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1. (WO2017172957) ESTROGEN RECEPTOR MODULATORS
注意: このテキストは、OCR 処理によってテキスト化されたものです。法的な用途には PDF 版をご利用ください。

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:


wherein:

X1, Y1 and Z1 are each independently C or N;

with the first proviso that at least one of X1, Y1 and Z1 is N;

with the second proviso that each of X1, Y1 and Z1 is uncharged; with third proviso that two of the dotted lines indicate double bonds;

with the fourth proviso that the valencies of X1, Y1 and Z1 can be each independently satisfied by attachment to a substituent selected from H and R12;

X2 is O, H or S;

A1 is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;

R1 is selected from the group consisting of an optionally substituted Ci-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(Ci-6 alkyl), an optionally substituted cycloalkenyl (Ci-6 alkyl), an optionally substituted aryl(Ci-6 alkyl), an optionally substituted heteroaryl (Ci-6 alkyl) and an optionally substituted heterocyclyl(Ci-6 alkyl);

R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-6 alkyl and an optionally substituted Ci-6 haloalkyl; or R2 and R3 together with the carbon to which R2 and R3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;

R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-6 alkyl and an optionally substituted Ci-6 haloalkyl; or R4 and R5 together with the carbon to which R4 and R5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;

R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine;

R10 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl;

R11 is hydrogen or an optionally substituted Ci-6 alkyl; and

R12 is hydrogen, halogen, an optionally substituted Ci-3 alkyl, an optionally substituted Ci-3 haloalkyl or an optionally substituted Ci-3 alkoxy;

provided that when R11 is hydrogen or methyl, X1 is H, Y1 and Z1 are each C, X2 is O, A1 is a phenyl, 2-fluorophenyl, or 2,6-difluorophenyl, both R2 and R3 are methyl or one of R2 and R3 is hydrogen and the other of R2 and R3 is methyl, and R4, R5, R6, R7, R8, R9 and R10 are each hydrogen, then R1 cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3 -fluoro-2-m ethyl propyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen.

3. The compound of any one of Claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted aryl.

4. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted phenyl.

5. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein A1 is a substituted phenyl.

6. The compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein A1 is an unsubstituted phenyl.

7. The compound of any one of Claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted cycloalkyl.

8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein A1 is an optionally substituted bicyclopentyl.

9. The compound of Claim 8, or a pharmaceutically acceptable salt thereof, wherein A1 is an unsubstituted bicyclopentyl.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of an optionally substituted Ci-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl (Ci-6 alkyl), an optionally substituted heterocyclyl and an optionally substituted heterocyclyl (Ci. 6 alkyl).

11. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is a substituted Ci-6 alkyl or a substituted cycloalkyl.

12. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein the substituted cycloalkyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted alkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.

13. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein the substituted alkyl is a Ci-6 haloalkyl.

14. The compound of Claim 11, or a pharmaceutically acceptable salt thereof, wherein the substituted Ci-6 alkyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted

cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.

15. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted Ci-6 alkyl selected from the group consisting of C4 alkyl, fluoro(C4 alkyl), and trifluoro(C2 alkyl).

16. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.

17. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted cycloalkyl (Ci-6 alkyl) selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethyl cyclopropylmethyl.

18. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.

19. The compound of Claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted heterocyclyl (Ci-6 alkyl) selected from the group consisting of unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of hydrogen, methyl, fluorom ethyl and difluorom ethyl.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein any one or more of each of R2, R3, R4, R5, R6, R7, R8, R9 and R10 is hydrogen.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R6 is hydroxy.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from the group consisting of halogen, hydroxy, and unsubstituted alkoxy.

24. The compound of Claim 23, or a pharmaceutically acceptable salt thereof, wherein R7 is fluoro or methoxy.

25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R8 is hydroxy.

26. The compound of Claim 1 selected from the group consisting of:

119

120

121

, or a pharmaceutically acceptable salt of any of the foregoing.

28. The compound of Claim 1 selected from the group consisting of:

COOH

123 OH

or a pharmaceutically acceptable salt of any of the foregoing.

29. The compound of Claim 1 selected from the group consisting of:


OEt


or a pharmaceutically acceptable salt of any of the foregoing

30. The compound of Claim 1, provided that when R10 is hydrogen, R11 is hydrogen or methyl, X1 is H, Y1 and Z1 are each C, A1 is an optionally substituted phenyl, one of R2 and R3 is hydrogen or an optionally substituted Ci-6 alkyl and the other of R2 and R3 is an optionally substituted Ci-6 alkyl, then R1 cannot be a substituted Ci-6 alkyl substituted with one or more substituents selected from the group consisting of halogen and hydroxy.

31. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

32. A method of inhibiting the growth of a cell, comprising

identifying a cell having an estrogen receptor alpha that mediates a growth characteristic of the cell; and

contacting the cell with an effective amount of the compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 31.

33. A method of treatment, comprising

identifying a subject that is in need of treatment for a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated; and administering to said subject an effective amount of the compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 31.

34. Use of the compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 31, in the manufacture of a medicament for the treatment of a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.

35. The method of Claim 33 or the use of Claim 34, wherein the disease or condition is selected from the group consisting of a breast cancer and a gynecological cancer.

36. The method of Claim 33 or the use of Claim 34, wherein the disease or condition is selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, and cervical cancer.

37. The method of Claim 33 or the use of Claim 34, wherein the disease or condition is breast cancer.

38. The method or use of any one of Claims 33 to 37, wherein said administering to said subject comprises an intravenous administration.

39. The method or use of any one of Claims 33 to 37, wherein said administering to said subject comprises an oral administration.

40. The method or use of any one of Claims 33 to 37, wherein said administering to said subject comprises an intramuscular administration.

41. The method or use of any one of Claims 33 to 37, wherein said administering to said subject comprises a subcutaneous administration.

42. The method or use of any one of Claims 33 to 37, wherein said administering to said subject comprises a topical administration.

43. The compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 31, for use in the treatment of a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.

44. The compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 31, for use in the treatment of breast cancer.


pound selected from the group consisting of

A compound of the following Formula 11-4:


A compound of the following Formula 11-5


49. A method of making a compound of Formula 11 A:


comprising:

reacting a compound of Formula 11-1 with benzaldehyde to form a compound of Formula 11-2:


reacting the compound of Formula 11-2 with tricyclo[1.1.1.01,3]pentane of Formula 11-3 to form a compound of Formula 11-4:


hydrogenating the compound of Formula 11-4 to form a compound of Formula 11-5:


reacting the compound of Formula 11-5 with (JE)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate to form a compound of Formula 11-6:


hydrolyzing the compound of Formula 11-6 to form the compound of Formula

11 A.