US2019142811A1PendingUtilityA1
Estrogen receptor modulators
Assignee: ZENO ROYALTIES & MILESTONES LLCPriority: Apr 1, 2016Filed: Mar 29, 2017Published: May 16, 2019
Est. expiryApr 1, 2036(~9.7 yrs left)· nominal 20-yr term from priority
Inventors:Peter Qinhua HuangDeborah Helen SleeSayee Gajanan HegdeChad Daniel HopkinsKevin Duane BunkerJoseph Robert PinchmanRakesh Kumar Sit
C07D 471/14A61K 31/437A61K 31/438A61P 5/30C07C 69/757A61P 35/00C07C 69/732C07B 59/002C07C 2603/62C07C 69/738C07D 471/04C07D 209/14C07D 209/10C07F 7/1804C07C 2602/38C07B 2200/07
56
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Claims
Abstract
Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
X 1 , Y 1 and Z 1 are each independently C or N;
with the first proviso that at least one of X 1 , Y 1 and Z 1 is N;
with the second proviso that each of X 1 , Y 1 and Z 1 is uncharged;
with third proviso that two of the dotted lines indicate double bonds;
with the fourth proviso that the valencies of X 1 , Y 1 and Z 1 can be each independently satisfied by attachment to a substituent selected from H and R 12 ;
X 2 is O, NH or S;
A 1 is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;
R 1 is selected from the group consisting of an optionally substituted C 1-6 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(C 1-6 alkyl), an optionally substituted cycloalkenyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl);
R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 2 and R 3 together with the carbon to which R 2 and R 3 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl and an optionally substituted C 1-6 haloalkyl; or R 4 and R 5 together with the carbon to which R 4 and R 5 are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl;
R 6 , R 7 , R 8 and R 9 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;
R 10 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl;
R 11 is hydrogen or an optionally substituted C 1-6 alkyl; and
R 12 is hydrogen, halogen, an optionally substituted C1-3 alkyl, an optionally substituted C 1-3 haloalkyl or an optionally substituted C1-3 alkoxy;
provided that when R 11 is hydrogen or methyl, X 1 is NH, Y 1 and Z 1 are each C, X 2 is O, A 1 is a phenyl, 2-fluorophenyl, or 2,6-difluorophenyl, both R 2 and R 3 are methyl or one of R 2 and R 3 is hydrogen and the other of R 2 and R 3 is methyl, and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each hydrogen, then R 1 cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an optionally substituted aryl.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an optionally substituted phenyl.
5 . (canceled)
6 . (canceled)
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an optionally substituted cycloalkyl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein A 1 is an optionally substituted bicyclopentyl.
9 . (canceled)
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted heterocyclyl and an optionally substituted heterocyclyl(C 1-6 alkyl).
11 . (canceled)
12 . (canceled)
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . (canceled)
17 . (canceled)
18 . (canceled)
19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl and difluoromethyl.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein any one or more of each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is hydrogen.
22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydroxy.
23 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 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 R 7 is fluoro or methoxy.
25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy.
26 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
27 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
28 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
29 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
30 . The compound of claim 1 , provided that when R 10 is hydrogen, R 11 is hydrogen or methyl, X 1 is NH, Y 1 and Z 1 are each C, A 1 is an optionally substituted phenyl, one of R 2 and R 3 is hydrogen or an optionally substituted C 1-6 alkyl and the other of R 2 and R 3 is an optionally substituted C 1-6 alkyl, then R 1 cannot be a substituted C 1-6 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 claim 1 , 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 claim 1 , or a pharmaceutically acceptable salt thereof.
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 claim 1 .
34 . (canceled)
35 . The method of claim 33 , 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 , 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 , wherein the disease or condition is breast cancer.
38 . The method of claim 33 , wherein said administering to said subject comprises an intravenous administration.
39 . The method of claim 33 , wherein said administering to said subject comprises an oral administration.
40 . The method of claim 33 , wherein said administering to said subject comprises an intramuscular administration.
41 . The method of claim 33 , wherein said administering to said subject comprises a subcutaneous administration.
42 . The method of claim 33 , wherein said administering to said subject comprises a topical administration.
43 . (canceled)
44 . (canceled)
45 . A compound selected from the group consisting of
46 . A compound selected from the group consisting of
47 . A compound of the following Formula 11-4:
48 . A compound of the following Formula 11-5:
49 . A method of making a compound of Formula 11A:
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[1.1.1.0 1,3 ]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 (E)-methyl-3-(3,5-difluoro-4-formylphenyl) acrylate to form a compound of Formula 11-6:
and
hydrolyzing the compound of Formula 11-6 to form the compound of Formula 11A.Cited by (0)
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