Synthesis and evaluation of (4-hydroxyphenyl)-substituted carbocycles as potent and selective estrogen receptor β agonists

Abstract

Disclosed are 4-hydroxyphenyl substituted carbocycles and their use as selective agonists of the estrogen receptor beta isoform (ERβ). The disclosed compounds may be formulated as pharmaceutical compositions and administered to treat diseases associated with ER activity, such as proliferative diseases and disorders and / or psychiatric diseases or disorders.

Description

[Technical field]

[0001] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant No. R15GM118304 awarded by the National Institutes of General Medical Sciences. The United States Government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 236,145, filed August 23, 2021. The contents of U.S. Provisional Application No. 63 / 236,145 are incorporated herein by reference in their entirety. [Background technology]

[0003] background The field of the invention relates to compounds that function as agonists of the estrogen receptor (ER). In particular, the field of the invention relates to (4-hydroxyphenyl) substituted carbocycles that are specific agonists for the estrogen receptor β (ERβ), and the use of such compounds in pharmaceutical compositions for treating diseases and disorders associated with ER activity.

[0004] Estrogen is a key regulator of many physiological processes, including reproduction, cognition, cardiovascular health, and bone metabolism (see, e.g., Deroo et al., "Estrogen Receptors and Human Disease", J. Clin. Invest. 116:561-570(2006)). Based on its widespread role in many physiological processes, estrogen has been linked to numerous diseases and disorders, including cell proliferative diseases and disorders (e.g., breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, and prostate cancer), neurodegenerative diseases and disorders, cardiovascular diseases, and osteoporosis, to name a few (see ibid.). In many of these diseases and disorders, estrogen conveys its effects via the estrogen receptor (ER).

[0005] ER exists in two major forms, ERα and ERβ, which have distinct tissue expression patterns (see Mueller et al. (2001), "Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice", Curr. Opin. Pharmacol. 1: 613-619). ERα and ERβ are encoded by separate genes, ESR1 and ESR2, respectively, found at different chromosomal locations, and both ERα and ERβ have numerous mRNA splice variants (see, e.g., Hernyk et al., "Estrogen receptor mutations in human disease", (2004) Endocr. Rev. 25:869-898). Due to their role in estrogen-related diseases, ERα and ERβ have been targeted for the development of specific ligands to modulate their activity. The ligand specificities of ERα and ERβ differ, and ligands that bind and function as agonists or antagonists of ERα may or may not bind and function as agonists or antagonists of ERβ.

[0006] One group of ER ligands that has been developed is the so-called "selective estrogen receptor modulators" or "SERMs", including tamoxifen and raloxifene. Tamoxifen and raloxifene have been observed to exhibit tissue-specific estrogenic activity. For example, tamoxifen is an antagonist in the breast, and has been a safe and effective adjuvant endocrine therapy for breast cancer for almost 20 years, whereas tamoxifen is an ER agonist in bone and uterus (see, for example, Deroo et al., "Estrogen Receptors and Human Disease", J. Clin. Invest. 116:561-570 (2006)). Raloxifene exhibits greater agonist activity in bone and less agonist activity in the uterus (see Fabian et al., "Selective estrogen-receptor modulators for primary prevention of breast cancer", J. Clin. Oncol. 23:1644-1655 (2005)). Whether a ligand is an ER agonist or ER antagonist in a particular tissue depends on several factors, including the type of estrogen receptor that predominates in the particular tissue, i.e., ERα or ERβ, where the ligand may exhibit different binding affinities, and / or the agonist / antagonist activity of ERα versus ERβ.

[0007] ERα and ERβ agonists have a wide range of biological effects that impact diseases such as cancers and disorders of the central nervous system (CNS). Clinical studies have shown that administration of estradiol (E2) in postmenopausal hormone replacement therapy (HRT) may increase the incidence of breast and endometrial cancer (Beral et al., "Breast cancer and hormone-replacement therapy in the Million Women Study", Lancet. 2003;362(9382:419-27. Epub 2003 / 08 / 21. PubMed PMID: 12927427 (Non-Patent Document 5); Gann et al., "Combined hormone therapy and breast cancer: a single-edged sword", JAMA : the journal of the American Medical Association. United States 2003. p. 3304-6 (Non-Patent Document 6); Li et al., "Relationship between long durations and different regimens of hormone therapy and risk of breast cancer", JAMA : the Journal of the American Medical Association. 2003;289(24):3254-63. Epub 2003 / 06 / 26. doi: 10.1001 / jama.289.24.3254. PubMed PMID: 12824206; and Anderson et al., "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial," JAMA: the journal of the American Medical Association.2004;291(14):1701-12. Epub 2004 / 04 / 15. doi: 10.1001 / jama.291.14.1701. PubMed PMID: 15082697 (see Non-Patent Document 8). This effect is primarily mediated by ERα, the predominant isoform present in the mammary gland and uterus (see Song et al., "Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats. The Journal of steroid biochemistry and molecular biology. 2012;130(1-2):26-35. Epub 2012 / 01 / 24. doi: 10.1016 / j.jsbmb.2011.12.018. PubMed PMID: 22266284).

[0008] Increasing cancer risk has led to reduced use of HRT in postmenopausal women. However, studies have also shown that HRT can provide a positive effect, primarily mediated by ERβ, of reduced dementia risk in postmenopausal women (see Leblanc et al., "US Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. Hormone Replacement Therapy and Cognition. Rockville (MD): Agency for Healthcare Research and Quality (US); 2002). Thus, specific ERβ agonists could provide the CNS benefits of E2 with minimal side effects. However, current SERMs such as tamoxifen and raloxifene are not ERβ specific, have carcinogenic side effects, and provide little memory enhancement (Yaffe et al., "Cognitive function in postmenopausal women treated with raloxifene. New England Journal of Medicine. 2001;344:1207-13; and Paganini-Hill et al., "Preliminary assessment of cognitive function in breast (See, e.g., Breast Cancer Research and Treatment. 2000;64:165-76.) By selectively targeting ERβ, safer and more effective treatments can be developed.

[0009] Therefore, new estrogen receptor ligands are desired.In particular, new ligands are desired that show selective agonistic or antagonistic activity on ERβ compared to ERα.These new ligands should be suitable for treating diseases and disorders related to ER activity, such as cell proliferation diseases and disorders, psychiatric diseases and disorders, or vasomotor diseases and disorders.Such new ligands are disclosed herein in the form of (4-hydroxyphenyl) substituted carbocycles. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Deroo et al., “Estrogen Receptors and Human Disease”, J. Clin. Invest. 116:561-570(2006) [Non-Patent Document 2] (Mueller et al. (2001), “Estrogen receptors and endocrine diseases: lessons from estrogen receptor knockout mice”, Curr. Opin. Pharmacol. 1: 613-619 [Non-Patent Document 3] Hernyk et al., “Estrogen receptor mutations in human disease”, (2004) Endocr. Rev. 25:869-898 [Non-Patent Document 4] Fabian et al., “Selective estrogen-receptor modulators for primary prevention of breast cancer”, J. Clin. Oncol. 23:1644-1655 (2005) [Non-Patent Document 5] Beral et al., 「Breast cancer and hormone-replacement therapy in the Million Women Study」, Lancet. 2003;362(9382:419-27. Epub 2003 / 08 / 21. PubMed PMID: 12927427

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

[0011] overview Disclosed are 4-hydroxyphenyl substituted carbocycles and their use as selective agonists of the estrogen receptor beta (ERβ). The disclosed compounds may be formulated as pharmaceutical compositions and administered to treat diseases associated with ER activity.

[0012] The disclosed compounds may include an optionally substituted cyclic, spirocyclic, fused, or bridged ring structure attached to an optionally substituted phenolic group (e.g., at the para position (4-position) of the optionally substituted phenolic group), where the phenolic group is optionally hydroxyl protected. The spirocyclic ring structure may include an optionally substituted spiro[5.3]nonane group: The fused ring structure may include an optionally substituted bicyclo[3.3.0]octane group, an optionally substituted bicyclo[3.3.0]octene group, an optionally substituted bicyclo[3.1.0]hexane group: The bridged ring structure may include an optionally substituted adamantyl group, an optionally substituted bicyclo[3.3.1]nonane group, or an optionally substituted bicyclo[3.3.1]nonene group. TIFF2024534126000003.tif34128. The cyclic ring structure may include an optionally substituted cyclohexyl group.

[0013] In some embodiments, the disclosed compounds have formula I: TIFF2024534126000004.tif41128, During the ceremony, X 1 , X 2 , Y 1 , and Y 2 is independently selected from the group consisting of hydrogen, halogen, and hydroxyl; Optionally, X 1 and X 2 When is a halogen, Y 1 and Y 2 is hydrogen, and optionally, Y 1 and Y 2 When is a halogen, X 1 and X 2 is the condition that the atom is hydrogen, W is selected from the group consisting of hydrogen, hydroxyl, and oxo; R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 4 is hydrogen or a hydroxyl protecting group.

[0014] In some embodiments, W in the compound having formula I is oxo and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5 , R 6 is hydrogen, and the compound has formula I(a): I have TIFF2024534126000005.tif42128.

[0015] In some embodiments, X in the compound having formula I 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , and R 6 is hydrogen, and the compound has formula I(b): I have TIFF2024534126000006.tif32128.

[0016] In some embodiments, W and R in the compound having formula I 4 is hydrogen, and the compound has formula I(c): I have TIFF2024534126000007.tif39128.

[0017] In other embodiments, the disclosed compounds may include an optionally substituted adamantyl group attached to an optionally substituted phenolic group (e.g., at the para position (4-position) of the optionally substituted phenolic group), where the phenolic group is optionally hydroxyl protected. In some embodiments, the disclosed compounds have Formula II: TIFF2024534126000008.tif39128, During the ceremony, R 1a and R 1b is independently selected from hydrogen, hydroxyl, carboxyalkyl ester, and hydroxyalkyl; and optionally, R 1a and R 1b is the condition that they are not the same, R 1c is selected from hydrogen and hydroxyl; R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 4 is hydrogen or a hydroxyl protecting group.

[0018] In some embodiments, R in the compound having formula II 1c is hydroxyl and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5 , and R 6 is hydrogen, and the compound has formula II(a): I have TIFF2024534126000009.tif38128.

[0019] In some embodiments, R in the compound having formula II 1c is hydrogen, and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5 , and R 6 is hydrogen, and the compound has formula II(b): I have TIFF2024534126000010.tif37128.

[0020] In some embodiments, R in the compound having formula II 1c , R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen, and the compound has formula II(c): I have TIFF2024534126000011.tif35128.

[0021] In other embodiments, the disclosed compounds may include an optionally substituted cyclohexyl group attached to an optionally substituted phenolic group (e.g., at the para position (4-position) of the optionally substituted phenolic group), where the phenolic group is optionally hydroxyl protected. In some embodiments, the disclosed compounds may be represented by formula III: TIFF2024534126000012.tif31128, During the ceremony, R 1 is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, and haloalkyl; R 2 , R 3 , R 5 , and R 6 are independently selected from hydrogen, deuterium, and halogen, with the proviso that R 3 , R 5 , and R 6 If is hydrogen, then R 1is haloalkyl, R 4 is hydrogen or a hydroxyl protecting group.

[0022] In some embodiments, R in the compound having formula III 2 , R 4 , and R 6 is hydrogen, and R 1 is selected from hydroxyalkyl, haloalkyl, and hydroxyl, and the compound has formula III(a): I have TIFF2024534126000013.tif33128.

[0023] In some embodiments, R in the compound having formula III 2 , R 4 , and R 6 is hydrogen, and R 1 is hydroxyalkyl, and the compound has formula III(b): I have TIFF2024534126000014.tif36128.

[0024] In other embodiments, the disclosed compounds may include an optionally substituted bridged or fused ring structure attached to an optionally substituted phenolic group (e.g., at the para position (4-position) of the optionally substituted phenolic group), where the phenolic group is optionally hydroxyl protected. In some embodiments, the disclosed compounds have formula IV: TIFF2024534126000015.tif38128, During the ceremony, R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 7 is hydrogen or alkyl; R 8 and R 9 is independently selected from the group consisting of hydrogen, hydroxyl, and hydroxyalkyl; a is 0 or 1, b is 0 or 1, n is 0 or 1.

[0025] In some embodiments, in the compound having formula IV, n is 0, a and b are 1, and R 7 is hydrogen or methyl, and the compound has formula IV(a): I have TIFF2024534126000016.tif39128.

[0026] In some embodiments, in the compound having formula IV, a, b, and n are 1 and R 7 is hydrogen, and the compound has formula IV(b): I have TIFF2024534126000017.tif39128.

[0027] In some embodiments, in the compound having formula IV, a, b, and n are 0 and R 7 and R 8 is hydrogen, and R 9 is hydroxymethyl, and the compound has formula IV(c): I have TIFF2024534126000018.tif39128.

[0028] Disclosed compounds can be used to prepare and formulate pharmaceutical compositions.Therefore, also disclosed herein is a pharmaceutical composition that comprises an effective amount of any compound disclosed herein or the pharmaceutically acceptable salt of any compound disclosed herein together with pharmaceutically acceptable excipient, carrier or diluent.

[0029] In some embodiments, the disclosed compounds may be used to prepare pharmaceutical agents for treating diseases or disorders related to estrogen receptor beta (ERβ) activity, particularly diseases or disorders that can be treated with ERβ agonists.Thus, the disclosed compounds may exhibit ERβ agonist activity, and preferably, the compounds exhibit specificity as ERβ agonists compared to activity as ERβ antagonists, and / or compared to activity as estrogen receptor alpha (ERα) agonists and / or activity as ERα antagonists. [Brief description of the drawings]

[0030] [Figure 1] Achiral estrogen receptor β selective ligands and optically active estrogen receptor β selective ligands. [Diagram 2] ORTEP of 7-(4-hydroxyphenyl)spiro[3.5]-nonan-2-ol (±)-11. [Figure 3a] Induced-fit docking pose of (a) 5b (Glide score -10.676) or (b) (S)-11 (Glide score -10.001) in the human ERβ ligand pocket. Hydrogen-bonding interactions of the phenolic hydroxyl with Glu305 and Arg346 and the aliphatic hydroxyl with His475 are shown as yellow dashed lines. The π-π interaction with Phe356 (blue dashed line) and van der Waals interaction with Leu298 are maintained by both ligands. [Figure 3b] See legend to Figure 3a. [Figure 4] CYP450 enzyme inhibition assay. CYP2C9 inhibition by 5a / b (red squares, IC50 of 10±0.5 μM) and (±)-11 (blue circles). No significant inhibition of CYP2D6 or CYP3A4 was observed up to 62.5±0.5 μM. [Figure 5a]Predicted CYP450 metabolism. (a) Intrinsic reactivity to CYP450 hydroxylation of the carbon atoms in 5b and (b) 11. (c) Schematic of all data for predicted CYP2C9 metabolism of 5b and (d) Schematic of all data for predicted CYP2C9 metabolism of 11. Green lines relate to Fe accessibility in the docked complex. Larger, darker circles indicate greater predicted site of metabolism (SOM) scores, proximity to the CYP450 heme iron, and greater intrinsic reactivity scores. (e) Docked pose of 5b in CYP2C9 showing the phenolic hydrogen closest to the heme Fe. [Figure 5b] See legend to Figure 5a. [Figure 5c] See legend to Figure 5a. [Figure 5d] See legend to Figure 5a. [Figure 5e] See legend to Figure 5a. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description The present invention is described herein using several definitions, as set forth below and throughout the application.

[0032] Unless otherwise specified or indicated by context, the terms "a," "an," and "the" mean "one or more." For example, "a substitution" shall be interpreted as meaning "one or more substitutions." Similarly, "a substituent" shall be interpreted as meaning "one or more substituents."

[0033] As used herein, "about," "approximately," "substantially," and "significantly" will be understood by those of ordinary skill in the art and will vary, to an extent, depending on the context in which the terms are used. If there are uses of these terms that would not be clear to a person of ordinary skill in the art, given the context in which the terms are used, "about" and "approximately" will mean plus or minus ≦10% of the particular term, and "substantially" and "significantly" will mean plus or minus >10% of the particular term.

[0034] The terms "include" and "including" as used herein have the same meaning as the terms "comprise" and "comprising". The terms "comprise" and "comprising" should be interpreted as "open" transitional terms that may further include additional elements to the elements recited in the claim. The terms "consist" and "consisting of" should be interpreted as "closed" transitional terms that may not include additional elements other than the elements recited in the claim. The term "consisting essentially of" should be interpreted as being partially closed and may only include additional elements that do not fundamentally change the content of the claimed subject matter.

[0035] Disclosed are (4-hydroxyphenyl)-substituted carbocycles and their use as selective agonists of the estrogen receptor β isoform (ERβ).Preferred embodiments of the disclosed compounds include (4-hydroxyphenyl)-substituted spiro[5.3]nonane, (4-hydroxyphenyl)-substituted admantane, (4-hydroxyphenyl)-substituted cyclohexane, (4-hydroxyphenyl)-substituted bicyclo[3.3.0]octane, (4-hydroxyphenyl)-substituted bicyclo[3.3.0]octene, (4-hydroxyphenyl)-substituted bicyclo[3.3.1]nonane, (4-hydroxyphenyl)-substituted bicyclo[3.3.1]nonene, and (4-hydroxyphenyl)-substituted bicyclo[3.1.0]hexane. Alternatively, the disclosed compounds may be referred to as (4-hydroxyphenyl)substituted carbocycles containing one or more substitutions on the carbocycle substituent, which is preferably a spiro[5.3]nonane substituent, an adomantyl substituent, a cyclohexyl substituent, a bicyclo[3.3.0]octanyl substituent, a bicyclo[3.3.0]octenyl substituent, a bicyclo[3.3.1]nonanyl substituent, a bicyclo[3.3.1]nonenyl substituent, or a bicyclo[3.1.0]hexanyl substituent.

[0036] The disclosed compounds may include an optionally substituted spiro ring substituent, which may include a spiro[5.3]nonane substituent. In some embodiments, the disclosed compounds have Formula I: TIFF2024534126000019.tif41128, During the ceremony, X 1 , X 2 , Y 1 , and Y 2 is independently selected from the group consisting of hydrogen, halogen, and hydroxyl; Optionally, X 1 and X 2 When is a halogen, Y 1 and Y 2 is hydrogen, and optionally, Y 1 and Y 2 When is a halogen, X1 and X 2 is the condition that the atom is hydrogen, W is selected from the group consisting of hydrogen, hydroxyl, and oxo; R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 4 is hydrogen or a hydroxyl protecting group.

[0037] In some embodiments, the halogen in the compound of formula I is chloro.

[0038] In some embodiments, the hydroxyl protecting group in the compound of formula I is a tert-butyldimethylsilyl group.

[0039] In some embodiments, W in the compound of formula I is oxo and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5 , R 6 is hydrogen, and the compound has formula I(a) (wherein X and Y are as defined for formula I): TIFF2024534126000020.tif42128.

[0040] In some embodiments, X in the compound of formula I(a) 1 and X 2 is chloro and Y 1 and Y 2 is hydrogen.

[0041] In some embodiments, Y in the compound of formula I(a) 1 and Y 2 is chloro and X 1 and X 2 is hydrogen.

[0042] In some embodiments, X in the compound of formula I(a) 1 , X2 , Y 1 , and Y 2 is hydrogen.

[0043] In some embodiments, X in the compound of formula I 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , and R 6 is hydrogen, and the compound has formula I(b), 3 , and R 5 is as defined for formula I): TIFF2024534126000021.tif31128.

[0044] In some embodiments, R in the compound of formula I(b) 3 and R 5 is hydrogen and W is oxo.

[0045] In some embodiments, R in the compound of formula I(b) 3 and R 5 is hydrogen and W is hydroxyl.

[0046] In some embodiments, R in the compound of formula I(b) 3 and R 5 is deuterium and W is hydroxyl.

[0047] In some embodiments, W and R in the compound of formula I 4 is hydrogen, and the compound has formula I(c), 2 , R 3 , R 5 , R 6 , X 1 , X 2 , Y 1 , and Y 2 is as defined for formula I): TIFF2024534126000022.tif39128.

[0048] In some embodiments, X in the compound of formula I(c) 1 , X 2 , and Y 1 is hydrogen, and Y 2 is hydroxyl.

[0049] In some embodiments, Y in the compound of formula I(c) 1 , Y 2 , and X 1 is hydrogen, and X 2 is hydroxyl.

[0050] The disclosed compounds may include an optionally substituted adamantyl substituent. In some embodiments, the compounds have the formula II: TIFF2024534126000023.tif39128, During the ceremony, R 1a and R 1b is independently selected from hydrogen, hydroxyl, carboxyalkyl ester, and hydroxyalkyl; and optionally, R 1a and R 1b is the condition that they are not the same, R 1c is selected from hydrogen and hydroxyl; R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 4 is hydrogen or a hydroxyl protecting group.

[0051] In some embodiments, the carboxyalkyl ester in the disclosed compounds of formula II is a carboxymethyl ester (-C(O)OCH3).

[0052] In some embodiments, the hydroxyalkyl in the disclosed compounds of formula II is hydroxymethyl (-CHOH).

[0053] In some embodiments, the hydroxyl protecting group in the disclosed compounds of formula II is a benzyl group (-CH2-Ph).

[0054] In some embodiments, R in the disclosed compounds having formula II 1c is hydroxyl and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5 , and R 6 is hydrogen, and the compound has formula II(a), 1a and R 1b is as defined for formula II): TIFF2024534126000024.tif39128.

[0055] In some embodiments, R in the compound of formula II(a) 1b is a carboxymethyl ester (-C(O)OCH3), and R 1a is hydrogen.

[0056] In some embodiments, R in the compound of formula II(a) 1a is a carboxymethyl ester (-C(O)OCH3), and R 1b is hydrogen.

[0057] In some embodiments, R in the compound of formula II(a) 1b is hydroxymethyl (-CHOH), and R 1a is hydrogen.

[0058] In some embodiments, R in the compound of formula II(a) 1a is hydroxymethyl (-CHOH), and R 1b is hydrogen.

[0059] In some embodiments, R in the disclosed compounds having formula II 1c is hydrogen, and R 4 is a hydroxyl protecting group, R 2 , R 3 , R 5, and R 6 is hydrogen, and the compound has formula II(b), 1a and R 1b is as defined for formula II): TIFF2024534126000025.tif37128.

[0060] In some embodiments, R in the compound of formula II(b) 1b is hydroxymethyl (-CHOH), and R 1a is hydrogen.

[0061] In some embodiments, R in the compound of formula II(b) 1a is hydroxymethyl (-CHOH), and R 1b is hydrogen.

[0062] In some embodiments, R in the disclosed compounds having formula II 1c , R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen, and the compound has formula II(c), 1a and R 1b is as defined for formula II): TIFF2024534126000026.tif36128.

[0063] In some embodiments, R in the compound of formula II(c) 1b is hydroxymethyl (-CHOH), and R 1a is hydrogen.

[0064] In some embodiments, R in the compound of formula II(c) 1a is hydroxymethyl (-CHOH), and R 1b is hydrogen.

[0065] The disclosed compounds may include an optionally substituted cyclohexyl substituent. In some embodiments, the compounds have Formula III: TIFF2024534126000027.tif32128, During the ceremony, R 1 is selected from hydrogen, hydroxyl, alkyl, hydroxyalkyl, and haloalkyl; R 2 , R 3 , R 5 , and R 6 are independently selected from hydrogen, deuterium, and halogen, with the proviso that R 3 , R 5 , and R 6 If is hydrogen, then R 1 is haloalkyl, R 4 is hydrogen or a hydroxyl protecting group.

[0066] In some embodiments, R in the disclosed compounds having formula III 2 , R 4 , and R 6 is hydrogen, and R 1 is selected from hydroxyalkyl, haloalkyl, and hydroxyl.

[0067] In some embodiments, R in the disclosed compounds having formula III 2 , R 4 , and R 6 is hydrogen, and R 1 is selected from hydroxyalkyl, haloalkyl, and hydroxyl, and the compound has formula III(a): 3 and R 5 is as defined for formula III): TIFF2024534126000028.tif36128.

[0068] In some embodiments, R in the compound of formula III(a) 1 is monofluoromethyl (-CHF), and R 3 and R 5 is hydrogen.

[0069] In some embodiments, R in the compound of formula III(a) 1 is trifluoromethyl (-CF3), and R 3 and R 5 is hydrogen.

[0070] In some embodiments, R in the compound of formula III(a) 1 is hydroxyl and R 3 is fluoro and R 5 is hydrogen.

[0071] In some embodiments, R in the compound of formula III(a) 1 is hydroxymethyl, R 3 and R 5 is deuterium.

[0072] In some embodiments, R in the disclosed compounds having formula III 2 , R 4 , and R 6 is hydrogen, and R 1 is hydroxyalkyl, and the compound has formula III(b): 3 and R 5 is as defined for formula III): TIFF2024534126000029.tif33128.

[0073] In some embodiments, R in the compound of formula III(b) 3 is fluoro and R 5 is hydrogen, and R 1 is hydroxymethyl.

[0074] In some embodiments, R in the compound of formula III(b) 3 and R 5 is fluoro and R 1 is hydroxymethyl.

[0075] The disclosed compounds may include optionally substituted fused or bridged ring structures. In some embodiments, the compounds have formula IV: has TIFF2024534126000030.tif38128, During the ceremony, R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; R 7 is hydrogen or alkyl; R 8 and R 9 is independently selected from the group consisting of hydrogen, hydroxyl, and hydroxyalkyl; a is 0 or 1, b is 0 or 1, n is 0 or 1.

[0076] In some embodiments, in the disclosed compounds having formula IV, n is 0, a and b are 1, and R 7 is hydrogen or methyl, and the compound has formula IV(a), 2 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 is as defined for formula IV): TIFF2024534126000031.tif39128.

[0077] In some embodiments, R in the compound of formula IV(a) 8 is hydroxyl or hydroxymethyl, R 9 is hydrogen.

[0078] In some embodiments, the compound of formula IV(a) has the structure: I have TIFF2024534126000032.tif29128.

[0079] In some embodiments, in the disclosed compounds having formula IV, a, b, and n are 1 and R 7is hydrogen, and the compound has formula IV(b), 2 , R 3 , R 5 , R 6 , R 8 , and R 9 is as defined for formula IV): TIFF2024534126000033.tif39128.

[0080] In some embodiments, R in the compound of formula IV(b) 8 is hydroxyl or hydroxymethyl, R 9 is hydrogen.

[0081] In some embodiments, in the disclosed compounds having formula IV, a, b, and n are 0 and R 7 and R 8 is hydrogen, and R 9 is hydroxymethyl, and the compound has formula IV(c), 2 , R 3 , R 5 , and R 6 is as defined for formula IV): TIFF2024534126000034.tif39128.

[0082] The compounds disclosed herein (e.g., compounds having any of formulas I, I(a), I(b), I(c), II, II(a), II(b), II(c), III, III(a), III(b), IV, IV(a), IV(b), or IV(c)) may have some chiral centers, and stereoisomers, epimers, and enantiomers of the disclosed compounds are contemplated. The compounds may be optically pure with respect to one or more chiral centers (e.g., some or all of the chiral centers may be entirely in the S configuration; and / or some or all of the chiral centers may be entirely in the R configuration, etc.). Additionally or alternatively, one or more of the chiral centers may be present as a mixture of configurations (e.g., a racemic or other mixture of R and S configurations). Compositions comprising substantially purified stereoisomers, epimers, or enantiomers of a compound having either Formula I or II (e.g., compositions comprising at least about 90%, 95%, or 99% pure stereoisomer, epimer, or enantiomer) are contemplated herein.

[0083] Also disclosed herein are hydroxy-protected derivatives of the compounds disclosed herein. For example, the compounds disclosed herein (e.g., compounds having any of formulas I, I(a), I(b), I(c), II, II(a), II(b), II(c), III, III(a), III(b), IV, IV(a), IV(b), or IV(c)) may include a hydroxy-protecting group at any hydroxy group. A "protected hydroxy" group as intended herein is a hydroxy group that is derivatized or protected by any group commonly used for temporary or permanent hydroxy functional group protection (e.g., alkoxycarbonyl, acyl, silyl, or alkoxyalkyl group). A "hydroxy-protecting group" refers to any group commonly used for temporary hydroxy functional group protection, such as, for example, alkoxycarbonyl, acyl, alkylsilyl, or alkylarylsilyl group (hereinafter simply referred to as "silyl" group), and alkoxyalkyl group. Alkoxycarbonyl protecting groups are alkyl-O-CO- groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl.

[0084] As intended herein, the term "alkyl" as used in the description or claims refers to straight-chain or branched alkyl radicals of 1 to 6 carbons in all isomeric forms.

[0085] "Alkoxy" refers to any alkyl radical attached by an oxygen (i.e., a group represented by "alkyl-O-"). Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl. Preferred silyl protecting groups are trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl, and similar alkylated silyl radicals.

[0086] The term "aryl" refers to a phenyl group, or an alkyl-, nitro-, or halo-substituted phenyl group.

[0087] The terms "hydroxyalkyl," "deuteroalkyl," and "fluoroalkyl" refer to an alkyl radical substituted with one or more hydroxy, deuterium, or fluoro groups, respectively.

[0088] "Alkylidene" is a compound of the general formula C k H 2k -, where K is an integer (eg, 1 to 6).

[0089] The term "acyl" refers to an alkanoyl group of 1 to 6 carbons in all its isomeric forms, or a carboxyalkanoyl group of 1 to 6 carbons, such as oxalyl, malonyl, succinyl, glutaryl, or an aromatic acyl group, such as benzoyl, or halogen-substituted benzoyl, nitro-substituted benzoyl, or alkyl-substituted benzoyl.

[0090] The term "carboxyalkyl ester" refers to a -C(O)O-alkyl group, for example, carboxymethyl ester, carboxyethyl ester, carboxypropyl ester, etc. The term "halogen" refers to fluoro, chloro, bromo, and iodo.

[0091] As used herein, the symbols in the compounds described herein TIFF2024534126000035.tif4128 indicates a single or double bond.

[0092] The compounds disclosed herein can exhibit binding to estrogen receptor and agonistic and / or antagonistic activity to estrogen receptor.As used herein, "ERα" refers to estrogen receptor-α, particularly human estrogen receptor-α.As used herein, "ERβ" refers to estrogen receptor β, particularly human estrogen receptor β. Agonists and antagonists of ERα and ERβ are known in the art, as are assays for determining the binding affinity of a compound to ERα and ERβ and for determining whether a bound compound is an agonist or antagonist of ERα and ERβ (see, e.g., McCullough et al., "Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: a combined synthesis, binding and docking study", Biorg. & Med. Chem. (2014) Jan 1;22(1):303-10. doi: 10.1016 / j.bmc.2013.11.024. Epub (2013) Nov 21 and corresponding supplemental information, the contents of which are incorporated herein by reference in their entireties). Suitable assays for determining the binding affinity of a compound to ERα and ERβ and whether a bound compound is an agonist or antagonist of ERα and ERβ may include a fluorescence polarization displacement assay and a cell-based ERα luminescence activity assay and an ERβ luminescence activity assay.

[0093] As used herein, the term "selective agonist" may be used to refer to a compound that selectively binds to an estrogen receptor, particularly ERβ, relative to another estrogen receptor, particularly ERα. For example, a compound that is a selective agonist of ERβ (e.g., K d It may have a binding affinity for the ERβ receptor that is at least 3-fold (or at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold) greater than its binding affinity for ERα (measured in nM). Preferably, a selective agonist of ERβ has a K for ERβ of less than 100 nM, more preferably less than 10 nM, or even more preferably less than 1 nM. d Preferably, the selective agonist of ERβ has a K for ERα of greater than 500 nM, more preferably greater than 1000 nM, or even more preferably greater than 2000 nM. d (nM).

[0094] As used herein, the term "selective agonist" may be used to refer to a compound that selectively binds to and agonizes an estrogen receptor, particularly ERβ, relative to another estrogen receptor, particularly ERα. For example, a compound that is a selective agonist of ERβ has an IC of less than 100 nM, preferably less than 10 nM, and even more preferably less than 1 nM in an ERβ receptor agonist activity assay. 50 (nM), and compounds that are selective agonists of ERβ have an IC of greater than 100 nM, preferably greater than 500 nM, and even more preferably greater than 1000 nM in an ERα receptor agonist activity assay. 50 (nM).

[0095] As used herein, the term "selective agonist" may be used to refer to a compound that selectively binds to and stimulates estrogen receptors, particularly ERβ, rather than antagonizing estrogen receptors, particularly ERβ. For example, a compound that is a selective agonist of ERβ has an IC of less than 100 nM, preferably less than 10 nM, and even more preferably less than 1 nM in an ERβ receptor agonist activity assay. 50 Compounds that are selective agonists of ERβ may have an IC50 of greater than 100 nM, preferably greater than 500 nM, and even more preferably greater than 1000 nM in an ERβ receptor agonist activity assay. 50 (nM).

[0096] Pharmaceutically acceptable salts of the disclosed compounds are also contemplated herein and may be utilized in the disclosed treatment methods. For example, the substituents of the disclosed compounds may be protonated or deprotonated and may be present with an anion or cation, respectively, as pharma-ceutically acceptable salts of the compounds. The term "pharma-ceutically acceptable salts" as used herein refers to salts of compounds that are substantially non-toxic to living organisms. Representative pharma-ceutically acceptable salts include salts prepared by reacting the compounds disclosed herein with pharma-ceutically acceptable mineral or organic acids or organic or inorganic bases. Such salts are known as acid addition salts and base addition salts. It will be understood by the skilled reader that most or all of the compounds disclosed herein can form salts, and that the salt form of the drug is commonly used. This is because in many cases, the salt form is easier to crystallize and purify than the free acid or free base.

[0097] Acids commonly used to form acid addition salts can include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of suitable pharma- ceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-diphosphate, tetrahydrofuran ... oate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, alpha-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0098] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc. Bases useful in the preparation of such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[0099] It will be recognized that the particular counterion forming a part of any salt of the compounds disclosed herein is usually not essential, so long as the overall salt is pharmacologically acceptable and so long as the counterion does not impart undesirable qualities to the overall salt, which may include undesirable solubility or toxicity.

[0100] It is further understood that the disclosed compounds may be in equilibrium with various internal salts. For example, internal salts include salts in which the compounds contain a deprotonated and a protonated substituent.

[0101] The disclosed compounds may be used to prepare and formulate pharmaceutical compositions.Accordingly, also disclosed herein is a pharmaceutical composition comprising an effective amount of any compound disclosed herein or a pharma- ceutically acceptable salt of any compound disclosed herein together with a pharmaceutical excipient.In some embodiments, the disclosed compounds may be used to prepare a medicament for treating diseases or disorders related to estrogen receptor beta (ERβ) activity, particularly diseases or disorders that can be treated with specific ERβ agonists.Accordingly, the disclosed compounds may exhibit ERβ agonist activity, and preferably, the compounds exhibit specificity as ERβ agonists relative to ERβ antagonists, ERα agonists, and / or ERα antagonists.

[0102] The disclosed compounds may be used to prepare and formulate pharmaceutical compositions for treating diseases associated with estrogen ERβ activity.Diseases and disorders associated with ERβ activity may include, but are not limited to, cell proliferation diseases and disorders (e.g., breast cancer, ovarian cancer, and endometrial cancer), psychiatric diseases and disorders (e.g., depression or anxiety), vasomotor diseases and disorders (e.g., hot flashes), neurodegenerative diseases or disorders, bone metabolic diseases or disorders (e.g., osteoporosis), metabolic diseases or disorders (e.g., obesity or insulin resistance), and cardiovascular diseases or disorders.The disclosed pharmaceutical compositions may be administered to a patient in need thereof in a method for treating diseases and disorders associated with ERβ activity.

[0103] The compounds and pharmaceutical compositions disclosed herein may be administered to a subject in need thereof to treat a disease or disorder. In some embodiments, to treat a disease or disorder associated with ERβ activity, the compounds disclosed herein may be administered at an effective concentration such that the compound functions as an ERβ agonist. In some embodiments, the amount of the disclosed compound effective for the compound to function as an ERβ agonist is about 0.05-50 μM (or about 0.05-10 μM or about 0.05-1 μM).

[0104] As used herein, "patient" may be interchangeable with "subject" or "individual" and refers to an animal, which may be a human or a non-human animal, in need of treatment. Patients suitable for the disclosed methods may include, for example, mammals, such as humans, monkeys, dogs, cats, horses, rats, and mice. Suitable human patients include, for example, human patients with a disease or disorder associated with ERβ activity or identified as at risk of developing a disease or disorder associated with ERβ activity.

[0105] As used herein, a "patient in need of treatment" may include a patient with a disease, disorder, or condition that is responsive to ERβ agonist therapy. For example, a "patient in need of treatment" may include a patient with a cell proliferative disease, disorder, or condition, such as cancer (e.g., cancer such as breast cancer). In addition, a "patient in need of treatment" may include a patient with a psychiatric disease or disorder (e.g., depression or anxiety). In addition, a "patient in need of treatment" may include a patient with a vasomotor disease or disorder (e.g., hot flashes).

[0106] As used herein, the terms "treat" or "to treat" refer to, respectively, alleviating symptoms, eliminating temporarily or permanently the cause of the resulting symptoms, and / or preventing or slowing the appearance of the resulting symptoms or reversing the progression or severity of the referred disorder. Thus, the methods disclosed herein include therapeutic and prophylactic administration.

[0107] The term "effective amount" as used herein refers to an amount or dose of the compound, either in a single dose or in multiple doses administered to a subject, that produces a desired effect in the subject being diagnosed or treated. The disclosed methods may include administering an effective amount of the disclosed compound (e.g., as present in a pharmaceutical composition) to treat a disease or disorder associated with ERβ activity in a patient, whereby the effective amount induces, promotes, or causes ERβ agonist activity in the patient.

[0108] Effective amount can be easily determined by the attending diagnostician who is skilled in the art by using known techniques and observing the results obtained under similar circumstances.When determining the effective amount or dosage of the compound to be administered, the attending diagnostician may take into account many factors, such as the species of the subject; its size, age and overall health; the degree of involvement or severity of the disease or disorder involved; the response of each individual patient; the specific compound to be administered; the method of administration; the bioavailability characteristics of the preparation to be administered; the selected dosing schedule; the use of concomitant drugs; and other relevant circumstances.

[0109] In some embodiments, the daily dose of the disclosed compounds may contain about 0.01 mg / kg to about 100 mg / kg (e.g., about 0.05 mg / kg to about 50 mg / kg and / or about 0.1 mg / kg to about 25 mg / kg) of each compound used in the treatment methods of the invention. This dose can be administered under any suitable regimen (e.g., weekly, daily, twice daily).

[0110] The pharmaceutical composition for use according to the method disclosed herein may comprise one compound as active ingredient, or may comprise a combination of compounds as active ingredient.For example, the method disclosed herein may be carried out using a composition that contains one compound that is an ERβ agonist.Or, the method disclosed herein may be carried out using a composition that contains two or more compounds that are ERβ agonists, or a compound that is an ERβ agonist and a compound that is an ERα antagonist.

[0111] Instead of administering a pharmaceutical composition comprising a compound that is an ERβ agonist together with a compound that is an ERα antagonist, the disclosed methods may be practiced by administering a first pharmaceutical composition (e.g., a pharmaceutical composition comprising an ERβ agonist) and a second pharmaceutical composition (e.g., a pharmaceutical composition comprising an ERα antagonist), where the first pharmaceutical composition may be administered before, simultaneously with, or after the second composition. Thus, the first pharmaceutical composition and the second pharmaceutical composition, regardless of their names, may be administered simultaneously or in any order.

[0112] As one of skill in the art would understand, the disclosed pharmaceutical compositions can be prepared using materials (e.g., active excipients, carriers, diluents, etc.) that have properties (e.g., purity) that make the formulation suitable for administration to humans, or the formulations can be prepared using materials that have purity and / or other properties that make the formulation suitable for administration to non-human subjects, but not for administration to humans.

[0113] The compound utilized in the method disclosed herein may be formulated as a pharmaceutical composition in solid dosage form, but any pharma- ceutically acceptable dosage form can be utilized.Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or granules, and the solid dosage form may be, for example, a fast-dissolving dosage form, a sustained release dosage form, a lyophilized dosage form, a delayed release dosage form, a prolonged release dosage form, a pulsatile release dosage form, a mixed immediate release and sustained release dosage form, or a combination thereof.Alternatively, the compound utilized in the method disclosed herein may be formulated as a pharmaceutical composition in liquid form (e.g., injection solution or gel).

[0114] The compound utilized in the methods disclosed herein may be formulated as a pharmaceutical composition containing an excipient, carrier, or diluent.For example, the excipient, carrier, or diluent may be selected from the group consisting of protein, carbohydrate, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste.

[0115] The compound utilized in the method disclosed herein may also be formulated as a pharmaceutical composition that includes one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrating agents, and effervescent agents. Fillers can include lactose monohydrate, anhydrous lactose, and various starches. Examples of binders are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCC®). Suitable lubricants, including agents that affect the flowability of the powder to be compressed, can include colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners can include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents include Magnasweet® (registered trademark of MAFCO), bubble gum flavoring, and fruit flavoring. Examples of preservatives can include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other parahydroxybenzoic acid esters, such as butylparaben, alcohol, such as ethyl alcohol or benzyl alcohol, phenolic compounds, such as phenol, or quaternary compounds, such as benzalkonium chloride.

[0116] Suitable diluents for pharmaceutical compositions can include pharmaceutically acceptable inactive fillers, such as crystalline cellulose, lactose, calcium hydrogen phosphate, sugars, and any mixture of the above.Examples of diluents include crystalline cellulose, such as Avicel PH101 and Avicel PH102; lactose, such as lactose monohydrate, anhydrous lactose, and Pharmatose DCL21; calcium hydrogen phosphate, such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose.

[0117] The disclosed pharmaceutical compositions may also include disintegrants.Suitable disintegrants include slightly cross-linked polyvinylpyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof.

[0118] The disclosed pharmaceutical compositions may also include effervescent agents. Examples of effervescent agents are effervescent couples, such as organic acids and carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, as well as anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present.

[0119] Pharmaceutical compositions containing the compounds may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the carrier or excipient.

[0120] Pharmaceutical compositions adapted for oral administration may be presented as discrete units, for example, capsules or tablets; powders or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; edible foams or whips; or an oil-in-water or water-in-oil liquid emulsion.

[0121] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time, for example, the active ingredient may be delivered from the patch by iontophoresis.

[0122] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols, or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration, and emollients in ointments and creams.

[0123] When applied to the eye or other external tissues, such as mouth and skin, the pharmaceutical composition is preferably applied as a topical ointment or cream.When formulated into an ointment, the compound may be used with a paraffinic or water-miscible ointment base.Alternatively, the compound may be formulated into a cream containing an oil-in-water cream base or a water-in-oil base.Pharmaceutical compositions adapted for topical administration to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

[0124] Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.

[0125] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.

[0126] A pharmaceutical composition adapted for nasal administration wherein the carrier is a solid and comprises a coarse powder having a particle size (e.g. in the range 20 to 500 microns) which can be administered in the manner of snuff (i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose). Suitable formulations wherein the carrier is a liquid for administration as a nasal spray or "nasal drops" include aqueous or oily solutions of the active ingredient.

[0127] Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists, which may be generated by various types of metered dose pressurized aerosols, nebulizers, or insufflators.

[0128] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0129] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.The preparations may be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use.Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. EXAMPLES

[0130] The following examples are illustrative and should not be construed as limiting the claimed subject matter.

[0131] Example 1. Discovery of two novel (4-hydroxyphenyl)-substituted polycyclic carbocycles as potent and selective estrogen receptor beta agonists See also Wetzel et al., Discovery of Two Novel (4-Hydroxyphenyl) Substituted Polycyclic Carbocycles as Potent and Selective Estrogen Receptor Beta Agonists, Bioorg. Med. Chem. Lett., 73(2022) 128906, the contents of which are incorporated herein by reference in their entirety.

[0132] summary Two (4-hydroxyphenyl)-substituted polycyclic carbocycles were prepared and assayed for estrogen receptor activity. 3,7 ]Decan-1-methanol (5a / b) and 7-(4-hydroxyphenyl)spiro[3.5]nonan-2-ol ((±)-11) were found to be potent ERb agonists (1.9±0.4 nM and 6.2±1.4 nM, respectively) in cell-based functional assays. Furthermore, both 5a / b and 11 were highly selective for ERb over ERa (377-fold and 1,100-fold selectivity, respectively). Neither compound inhibited CYP2D6 or CYP3A4 up to 62.5 mM, whereas 5a / b had an IC of 10±0.5 mM. 50 Computational evaluation of 5a / b and 11 predicted that the most likely site of metabolism was ortho to the phenolic hydroxyl group.

[0133] 1. Introduction Estrogen receptors α and β (ERα and ERβ) belong to the nuclear hormone family of intracellular receptors for which 17β-estradiol (E2, Figure 1) is the endogenous ligand. The two receptors exhibit overlapping but distinct tissue distribution patterns as well as different types of transcriptional regulation. 1 Menopause significantly reduces estrogen production and is therefore associated with adverse symptoms such as hot flashes and memory loss. Hormone replacement therapy (HRT) consisting of estradiol or conjugated estrogens has been used to alleviate these symptoms as well as to address loss of bone density. 2 However, HRT is associated with an increased risk of breast cancer and blood clots that can lead to stroke. 3 Activation of ERα, but not ERβ, is responsible for the increased health risks of HRT 4 .

[0134] The crystal structures of E2 with human ERα and ERβ revealed hydrogen-bond interactions between the phenolic hydroxyl group and a bound water molecule and two amino acid residues (Glu353 and Arg394 in ERα, Glu305 and Arg346 in ERβ) and between the aliphatic hydroxyl and a histidine residue (His524 in ERα, His475 in ERβ). 5 These interactions are spaced approximately 11 Å apart. Besides these hydrogen-bonding interactions, the remainder of the ligand-binding pocket consists of a lipophilic cavity in which other agonists can bind.

[0135] The search for selective estrogen receptor beta agonists (SERBAs) has led to the discovery of a number of such compounds. Two such nonsteroidal SERBAs are LY-500307 (elteberel, EC 50 =0.66nM, 32-fold selectivity) 6 and DPN(EC 50 = 66.0 nM, 78-fold selectivity) 7 Recently, the present inventors have identified two nonsteroidal SERBAs, ISP163 (EC 50 = 33 ± 5 nM, 318-fold selectivity) 8 and ISP358-2 / EGX358(EC50 = 27 ± 4 nM, 750-fold selectivity) 9 reported that chronic oral administration of EGX358 (0.5 mg / Kg) showed efficacy on memory consolidation and attenuated drug-induced vasodilation in an ovariectomized mouse model of menopause. 10 The disubstituted 1,12-dicarba-closo-dodecaborane BE120, which contains a large lipophilic linker between the phenol and hydroxymethylene groups, is approximately 100 times more potent than E2 but exhibits lower selectivity (ERβ:ERα=1.4). 11a-c More recently, Bartunek and Coss 11d added alkyl groups to the BE120 structure (e.g., A, Fig. 1), but at the expense of potency (EC 50 They demonstrated improved potency (~20-30 nM) and ERβ selectivity (~200-fold selectivity). As with dicarbadodecaborane, the adamantane moiety is viewed as merely providing significant lipophilicity to known pharmacophores. 12 Taking inspiration from these features, we report herein the synthesis and evaluation of two new potent and selective ERβ agonists.

[0136] 2. Results and Discussion 2.1 Chemistry 2-Adamantanone-5-carboxylic acid was esterified with methanol / thionyl chloride to give the known 13 The methyl ester 1 was obtained (Scheme 1). A slight excess of 4-benzyloxyphenyl Grignard reagent (1.04 equiv.) was added to 1 to give the stereoisomeric tertiary alcohols 2a / b, which were confirmed to be approximately a 1:1 mixture based on the integration of the methyl ester singlets (δ 3.67 and 3.54 ppm). Reduction of the mixture 2a / b with LiAlH4 gave a mixture of primary alcohols 3a / b. Ionic reduction of this mixture gave a mixture of 4a / b. Finally, benzyl ether cleavage of 4a / b using H2 and 10% Pd / C catalyst gave 5a / b, which was revealed to be a 1.8:1 mixture based on the integration of the alcohol methylene singlets (δ 3.18 and 2.99 ppm).

[0137] Scheme 1. 4-(4-hydroxyphenyl)tricyclo-[3.3.1.1 3,7 ]Preparation of decane-1-methanol [Reagents: a, MeOH / SOCl2 (66%); b, 4-benzyloxyphenylmagnesium bromide / THF (72%, 2a:2b ca. 1:1); c, LiAlH4 / THF (74%, 3a:3b ca. 1:1); d, NaBH3CN / BF3-Et2O (52%, 4a:4b ca. 1.8:1); e, H2, Pd / C, MeOH (83%, 5a:5b ca. 1.8:1)] TIFF2024534126000036.tif130128

[0138] Recognizing that the primary alcohol functionality present in 5a / b presents a potential metabolic tendency, we hypothesized that analogs containing a cyclobutanol functionality would be less prone to oxidation. Toward this goal, dichloroketene, generated by reduction of trichloroacetyl chloride with zinc, was synthesized. 15 4-[4-(t-butyldimethysilyl-oxy)phenyl]methylenecyclohexane reacted with 9 (6, Scheme 2) resulted in an inseparable mixture of spirocyclic dichlorocyclobutanones 7 and 8 resulting from exo- and endo-addition. Reduction of this mixture with Zn in acetic acid gave cyclobutanone 9, which was deprotected by reaction with HF-pyridine to give 10. The structure of 10 is 16a The known regioselectivity for the cycloaddition of dichloroketene to 1 Based tentatively on the H NMR spectral data. In particular, the signals of the cyclobutanone methylene protons of 10 appear as two singlets (δ 2.81 and 2.77 ppm). 3 J H-H The absence is in contrast to what would be expected for 2,2-disubstituted cyclobutanones, where the methylene protons appear as two triplets (J about 8 Hz). 16bReduction of 10 under Luche conditions gave the cyclobutanol (±)-11. The structure of 11 was tentatively assigned on the basis of its NMR spectroscopic data. In particular, 2 o The signal of the alcohol CH proton appears as a narrow pentet (J = 7.3 Hz) at δ 4.21. This tentative structural assignment was confirmed by crystal X-ray diffraction (Figure 2), which gave an O-O distance of 11.4 Å. 14 .

[0139] Scheme 2. Preparation of 7-(4-hydroxyphenyl)spiro[3.5]-nonan-2-ol [Reagents: a, TBSCl / imidazole (83%); b, Ph3PCH3 + I - / n-BuLi(84%);c, Cl3CCOCl / Zn / Cu(OAc)2(52%);d, Zn / HOAc(87%);e, HF-pyr / MeOH(73%);f, NaBH4 / CeCl3-7H2O / MeOH(86%)] TIFF2024534126000037.tif74128

[0140] Scheme 3. Preparation of (3aR,6aR)-5-(4-hydroxyphenyl)-3a,6a-dimethyl-1,2,3,3a,4,6a-hexahydropentalen-2-ol [Reagents: a, (4-bromophenoxy)-tert-butyldimethylsilane / n-butyllithium / THF / -78°C, then 12; b, p-toluenesulfonic acid / benzene / reflux; c, HF-pyridine / THF / pyridine; d, LiAlH4 / THF] TIFF2024534126000038.tif45128

[0141] Scheme 4. Proposed synthesis of 7-(4-hydroxyphenyl)spiro[3.5]-nonan-1-ol [Reagents: a, cyclopropylphenylsulfide / n-butyllithium; b, trimethyloxonium tetrafluoroborate followed by NaOH; c, NaBH4; d, H2, Pd / C, MeOH] TIFF2024534126000039.tif46128

[0142] Scheme 5. Proposed synthesis of 2-(4-hydroxyphenyl)-6-hydroxydicyclo[3.3.1]non-2-ene [Reagents: a, (4-bromophenoxy)-tert-butyldimethylsilane / n-butyllithium / THF / -78°C followed by bicyclo[3.3.1]-nonane-2,6-dione; b, methanesulfonyl chloride / triethylamine; c, SiO2; d, TBAF; e, NaBH4] TIFF2024534126000040.tif61128

[0143] Scheme 6. Proposed synthesis of 6-hydroxymethylene-3-(4-hydroxyphenyl)bicyclo[3.1.0]hexane [Reagents: a, allylmagnesium bromide (2 equiv.); b, Grubbs second generation catalyst; c, NaBH3CN / BF3-Et2O; d, N2CHCO2R / Rh2(OAc)4; (e) LiAlH4; (f) H2, Pd / C, MeOH] TIFF2024534126000041.tif87148

[0144] 2.2 Biological activity evaluation 2.2.1. Binding and cell-based assays Affinity of 5a / b (IC 50 = 1.3 nM) was determined using the previously reported lead molecule EGX358, 9EGX358 was 18-fold more potent than EGX358, and (±)-11 was an additional 6-fold more potent (Table 1, Supplementary Figure S1). The TR-FRET binding assay measures the ability to displace fluorescently labeled E2 agonists from the ligand-binding domain and therefore does not reflect the ability to bind in the presence of coactivators or to activate transcription as an agonist. When the coactivator version of the TR-FRET LBD assay was performed, 5a / b and 11 were 9.5- and 2.3-fold more potent than EGX358 for binding to the ER and recruiting PPARγ coactivator peptides (Table 1, Supplementary Figure S2). This assay measures ER LBD activation in that it measures binding and agonist-induced recruitment of coactivator peptides, not simply agonist-receptor binding. Finally, the agonist and antagonist activities of 5a / b and (±)-11 were measured in a cell-based transcription activation assay (Table 1, Supplementary Figure S3). This assay uses full-length and native ER (as opposed to only the LBD) to best mimic the in vivo situation. Adamantylphenols 5a / b have an ERβ EC of 1.9 ± 0.4 nM. 50 5a / b showed the greatest potency of the three compounds at ERβ activation (Fig. 4a). 5a / b showed 377-fold selectivity for ERβ compared to ERα activation (Fig. 4a). The spirocyclic butanol (±)-11 was less potent than 5a / b but had an ERβ EC of 6.2 ± 1.6 nM. 50 and is more selective than 5a / b with 1,100-fold selectivity for ERβ over ERα (Figure 4b). Both compounds are more potent than EGX358, but 5a / b loses selectivity compared to EGX358.

[0145] Table 1. TR-FRET binding and biological evaluation in cell-based transcription assays. I C 50 / EC 50 Values ​​are in nM. TIFF2024534126000042.tif52166 a EGX358 data from ref.8

[0146] 2.2.2 Estrogen receptor docking results The ERβ vs. ERα selectivity of 5a / b and (±)-11 in the cell-based functional assay is much greater than that in the TR-FRET coactivator binding assay. The TR-FRET coactivator binding assay for ERβ or ERα uses only the ligand-binding domain, and therefore, the assay measures only the binding synergy induced by coactivator binding. In comparison, the more biologically relevant cell-based assay measures a dose-response effect based on the conformational change induced by the binding of the estrogen receptor to an agonist, i.e., transcription activation in the nucleus due to the rotation of helix-12, which allows the binding of coactivators that are part of the activated transcription initiation complex. In other words, it measures the actual agonist activity in the cell, which is a multi-step process and not just a simple affinity for the receptor.

[0147] The adamantylphenols 5a and 5b and the spirocyclobutanols (S)-11 and (R)-11 were subjected to Glide Induced Fit Docking from the Schrodinger Suites into the ligand-binding pocket of ERβ (PDB ID: 2JJ3) (Figure 3; Supplementary Figure S4a-d). All structures docked with high affinity (-9.885 to -10.823 kcal / mol) into the ERβ ligand pocket. As is typical for estrogens and SERBAs, the phenolic hydroxyl group is hydrogen bonded to the Glu305-Arg346-water triad. 9 On the other side of the pocket, 11 Å away, the aliphatic hydroxyl of 5b is hydrogen bonded to the δ1 nitrogen of His475. This hydrogen bond is absent from the aliphatic hydroxyl of stereoisomer 5a, which may contribute to the weaker docking of this stereoisomer. All have significant π-π interactions with Phe356.

[0148] The spirocyclobutyl rings of (S)-11 and (R)-11 appear to position the aliphatic hydroxyl well to hydrogen bond to His475. Surprisingly, induced fit docking of 5a, 5b, (S)-11 and (R)-11 into the ligand binding pocket of ERα (PDB ID: 1ere) yielded docking energies similar to those for docking into ERβ. These similar docking energies are consistent with the ERβ:ERα selectivity observed in TR-FRET coactivator binding rather than cell-based functional assays. We have previously observed this in docking of EGX358 with ERβ and ERα. 9 .

[0149] 2.2.3 CYP450 metabolism Experimental measurements of CYP450 binding in CYP450 enzyme kinetic inhibition assays showed that 5a / b binds only to CYP2C9 out of the three CYP450s tested (CYP3A4, CYP2D6, and CYP2C9) with an IC of 10 ± 0.5 μM. 50 (Figure 4; Supplementary Figure S5a-b). In contrast, spirocyclobutanol (±)-11 does not bind with significant activity to any of these CYP450 enzymes. Therefore, 11 is a preferred drug lead molecule in terms of its potential metabolic tendency.

[0150] The predicted metabolism of 5b and 11 based on Schrodinger calculations is shown in Figure 5. This indicates that the most likely metabolic site for both molecules is the phenol ring, specifically the ortho position to the phenolic hydroxyl group (Figure 5a-d). This is based on the intrinsic reactivity of this position and docking into the CYP450 active site pocket (Figure 5e). Although the aliphatic hydroxyls could also potentially be oxidized, the primary alcohol of 5b (Figure 5a) is predicted to be significantly less stable than the secondary alcohol of 11 (Figure 5b), as expected.

[0151] Bioavailability predictions were performed using Schrodinger QikProp. As Caco-2 permeability, predicted transport across the intestinal mucosa was highest for 5b (1126 nm / sec), followed by EGX358 (1005 nm / sec) and then 11 (935 nm / sec). As MDCK permeability, predicted transport across the blood-brain barrier (BBB) ​​was highest for 5b (562 nm / sec), followed by EGX358 (497 nm / sec) and then 11 (460 nm / sec). In all cases, however, relatively favorable transport properties were predicted, which is consistent with our previously reported results with orally delivered EGX358 in mouse model studies. 9,10 Consistent with efficacy studies.

[0152] conclusion In summary, two new polycyclic 4-substituted phenols, 5a / b and (±)-11, were prepared. Each was found to be a single-digit nanomolar ERβ agonist in cell-based functional assays (EC 50 = 1.9 ± 0.4 and 6.2 ± 1.4 nM). Spirocyclobutanol analog 11 showed remarkable ERβ:ERα selectivity (1,100-fold selectivity). Furthermore, 11 did not inhibit the P450 enzymes CYP2C9, CYP2D6, or CYP3A4 up to 62.5 μM. One of the predicted metabolic sites of 5a / b was the primary alcohol functionality, but computational predictions indicated that the cyclobutanol functionality of 11 was much less prone to react. Future studies will involve separation of stereoisomers 5a / b and separation of enantiomers (S)-11 and (R)-11, evaluation of their respective ERβ and ERα activation, in vivo testing for efficacy in hot flash relief and memory consolidation in an ovariectomized mouse model, as well as microsomal stability, PK, and safety toxicology. These results will be reported in due course.

[0153] 4. Experiment 4.1 Chemistry 4.1.1 General Experiments All reactions involving moisture- or air-sensitive reagents were carried out in oven-dried glassware with anhydrous solvents under a nitrogen atmosphere. THF and ether were distilled from sodium / benzophenone. Chromatographic purification was performed using flash silica gel (32-63μ). NMR spectra were recorded on a Varian Mercury+ 300 MHz or Varian UnityInova 400 MHz instrument. CDCl3, CD3OD, and d6-DMSO were purchased from Cambridge Isotope Laboratories. 1 H NMR spectra were calibrated at 7.27 ppm for residual CHCl3 and 3.31 ppm for CD2HOD. 13 C NMR spectra were calibrated from the central peak at 77.23 ppm for CDCl3 and 49.15 ppm for CD3OD. Coupling constants are reported in Hz. High-resolution mass spectra were obtained from the Mass Spectrometry Facility at the University of Wisconsin-Milwaukee.

[0154] 4.1.2 Methyl 4-oxoadamantane-1-carboxylate (1) To a solution of 2-adamantanone-5-carboxylic acid (5.00 g, 25.7 mmol) dissolved in methanol (50 mL) was added SOCl2 (4.67 mL, 64.4 mmol) dropwise. The solution was heated at reflux for 6 h. The solution was cooled to room temperature and quenched with water (20 mL). Methanol was evaporated under reduced pressure, followed by addition of saturated aqueous sodium bicarbonate (10 mL). The resulting mixture was extracted several times with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 1 (3.520 g, 66%) as a colorless solid. TIFF2024534126000043.tif20165The spectral data of this compound are based on literature spectral data. 13 It matched.

[0155] 4-(4-benzyloxyphenyl)-4-hydroxytricyclo[3.3.1.1 3,7 ]-Decane-1-carboxylic acid methyl ester (2a / b) To a solution of 1 (1.20 g, 5.76 mmol) dissolved in dry THF (30 mL) at 0 °C was added dropwise a solution of 4-benzyloxyphenyl-magnesium bromide (1.0 M in THF, 6.0 mL, 6.0 mmol). The reaction was allowed to warm to room temperature and stirred for 4 h. The reaction was quenched with saturated NH4Cl (20 mL) and partitioned between ether (30 mL) and water (20 mL). The aqueous layer was extracted several times with ether and the combined ether layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 4:1) to give 2a / b (1.620 g, 72%) as a dark yellow paste. NMR spectroscopy revealed this to be a mixture of two stereoisomers (approximately 1:1 ratio by integration). TIFF2024534126000044.tif41170

[0156] 4-(4-benzyloxyphenyl)-4-hydroxytricyclo[3.3.1.1 3,7 ]-Decane-1-methanol (3a / b) To a solution of 2a / b (1.50 g, 4.96 mmol) in dry THF (20 mL) at 0° C. was added solid LiAlH4 (753 mg, 19.8 mmol). The reaction was warmed to room temperature and stirred for 2 h. The reaction was carefully quenched with water (15 mL) and extracted several times with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate=7:3) to give 3a / b (1.330 g, 74%) as a colorless solid. NMR spectroscopy revealed this to be a mixture of two stereoisomers (1:1 ratio by integration). TIFF2024534126000045.tif42166

[0157] 4-(4-benzyloxyphenyl)tricyclo[3.3.1.13,7 ]-Decane-1-methanol (4a / b) To a solution of 3a / b (1.27 g, 3.50 mmol) dissolved in dry THF (20 mL) at -78 °C was added NaCNBH3 (1.100 g, 17.5 mmol). The reaction was stirred for 30 min, then BF3-Et2O (2.5 mL, 17.5 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction was carefully quenched with water (10 mL) and the resulting mixture was extracted several times with ethyl acetate. The combined organic layers were washed successively with saturated aqueous sodium bicarbonate, water, and brine. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 4:1) to give 4a / b (630 mg, 52%) as a colorless oil, which solidified upon standing. NMR spectroscopy revealed this to be a mixture of two stereoisomers (1:1.2 ratio by integration). mp 112-114°C; TIFF2024534126000046.tif49165

[0158] 4-(4-hydroxyphenyl)tricyclo[3.3.1.1 3,7 ]-Decane-1-methanol (5a / b) To a solution of 4a / b (570 mg, 1.64 mmol) in methanol (15 mL) was added 10% Pd / C (349 mg, 3.28 mmol). The mixture was stirred at room temperature for 12 h under a balloon filled with H2. The reaction mixture was filtered through a sheet of Celite, dried (MgSO4), and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate 4:1) to give 5a / b (350 mg, 83%) as a colorless solid. NMR spectroscopy revealed this to be a mixture of two stereoisomers (approximately 1:1.8 ratio by integration). mp 148-150 °C; TIFF2024534126000047.tif42165

[0159] Exo-7-[4-(t-butyldimethylsilyloxy)phenyl]-1,1-dichloro-spiro[3.5]nonan-2-one (7) and endo-7-[4-(t-butyldimethylsilyloxy)phenyl]-1,1-dichloro-spiro[3.5]nonan-2-one (8) To a solution of 6 (1.0 g, 3.3 mmol) dissolved in anhydrous ether (15 mL) was added granulated Zn (0.648 g, 9.92 mmol) under N2. Trichloroacetyl chloride (0.6 mL, 0.901 g, 9.92 mmol) was slowly added to the solution via syringe. The mixture was stirred in an ultrasonic bath for 1 h and then heated at 45 °C with stirring for 3 h. After cooling to room temperature, the mixture was filtered through a sheet of Celite and the filtrate was diluted with ether. The ether layer was then washed with saturated aqueous NHC, followed by saturated aqueous NaHCO, and finally with brine. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 10:1) to give a mixture of stereoisomers 7 and 8 (0.712 g, 52%) as a colorless oil. The TIFF2024534126000048.tif27165 mixture was used in the following reaction without further characterization.

[0160] 7-[4-(t-butyldimethylsilyloxy)phenyl]spiro[3.5]nonan-2-one (9) Granulated Zn (0.648 g, 9.92 mmol) was added in one portion to a solution of 7 / 8 (0.300 mg, 0.726 mmol) dissolved in glacial acetic acid (10 mL) under N2, and the mixture was heated to 70 °C for 16 h. After cooling to room temperature, the mixture was filtered through a sheet of Celite to remove Zn residues. The filtrate was treated with water (30 mL) and extracted several times with ethyl acetate. The combined organic layers were diluted with 10 mL of ethyl acetate and concentrated to 100 mL. M It was washed with aqueous NaOH, then with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate=20:1) to give 9 (0.200 g, 80%) as a colorless oil along with a small amount of TBS-deprotected phenol. TIFF2024534126000049.tif27165 The material was used in the next step without further characterization.

[0161] 7-(4-Hydroxyphenyl)spiro[3.5]nonan-2-one (10) HF-pyridine complex (65% HF, 0.2 mL, 5.8 mmol) was added dropwise via syringe to a solution of 9 (0.200 g, 0.580 mmol) dissolved in methanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water and methanol was evaporated under reduced pressure. The resulting mixture was extracted several times with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give 10 (0.098 g, 73%) as a white solid. mp 150-154 °C. mp 150-154 °C; TIFF2024534126000050.tif35165

[0162] 7-(4-Hydroxyphenyl)spiro[3.5]nonan-2-ol (11) Solid CeCl3-7H2O (167 mg, 0.449 mmol) was added to a solution of 10 (98 mg, 0.426 mmol) dissolved in methanol (10 mL) at 0 °C. After stirring for 10 min, solid NaBH4 (18 mg, 0.468) was added. The mixture was warmed to room temperature and stirred for 3 h. Ice-cold water (20 mL) was added to quench the reaction, and then methanol was evaporated under reduced pressure. The residue was extracted several times with ethyl acetate, and the combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 4:1) to give 11 (0.085 g, 86%) as a colorless solid. mp 194-195 °C; TIFF2024534126000051.tif27165

[0163] 7-[4-(t-butyldimethylsilyloxy)phenyl]-1,5-dimethylbicyclo[3.3.0]oct-6-en-3-one (13) A solution of 1-bromo-4-(t-butyldimethylsilyloxy)benzene (569 mg, 1.98 mmol) in dry THF (20 mL) at -78 °C under N2 was diluted with n-butyllithium (1.1 mL, 2.0 M A solution of monoketal 12 (500 mg, 1.98 mmol) dissolved in dry THF (15 mL) was added. The mixture was stirred for 1 h. To the reaction mixture was added a solution of monoketal 12 (500 mg, 1.98 mmol) dissolved in dry THF (15 mL) at -78 °C, and the mixture was stirred for 3 h. The mixture was warmed to room temperature, quenched with water (25 mL), and the mixture was partitioned with CHCl. ​​The combined organic layers were dried (MgSO) and concentrated. The crude product was dissolved in a mixture of benzene (15 mL) and acetone (10 mL), and p-toluenesulfonic acid (101 mg, 0.586 mmol) was added. The mixture was heated to 70 °C for 16 h, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with saturated aqueous NaHCO, followed by brine, and the combined aqueous layers were extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO) and concentrated. The residue was purified by flash chromatography (SiO2, hexane-ethyl acetate=4:1) to give (±)-13 (160 mg, 23%) as a colorless oil. TIFF2024534126000052.tif34165

[0164] 7-(4-Hydroxyphenyl)-1,5-dimethylbicyclo[3.3.0]oct-6-en-3-one (14) To a solution of (±)-13 (155 mg, mmol) dissolved in dry THF (10 mL) and pyridine (1 mL) in a Teflon reaction vessel was added 65% HF-pyridine (0.1 mL). The reaction mixture was stirred at room temperature for 20 h. At this time, TLC (hexane-ethyl acetate=3:1) indicated the disappearance of starting material. The mixture was diluted with ethyl acetate, quenched with 10% aqueous HCl (5 mL), and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were further extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO4) and concentrated to give (±)-14 (87 mg, 83%) as a colorless solid. TIFF2024534126000053.tif12165

[0165] (±)-Endo-7-(4-hydroxyphenyl)-1,5-dimethylbicyclo[3.3.0]oct-6-en-3-ol and (±)-exo-7-(4-hydroxyphenyl)-1,5-dimethylbicyclo[3.3.0]oct-6-en-3-ol (15) Solid LiAlH4 (55 mg, 1.4 mmol) was added portionwise to a solution of (±)-14 (74 mg, 0.31 mmol) in anhydrous THF (10 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 2 h, then H2O (1 mL) was added dropwise very slowly until the bubbling ceased. Dilute aqueous NaOH (1 mL) was added, followed by H2O (50 mL). The mixture was extracted several times with ethyl acetate, the combined extracts were dried (MgSO4), and the solvent was evaporated to give a colorless solid (65 mg, 86%). This 1 H NMR spectroscopy showed this to be a mixture of endo- and exo-alcohol stereoisomers. TIFF2024534126000054.tif49165

[0166] 4.2 Biological evaluation 4.2.1 TR-FRET Ligand Binding Displacement Assay Competitive ligand binding analysis was performed using the Thermo Fisher Scientific LanthaScreen™ assay. A "donor" terbium-labeled antibody against the GST-binding domain was bound to a GST-ERβ construct containing the ligand-binding domain (LBD). A fluorescently labeled tracer molecule (Fluoromone E2) containing 17-β-estradiol was bound to the GST-ERβ-LBD. Excitation of the "donor" antibody resulted in energy transfer to the "acceptor" tracer molecule. Displacement of the tracer molecule was measured after compound introduction and then calculated using the ratio of the fluorescein-labeled "acceptor" (520 nm) and terbium "donor" (495 nm) emission values. A 10-point titration was performed using 1:2 serial dilutions of compound starting at 1000 nM and analysis was performed at a final and fixed DMSO concentration of 1%. The emission ratio was calculated to be IC of 0.497 nM. 50 The data were normalized to the assay control of 17-β-estradiol with an IC of 0.01. Data were analyzed using GraphPad Prism® 6 for Windows, ver. 6.07 (June 12, 2015). The IC of each compound was 50 was calculated using a nonlinear least squares fit (normalized variable slope analysis) of Equation 1. Standard deviation values ​​are derived from this fitting process. y=100 / (1+10 (logIC50-x)*Hillslope) ) (1) In GraphPad Prism 6, Log(IC 50 ) standard deviation (SD) is obtained, so the following correction is made to obtain the standard deviation: I C 50 SD=(((LogIC 50 SD) / 0.434) * I C 50 ) (2) Note that a .

[0167] 4.2.2 Cell-Based Agonist and Antagonist Assays Agonist and antagonist activities were measured using ERα-based and ERβ cell-based assay kits supplied by Indigo Biosciences. The kits utilize non-human cells engineered to express full-length human estrogen receptor (ER) 1 (NR3A1). The cells contain a luciferase reporter gene linked to an ERα- or ERβ-responsive promoter that allows quantification of changes in receptor activity. Changes in ER activity are dependent on the agonist or antagonist properties of the added compounds. Luciferase detection reagents are used to quantify the luminescence intensity of ER-induced luciferase expression. Luminescence intensity is measured using a SpectraMax M5 plate reader. Ligand stock solutions were prepared in DMSO and diluted to final concentrations using Compound Screening Medium (CSM) supplied with the kit. The DMSO concentration of each stock solution was kept below the assay limit of 0.4%. The assay was performed according to the kit instructions, with the addition of vehicle controls for agonist and antagonist assays. Briefly, cells were removed directly from the freezer and diluted in Cell Recovery Media (CRM) provided with the kit. The cells were immediately placed in a warming bath at 37°C for 5 minutes. The cell suspension was split in half and estradiol (E2) was added to half of the cells for the antagonist assay, while the other half of the cells, without E2, was used for the agonist assay. The assay was performed in duplicate, with two tests with ERβ for 5a / b and (±)-11. The cells were plated and the compound of interest was added. The plates were then incubated at 37°C with 5% CO2 for 24 hours. The cell media was removed and luciferin detection reagent was added to measure luminescence. The data was normalized to E2 using GraphPad Prism and expressed as Equation 3: y=Y L +(Y H -Y L )(1+10 ((logEC50-x)*Hillslope) ) (3) It was made to fit. In the formula, Y L and Y H were the lower and upper plateau values, respectively. For the fitting, Y L was constrained to 0. Standard deviations were calculated according to Equation 2.

[0168] 4.2.3 Cytochrome P450 binding assay Cytochrome p450 inhibition screening was performed using the Promega P450-Glo™ screening system. The screening system instructions were followed for CYP2C9, CYP2D6, or CYP3A4 enzymes using luciferin-H, luciferin-ME EGE, or luciferin-PPXE as substrates, respectively. The kit components, i.e., membrane enzyme, control enzyme, substrate, and potassium phosphate buffer and / or TRIS buffer, were combined according to the final concentrations recommended in the System manual. Reactions were preincubated in white 96-well flat-bottom plates at 37°C for 10 minutes before initiating the reaction with 2x NADPH regeneration buffer. The 96-well plates were incubated according to the recommended times within the linear range of each enzyme / substrate reaction. The reaction was stopped with 2x luciferin detection reagent. After 20 minutes, luciferase products were detected using a SpectraMax M5 Molecular Devices plate reader with endpoint luminescence settings. Positive control inhibitors of CYP2C9, CYP2D6, and CYP3A4 enzymes were assayed at final concentrations of 10 μM sulfaphenazole, 1 μM quinidine, and 5 μM ketoconazole, respectively. Serial dilutions of 5a / b and (±)-11 were assayed at final concentrations of 62.5 μM, 31.25 μM, 15.125 μM, 7.812 μM, 3.906 μM, 1.953 μM, 0.977 μM, and 0.488 μM. Inhibition data were analyzed using GraphPad Prism® 6 for Windows, ver. 6.07 (June 12, 2015) software. Raw data were normalized to control enzyme and untreated CYP enzyme means and then analyzed by nonlinear regression using log(inhibitor) vs. normalized dose-response curves to determine IC 50s was evaluated. Standard deviations were calculated from the best-fit values. Data were normalized to vehicle and positive controls (sulfaphenazole for CYP2C9, quinidine for CYP2D6, and ketoconazole for CYP3A4), and nonlinear squared fits of the data were performed using Prism 6 (GraphPad).

[0169] 4.3.5 ERβ docking studies Docking of 5b and 11 into the binding pocket of human ERβ (PDB ID: 2JJ3) was performed using Schrodinger Maestro 12.5. 16 The Glide function of Preprocess was used, followed by review and modify and refine steps. The conditions set for preprocessing were to assign bond orders through the use of the CCD database, add hydrogens, create zero-order bonds to metals, create disulfide bonds, and generate “het” states using Epik with a pH between 7.0 + / - 2.0. Chain B was deleted in the review and modify step due to the fact that the lobes of ER-β are the same. To refine the preprocessed protein, the hydrogen bond assignments, the orientation of the sample waters, and the hydrogens were minimized. The minimization step centered the heavy atoms to an RMSD of 0.30 Å. The force field used for minimization was OPLS3e. LigPrep 17The structures of 5b and 11 were appropriately prepared for docking using the OPLSe force field. The molecules were prepared using the ionizer feature to generate possible states at a pH of 7.0 + / - 2.0. Additionally, the desalt feature was selected as well as the generate tautomer option. The remaining settings were set to default. Standard precision docking and flexible ligand sampling were used. The resulting diagram (Figure 3) shows the interactions with important residues and the orientation of the molecules in the active site.

[0170] 4.3.6 Cytochrome P450 metabolism prediction Previously prepared ligands (5a / b; 11) were analyzed using Schrodinger software's P450 Perform Calculations to predict their susceptibility to CYP450 metabolism. The CYP450 isoforms selected were 3A4, 2C9, or 2D6, which were calculated to predict intrinsic reactivity. The more positive the number, the more reactive the atom is. The 2C9 and 2D6 calculations also involved induced fit docking followed by a Fe accessibility measurement, which is the natural logarithm of the number of poses of atoms within 5 Å of the reactive heme Fe atom.

[0171] References and Notes TIFF2024534126000055.tif212166TIFF2024534126000056.tif215166TIFF2024534126000057.tif79166

[0172] In the above description, it is readily apparent to those skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein may be implemented without elements or limitations not specifically disclosed herein, as appropriate. The terms and expressions used are used as terms of description and not as terms of limitation, and in using such terms and expressions, it is not intended to exclude any equivalents of the shown and described features or portions thereof, and it is recognized that various modifications are possible within the scope of the invention. Thus, although the present invention has been illustrated by specific embodiments and optional features, it should be understood that modifications and / or variations of the concepts disclosed herein may be used by those skilled in the art, and such modifications and variations are considered to be within the scope of the present invention.

[0173] A number of patent and non-patent references have been cited herein. The cited references are incorporated herein by reference in their entirety. In the unlikely event that there is a discrepancy in the definition of a term in this specification compared to the definition of a term in a cited reference, the term shall be interpreted in accordance with the definition in this specification.

[0174] Example 2 trans-4-(4-(fluoromethyl)cyclohexyl)phenol The compound trans-4-(4-(hydroxymethyl)cyclohexyl)phenol dissolved in CH2Cl2 (12 mL) 1To a stirred solution of (0.065 g, 0.315 mmol) at -78 °C, bis(2-methoxyethyl)aminosulfur trifluoride (0.09 mL, 0.473 mmol) dissolved in CHCl (3 mL) was added. The mixture was stirred under N and gradually warmed to room temperature. Upon completion, saturated NaHCO (10 mL) was poured into the mixture. After CO evolution ceased, the mixture was extracted several times with CHCl and the combined extracts were dried (NaSO) and concentrated. The residue was purified by column chromatography (SiO, hexane-ethyl acetate=4:1) to give trans-4-(4-(fluoromethyl)cyclohexyl)phenol (0.037 g, 56%) as a colorless solid. mp 103-109 °C; TIFF2024534126000058.tif35165

[0175] 1-(4-(benzyloxy)phenyl)-4-(trifluoromethyl)cyclohexan-1-ol To a solution of 4-trifluoromethylcyclohexanone (0.200 mg, 1.20 mmol) dissolved in anhydrous THF (15 mL) at 0° C. under N2 was slowly added a solution of (4-(benzyloxy)phenyl)magnesium bromide (0.8 M in THF, 2.3 mL, 1.81 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 16 h. The solution was cooled to 0° C. and quenched with water (30 mL) followed by 1 M aqueous HCl (30 mL). The mixture was extracted several times with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude residue was purified by column chromatography (SiO2, hexane-ethyl acetate=4:1) to give 1-(4-(benzyloxy)phenyl)-4-(trifluoromethyl)cyclohexan-1-ol (0.260 g, 62%) as a mixture of cis and trans diastereomers as a yellow waxy solid. This material was carried on to the next step without further purification. TIFF2024534126000059.tif27166

[0176] trans-1-(benzyloxy)-4-(4-trifluoromethylcyclohexyl)benzene BF3-Et2O (0.20 mL, 1.5 mmol) was added slowly via syringe to a solution of 1-(4-(benzyloxy)phenyl)-4-(trifluoromethyl)cyclohexan-1-ol (0.260 g, 0.742 mmol) and triethylsilane (0.20 mL, 1.5 mmol) dissolved in dry CHCl2 (30 mL) at 0 °C under N2. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 3 h. Saturated aqueous NaHCO3 (20 mL) was added, the layers were separated, and the aqueous layer was extracted several times with CHCl2. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 20:1) to give trans-1-(benzyloxy)-4-(4-trifluoromethylcyclohexyl)benzene (0.150 g, 60%) as an off-white solid. mp=100~105℃. TIFF2024534126000060.tif34166

[0177] trans-4-(4-(trifluoromethyl)cyclohexyl)phenol To a solution of trans-1-(benzyloxy)-4-(4-trifluoromethylcyclohexyl)benzene (0.140 g, 0.419 mmol) in methanol (10 mL) was added 10% Pd / C (45 mg, 0.042 mmol, 10 mol%). The mixture was stirred at room temperature for 12 h under a balloon filled with H2. The reaction mixture was filtered through a sheet of Celite and concentrated to give trans-4-(4-(trifluoromethyl)cyclohexyl)phenol (0.090 g, 88%) as a brown solid. mp=95-100 °C; TIFF2024534126000061.tif27166

[0178] 2-Fluoro-4-(4-hydroxycyclohexyl)phenol 4-(3-Fluoro-4-hydroxyphenyl)cyclohexan-1-one dissolved in anhydrous methanol (10 mL)2 To a solution of (0.033 g, 0.159 mmol) was added NaBH4 (0.090 g, 2.38 mmol). The reaction was stirred at room temperature for 2 h and then diluted with water. The resulting mixture was extracted with ethyl acetate (2 x 15 mL) and the combined extracts were concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 13:7) to give 2-fluoro-4-(4-hydroxycyclohexyl)phenol (0.020 g, 61%) as a colorless solid. mp 179-186 °C. TIFF2024534126000062.tif34166

[0179] 4-(4-(benzyloxy)-3-fluorophenyl)cyclohexan-1-one To a solution of 4-(3-fluoro-4-hydroxyphenyl)cyclohexan-1-one (0.205 g, 0.984 mmol) dissolved in N,N-dimethylformamide (10 mL) was added benzyl bromide (0.219 g, 0.15 mL, 1.28 mmol) followed by potassium carbonate (0.177 g, 1.28 mmol). The mixture was heated at reflux for 6 h. After cooling to room temperature, the mixture was poured into ice-cold water and extracted with ethyl acetate (2x15 mL). The combined organic extracts were washed with brine (3x15 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate=9:1) to give 4-(4-(benzyloxy)-3-fluorophenyl)cyclohexan-1-one (0.232 g, 79%) as a colorless solid. mp 55-60 °C. TIFF2024534126000063.tif34165

[0180] 1-(benzyloxy)-2-fluoro-4-(4-methylenecyclohexyl)benzene A solution of n-butyllithium in hexane (2.5 M, 0.47 mL, 1.17 mmol) was slowly added to a stirred solution of methyltriphenyl-phosphonium bromide (0.556 g, 1.56 mmol) dissolved in dry THF (20 mL) at -10 °C. After 20 min, a solution of 4-(4-(benzyloxy)-3-fluorophenyl)cyclohexan-1-one (0.232 g, 0.778 mmol) dissolved in dry THF (10 mL) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was diluted with water (10 mL), extracted with ethyl acetate (2 x 25 mL), dried (Na2SO4), and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 9:1) to give 1-(benzyloxy)-2-fluoro-4-(4-methylene-cyclohexyl)benzene (0.165 g, 72%) as a colorless solid. TIFF2024534126000064.tif41166

[0181] (4-(4-(benzyloxy)-3-fluorophenyl)cyclohexyl)methanol At 0° C., a solution of 9-BBN (0.5 M A solution of 1-(benzyloxy)-2-fluoro-4-(4-methylene-cyclohexyl)benzene (0.108 g, 0.364 mmol) was added to a solution of 1-(benzyloxy)-2-fluoro-4-(4-methylene-cyclohexyl)benzene (0.108 g, 0.364 mmol) in THF (15 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred for 20 h. After the mixture was recooled to 0 °C, hydrogen peroxide solution (30% in water, 0.20 mL) and 1 N NaOH solution (0.50 mL) was added successively. The resulting mixture was warmed to room temperature, stirred for 15 min, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate=6:4) to give (4-(4-(benzyloxy)-3-fluorophenyl)cyclohexyl)methanol (0.025 g, 22%) as a colorless solid. This was the product of the hydroxymethylene doublet. 1H NMR integration confirmed a 1:2 mixture of cis and trans stereoisomers (δ 3.67 and 3.50 ppm, respectively). TIFF2024534126000065.tif34170

[0182] 2-Fluoro-4-(4-(hydroxymethyl)cyclohexyl)phenol To a solution of (4-(4-(benzyloxy)-3-fluorophenyl)cyclohexyl)methanol (0.050 g, 0.159 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (0.017 g, 10 mol%), and the mixture was stirred at room temperature for 12 h under a balloon filled with H2. The reaction mixture was filtered through a sheet of Celite and concentrated. The residue was purified by column chromatography (SiO2, hexane-ethyl acetate = 3:2) to give 2-fluoro-4-(4-(hydroxymethyl)cyclohexyl)phenol 82 (0.018 g, 51%) as a colorless solid. This was the elution product of the hydroxymethylene doublet. 1 H NMR integration confirmed a 1:2 mixture of cis and trans stereoisomers (δ 3.60 and 3.39 ppm, respectively). TIFF2024534126000066.tif34165

[0183] References for Example 2 TIFF2024534126000067.tif53165

Claims

1. Formula II: A compound having the formula: During the ceremony, R 1a and R 1b is independently selected from hydrogen, hydroxyl, carboxyalkyl ester, and hydroxyalkyl; and optionally, R 1a and R 1b is not the same, R 1c is selected from hydrogen and hydroxyl; R 2 , R 3 , R 5 , and R 6 is independently selected from hydrogen, deuterium, and halogen; and R 4 is hydrogen or a hydroxyl protecting group; The compound.

2. 2. The compound of claim 1, wherein the carboxyalkyl ester is a carboxymethyl ester.

3. 2. The compound of claim 1, wherein the hydroxyalkyl is hydroxymethyl.

4. 3. The compound of claim 2, wherein the hydroxyalkyl is hydroxymethyl.

5. 2. The compound of claim 1, wherein the hydroxyl protecting group is a benzyl group.

6. R 1c is hydroxyl and R 4 is a hydroxyl protecting group and R 2 , R 3 , R 5 , and R 6 is hydrogen, and the compound has formula II(a): The compound having the formula:

7. R 1b is a carboxymethyl ester and R 1a is hydrogen, or R 1a is a carboxymethyl ester and R 1b is hydrogen, The compound of claim 6.

8. R 1b is hydroxymethyl and R 1a is hydrogen, or R 1a is hydroxymethyl and R 1b is hydrogen, The compound of claim 6.

9. R 1c is hydrogen and R 4 is a hydroxyl protecting group and R 2 , R 3 , R 5 , and R 6 is hydrogen, and the compound has formula II(b): The compound having the formula:

10. R 1b is hydroxymethyl and R 1a is hydrogen, or R 1a is hydroxymethyl and R 1b is hydrogen, 10. The compound of claim 9.

11. R 1c , R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen, and the compound has formula II(c): The compound having the formula:

12. R 1b is hydroxymethyl and R 1a is hydrogen, or R 1a is hydroxymethyl and R 1b is hydrogen, 12. The compound of claim 11.

13. 13. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with a pharmaceutical excipient, carrier, or diluent.

14. 13. A pharmaceutical composition for treating a patient having a disease or disorder associated with estrogen receptor β (ERβ) activity, comprising an effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the disease or disorder is a cell proliferative disease or disorder.

16. 15. The pharmaceutical composition of claim 14, wherein the disease or disorder is a psychiatric disease or disorder.

17. 15. The pharmaceutical composition of claim 14, wherein the disease or disorder is a vasomotor disease or disorder.

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