canceled)

2. A compound or pharmaceutically acceptable salt thereof, given by formula I:

38. A method of treating breast cancer comprising administering to a subject the compound or pharmaceutically acceptable salt of claim 2.

39. The method of claim 38, wherein said breast cancer is an ER-positive breast cancer.

40. The method of claim 39, wherein said subject expresses a mutant ER-α

protein.

3-15. -15. (canceled)

16. A compound selected from the group consisting of (E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy) ethyl) amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-phenyl but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluoro-5-(trifluoromethyl) phenyl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(4-fluoro-1H-indazol-5-yl)-2-phenyl but-1-en-1-yl) phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(3,5-difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(3,4-difluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(3-chloro-5-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy) ethyl) amino)-N-methyl-N-(prop-2-yn-1-yl)but-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-N-(but-3-yn-1-yl)-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-1-(azetidin-1-yl)but-2-en-1-one;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-1-(pyrrolidin-1-yl)but-2-en-1-one;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-1-(piperidin-1-yl)but-2-en-1-one;

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide 2,2,2-trifluoro acetate;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-1-morpholinobut-2-en-1-one;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-N-ethyl-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-N-methyl-N-propylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-N,N,3-trimethylbut-2-enamide;

(Z)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenoxy) ethyl)amino)-1-morpholinobut-2-en-1-one;

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(4-fluoro-1H-indazol-5-yl)-2-phenylvinyl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((5-((Z)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl) oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenoxy) ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(4-isopropyl phenyl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-4-chloro-1-(1H-indazol-5-yl)-2-phenyl but-1-en-1-yl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(4-isopropyl phenyl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-(difluoromethoxy)phenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(2-(trifluoro-methoxy)phenyl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(2-isopropyl phenyl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-ethylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenoxy) ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenoxy)ethyl) amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((5-((Z)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyrimidin-2-yl) oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-1-(azetidin-1-yl)-4-((2-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl) phenoxy)ethyl)amino)but-2-en-1-one;

(E)-1-(azetidin-1-yl)-4-((2-(4-((E)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenoxy)ethyl)amino)but-2-en-1-one;

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl) phenoxy) ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

(E)-1-(azetidin-1-yl)-4-((2-(4-((E)-2-cyclobutyl-1-(1H-indazol-5-yl)-2-(o-tolyl) vinyl)phenoxy)ethyl)amino)but-2-en-1-one;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(2-fluoro phenyl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluoro phenyl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluorophenyl)but-1-en-1-yl) phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)vinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(2-fluoro-4-((Z)-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2,6-difluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(pyridin-3-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(pyridin-4-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-cyclopropyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((5-((Z)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((5-((Z)-2-(2-chloro-4-fluorophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide;

(E)-N,N-dimethyl-4-((2-(4-((E)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluoropyridin-4-yl)but-1-en-1-yl)phenoxy)ethyl)amino)but-2-enamide;

(E)-N,N-dimethyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluoropyridin-4-yl)but-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-enamide;

(E)-N,N-dimethyl-4-((2-(4-((E)-2-phenyl-1-(1H-pyrazolo[4,3-b]pyridin-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)but-2-enamide;

(E)-4-((2-(3-fluoro-4-((Z)-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2,4-difluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3,6-difluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(pyridin-2-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((5-((Z)-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-N,N-dimethyl-4-((2-(4-((E)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)but-2-enamide;

(E)-4-((2-((5-((Z)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)pyridin-2-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chlorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(pyridin-4-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(7-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-phenylpent-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3,7-difluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2,5-difluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-2-(3-fluoropyridin-4-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(3-fluoro-1H-indazol-5-yl)-3-methyl-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-5-((2-(4-((E)-4-fluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide;

(E)-5-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N,2-trimethylbut-2-enamide;

(E)-4-((2-(4-((E)-2-(2-chloro-4-fluorophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-(phenyl-d5)but-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)ethyl)amino)-N,N-dimethylpent-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((1-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)propan-2-yl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-((6-((Z)-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-3-yl)oxy)ethyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)propyl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)butan-2-yl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((1-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)-2-methylpropan-2-yl)amino)-N,N-dimethylbut-2-enamide;

(E)-4-((2-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenoxy)-2-methylpropyl)amino)-N,N-dimethylbut-2-enamide; and

(E)-4-((2-(4-((E)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenoxy)ethyl)amino)-N-(2-hydroxyethyl)-N-methylbut-2-enamide;

or a pharmaceutically acceptable salt thereof.

41. A method of treating breast cancer comprising administering to a subject a compound or pharmaceutically acceptable salt of claim 16.

17-19. -19. (canceled)

20. A compound given by formula III:

26. The compound or pharmaceutically acceptable salt of claim 20, wherein R₁ is —

CH₂CF₃.

27. The compound or pharmaceutically acceptable salt of claim 20, wherein R₁ is cyclobutyl.

47. A method of treating breast cancer comprising administering to a subject the compound or pharmaceutically acceptable salt of claim 20.

48. The method of claim 47, wherein said breast cancer is an ER-positive breast cancer.

49. The method of claim 47, wherein said subject expresses a mutant ER-α

protein.

50. The compound or pharmaceutically acceptable salt of claim 20, wherein R₈ is H.

51. The compound or pharmaceutically acceptable salt of claim 20, wherein R₂ is F.

52. The compound or pharmaceutically acceptable salt thereof of claim 20, wherein R₂ is H.

53. The compound or pharmaceutically acceptable salt of claim 20, wherein m is 2, and one of R4 is F and the other R4 is Cl.

54. The compound or pharmaceutically acceptable salt of claim 20, wherein R₁₀ is —

H and Y is —

C(O)NR₆R₇.

55. The compound or pharmaceutically acceptable salt of claim 54, wherein R₆ and R₇ are both methyl.

56. The compound or pharmaceutically acceptable salt of claim 20, wherein n is 0, p is 0, and R₉ is H.

57. The compound or pharmaceutically acceptable salt of claim 20, wherein m is 0.

21-25. -25. (canceled)

28-37. -37. (canceled)

42-46. -46. (canceled)