WO2022020605A1 - Treatment of metastasized estrogen receptor positive breast cancer - Google Patents

Abstract

A treatment method comprising a small molecule ERα biomodulator that kills therapy- resistant ERα cancer that metastasized to the brain is disclosed. In one embodiment, the small molecule biomodulator has increased therapeutic utility because of an increased ability to kill therapy-resistant breast cancer cells that metastasized to the brain compared to BHPI and other conventional therapies (endocrine therapies, tamoxifen and fulvestrant/TCI). The small molecule biomodulators not only inhibit proliferation of the cancer cells but kills them, which prevents reactivation of tumors years later.

Description

TREATMENT OF METASTASIZED ESTROGEN RECEPTOR POSITIVE BREAST CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 63/055,583, filed July 23, 2020, the disclosures of which are hereby incorporated herein by reference in their entirety. GOVERNMENT SUPPORT This invention was made with government support under Grant No. RO1 DK071909 and CA234025-01A1 awarded by the National Institutes of Health and Grant No. W81XWH-14-1- 0159 awarded by the U.S. Army Medical Research and Development Command. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Approximately 70% of breast cancers are ERD positive. Endocrine (hormonal) therapies for these tumors include aromatase inhibitors that block estrogen production. Examples of endocrine therapies include tamoxifen, which competes with estrogens for binding to ERD, and fulvestrant/Faslodex/ICI 182,780, which both competes with estrogens and promotes ERD degradation. Although effective initially, resistance sometimes develops in primary tumors and is nearly universal in the metastatic setting. Although resistance mechanisms are diverse, recent studies show that approximately 30% of these metastatic tumors harbor ERD mutations, most commonly ERDD538G and ERDY537S. There is abundant evidence that these tumors exhibit estrogen-independent proliferation and are therefore resistant to aromatase inhibitors that block estrogen production. They are also largely resistant to tamoxifen and partially resistant to fulvestrant. Notably, patients whose metastatic tumors contain the ERDD538G mutation have a 6-month shorter survival time, and those with the ERDY537S mutation have a 12-month shorter survival time, than patients whose metastatic tumors contain non-mutated wild-type ERD. Therefore, chemotherapeutic agents targeting breast cancer cells containing these mutations are urgently needed. The pathology of ERD positive breast cancer is unusual. While 5-year survival rates are impressive, the tumors often recur 10-20 years after initial diagnosis. This is thought to be due to reactivation and proliferation of dormant breast cancer cells. Accordingly, it is especially important to actually kill the tumor cells and not allow them to remain dormant and susceptible to reactivation. Current endocrine therapies are cytostatic, not cytotoxic. Current endocrine therapies therefore do not kill residual breast cancer cells. This allows the cells to lie dormant and reactivate at a later date. Therapeutic options for these recurrent tumors are poor and most breast cancer deaths are in patients with ERD positive tumors. Ovarian cancer usually presents at an advanced stage. Tumors often recur after surgery. Although 30-70% of ovarian tumors are ERD positive, and ERD expression is associated with a poor outcome, endocrine therapy is ineffective and recurrent tumors are usually treated with platinum-based chemotherapy and paclitaxel. Although initially responsive, after several cycles of treatment, tumors recur as resistant ovarian cancer, with poor therapeutic options. More than half of ovarian cancer patients die within five years. In ovarian cancer, a common mechanism for resistance to paclitaxel and other chemotherapy agents is multidrug resistance: energy dependent drug efflux caused by overexpression of ATP-dependent efflux pumps, especially Multidrug Resistance Protein 1 (MDR1)/P-glycoprotein/ABCB1. Despite intensive efforts, effective non-toxic MDR1 inhibitors have remained elusive. Furthermore, although many cancers of the uterine endometrium are ERD positive, current endocrine therapies work poorly. Accordingly, new small molecule therapeutic agents that are cytotoxic, and not merely cytostatic, are urgently needed to provide more efficacious therapy for cancer that metastasized to the brain. SUMMARY This disclosure provides small molecule therapeutic compounds with greatly increased therapeutic potential compared to known therapeutic compounds for cancer that metastasized to the brain. The compounds display an improved ability to actually kill cancer cells, including therapy-resistant cancer cells. The therapy-resistant cancer cells that metastasized to the brain can include breast cancer cells, ovarian cancer cells, and endometrial cancer cells. To prevent cancer recurrence, it is critical to destroy the entire population of growing and dormant therapy- resistant cancer cells. In various embodiments, this disclosure provides therapeutic compounds that, compared to BHPI and to endocrine therapies such as tamoxifen and fulvestrant, possess significantly increased ability to kill cancer cells, and thus, dramatically increased therapeutic potential. Examples of such compounds, ErSO and ErSO(OH), which can cross the blood-brain barrier have greatly increased ability to kill breast cancer cells metastasized to the brain and therefore shows dramatically increased therapeutic potential. Accordingly, this disclosure provides a method for treating an alpha estrogen receptor (ERD^ positive cancer that metastasized to the brain comprising administering to a subject having an ERD positive cancer that metastasized to the brain a therapeutically effective amount of a compound of Formula I:

or a salt thereof; wherein X is O, S, or NR^D; Z is O, S, or NR^D; R¹ is trifluoromethyl, trifluoromethoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -OR^A, -SR^A, or -N(R^A)₂; R², R³, and R⁴ are each independently H, halo, -OR^A, -SR^A, -N(R^A)₂, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A¹, A², and A³ are each independently H, OH, halo, or alkyl; G¹ is -OR^B, -SR^B, -S(=O)₂R^B, alkyl, or halo; G² is -OR^C, -SR^C, -S(=O)₂R^C, alkyl, or halo, wherein R^C is trifluoromethyl, H, alkyl, or acyl; G³ is H, -OR^W, -SR^W, -S(=O)₂R^W, halo, or alkyl; and R^A, R^B, R^D, and R^W are each independently H, alkyl, or acyl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents; wherein the cancer is thereby treated. In some embodiments, alkyl is substituted with three halo groups provides a trihaloalkyl such as a trifluoromethyl. Accordingly, any alkyl group of Formula I can be a trifluoromethyl group. Compounds of the formulas described herein can bind to the alpha estrogen receptor (ERD) and kill or inhibit the growth of cancer cells by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum. In various embodiments, the compound of Formula I is cytotoxic. Accordingly, this disclosure provides a method of treating a cancer that metastasized to the brain comprising administering to an ERD positive cancer subject in need thereof a therapeutically effective amount of a compound described herein, thereby treating the cancer in the subject. The cancer that metastasized to the brain can be from, for example, breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, lung cancer, pancreatic cancer, prostate cancer, or colon cancer. BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention. Figure 1. Blood-brain barrier penetrance of ErSO. Mice (CD-1) were treated with the indicated doses and times, then sacrificed and their serum and brains collected. Concentrations were determined via LC/MS/MS analysis. The average blood per mouse was approximated as 58.5 mL/kg. Figure 2. Mouse model of ERD+ metastasis to the brain. Tumors in brain were established by intracranial implantation of MYS-luc. cells. Treatment: vehicle or ErSO (40 mg/kg i.p. or p.o.) daily for 14 days; tumor burden quantitated by BLI. Dashed line represents 0% change. Representative ErSO-treated (i.p.) image shown; mean ± s.e.m.; n = 4 mice (vehicle), n= 5 mice (ErSO). Analysis by 2-way ANOVA with Bonferroni correction post-hoc test with p values: **: p ≤ 0.01, ***: p ≤ 0.001. Figure 3. Mouse model of ERD+ metastasis to the brain. Percent change comprising of Day 0 and Day 14 for MYSluc for the brain metastases model. Representative image showing ErSO induces regression in a brain tumor. Images are 3D-DLIT renders. Figure 4. ErSO induces profound regression of breast cancer in brain. 40 mg/kg ErSO injected subcutaneously daily for 14 days. Figure 5. ErSO induces profound regression of breast cancer in brain. Cells: MYS-Luc (MCF7-ERĮY537S-Luc cells); Tumor Model: Direct injection of MYS-Luc cells into the Brain; Tumor Outgrowth: 14 days showing Day 0 of treatment; Treatment: 40 mg/kg ErSO daily for 14 Days, injected subcutaneously in abdomen; Tumor Visualization: 3D tumor imaging with CAT scan of skeleton; Quantitation: Using a sensitive 2D imaging, this tumor regressed 96%. Figure 6. Ex-vivo imaging of vehicle control and ErSO-treated breast cancer in the brain. In general, vehicle tumors formed diffuse metastases throughout the brain hemisphere into which the breast cancer cells were injected but did not spread into the other brain hemisphere. Figure 7. Graph of ex-vivo imaging of vehicle control and ErSO-treated breast cancer in the brain. Figure 8. Representation of mechanism for leveraging ERĮ overexpression. Current endocrine therapy (i.e. AI, SERMs, and SERDs) are slow acting, cytostatic, and lead to resistant disease (e.g. ERĮ Y537S or D538G).^1-6 ErSO is an orally bioavailable, first-in-class therapy for the treatment of resistant ERĮ+ breast cancer. ErSO triggers an immunogenic necrotic cell death via hyperactivation of the anticipatory Unfolding Protein Response (a-UPR)^7,8 without ERĮ degradation. Figure 9. Graph showing ErSO is a cytotoxic a-UPR Activator. Figure 10. Data for ErSO showing pharmacokinetics, blood brain barrier penetration, and tolerability. ErSO BBB Penetration Brain:Blood Ratio = 27:73 (I.V. administration). Figure 11. Data showing ErSO treatment leads to complete regression of established tumors. (A) MCF-7 (ERĮ WT) orthotopic model, ovariectomized Nu/J mice with E2 pellet (0.36 mg), ErSO dosed daily (p.o.), Fulvestrant (5 mg/mouse) once-a-week, n = 6. (B) MCF-7 (ERĮ WT) bilateral orthotopic model, ovariectomized Nu/J mice with E2 pellet (0.36 mg), ErSO dosed daily (7 days, 40 mg/kg. p.o.), n = 4-5. Figure 12. Data showing ErSO eradicates mutant ERĮ tumors with no regrowth. (A) Quantitative regression of mutant ERĮ tumors. TYS-luc. orthotopic model, ovariectomized NSG mice no E2 pellet, ErSO dosed daily, n = 5-6. (B) Quantitative regression of mutant ERĮ metastasis. Brain Metastases: MYS-luc. Intracranial Model in NSG mice with no E2 pellet, ErSO dosed daily, n=4-5, *: p ≤ 0.05, ***: p ≤ 0.001. (C) Regression of mutant ERĮ PDX (Y537S). DETAILED DESCRIPTION Cancer cells can remain quiescent for extended periods of time and then reactivate. It is therefore desirable to kill the tumor cells, not merely to prevent them from proliferating. This disclosure provides therapeutic compounds, including cytotoxic compounds, and assays for testing compounds for the ability to kill cancer cells, including therapy-resistant breast cancer cells that metastasized to the brain. Provided herein are new compounds that are more effective than BHPI in killing breast cancer cells expressing both wild type estrogen receptor D (ERD) and ERD mutations that are common in metastatic breast cancer. These mutations are associated with resistance to current breast cancer therapies. Also provided herein are compounds active against ovarian cancer cells, uterine cancer cells, and other cancer cells that are ERD positive.

The compound BHPI, illustrated above, is a known anticancer drug. The compounds described herein share an oxindole core with BHPI but were surprisingly discovered to have vastly different therapeutic properties. Various endocrine therapies such as BHPI, the 7- trifluormethyl BHPI derivative 01-15, fulvestrant, and tamoxifen merely slow cancer cell growth, i.e., they are cytostatic. Conversely, it was surprisingly discovered that ErSO and ErSO(OH) are cytotoxic. Both ErSO and ErSO(OH) were identified by their distinct cytotoxicity profile and ability to quantitatively kill cancer cells, and therefore will be an effective therapy for treating tumors. In vivo efficacy studies of ErSO have demonstrated complete tumor regressions in multiple local and metastatic disease models. ErSO was found to penetrate the blood-brain barrier, suggesting a therapeutic application that quantitatively kills cancers within the central nervous system compartment. For complete disease regressions and ‘cures’, blood-brain barrier penetration is an important consideration. Further details are provided in U.S Patent Application No.16/801,839 filed on February 26, 2020 and U.S Provisional Application No. 63/018,863 filed on May 1, 2020, which are incorporated herein by reference in their entity. Definitions The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley’s Condensed Chemical Dictionary 14^th Edition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001. References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described. The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and/or the recitation of claim elements or use of "negative" limitations. The term "and/or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl ring refers to one to five substituents on the ring. As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect. The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph. As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “number1” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, … 9, 10. It also means 1.0, 1.1, 1.2.1.3, …, 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on. If the variable disclosed is a number less than “number10”, it implies a continuous range that includes whole numbers and fractional numbers less than number10, as discussed above. Similarly, if the variable disclosed is a number greater than “number10”, it implies a continuous range that includes whole numbers and fractional numbers greater than number10. These ranges can be modified by the term “about”, whose meaning has been described above. One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation. The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., in a solution, in a reaction mixture, in vitro, or in vivo. An "effective amount" refers to an amount effective to treat a disease, disorder, and/or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect. Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment). The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and/or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and/or prophylactic administration, as appropriate. As used herein, "subject" or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods provided herein, the mammal is a human. As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compound can be administered by any appropriate route that results in delivery to a desired location in the subject. The compounds and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs. The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting. The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%. Wherever the term “comprising” is used herein, options are contemplated wherein the terms “consisting of” or “consisting essentially of” are used instead. As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the aspect element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation, or limitations not specifically disclosed herein. The term "halo" or "halide" refers to fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "alkyl" refers to a branched or unbranched hydrocarbon having, for example, from 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (iso-propyl), 1-butyl, 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include an alkenyl group or an alkynyl group. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene). An alkylene is an alkyl group having two free valences at carbon or two different carbon atoms of a carbon chain. Similarly, alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms. The term "cycloalkyl" refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like. The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4- oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group. The term "aromatic" refers to either an aryl or heteroaryl group or substituent described herein. Additionally, an aromatic moiety may be a bisaromatic moiety, a trisaromatic moiety, and so on. A bisaromatic moiety has a single bond between two aromatic moieties such as, but not limited to, biphenyl, or bipyridine. Similarly, a trisaromatic moiety has a single bond between each aromatic moiety. The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted with a substituent described below. The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted". Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5-membered rings, two 6-membered rings, or a 5-membered ring fused to a 6-membered ring. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H- quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, E-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non- peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (C₁-C₆)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto. As used herein, the term "substituted" or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a selection from the indicated group(s), or with a suitable group known to those of skill in the art, provided that the indicated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfinyl, and alkylsulfonyl. Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano. Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', OC(O)N(R')₂, CN, CF₃, OCF₃, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')₂, SR', SOR', SO₂R', SO₂N(R')₂, SO₃R', C(O)R', C(O)C(O)R', C(O)CH₂C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')₂, OC(O)N(R')₂, C(S)N(R')₂, (CH₂)_{0- 2}NHC(O)R', N(R')N(R')C(O)R', N(R')N(R')C(O)OR', N(R')N(R')CON(R')₂, N(R')SO₂R', N(R')SO₂N(R')₂, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')₂, N(R')C(S)N(R')₂, N(COR')COR', N(OR')R', C(=NH)N(R')₂, C(O)N(OR')R', or C(=NOR')R' wherein R’ can be hydrogen or a carbon-based moiety (e.g., (C₁-C₆)alkyl), and wherein the carbon-based moiety can itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is divalent, such as O, it is bonded to the atom it is substituting by a double bond; for example, a carbon atom substituted with O forms a carbonyl group, C=O. Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate (defined below), which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The term “enantiomerically enriched” (“ee”) as used herein refers to mixtures that have one enantiomer present to a greater extent than another. Reactions that provide one enantiomer present to a greater extent than another would therefore be “enantioselective” (or demonstrate “enantioselectivity”). In one embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 2% ee; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 5% ee; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 20%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 50%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 80%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 90%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 95%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 98%; in another embodiment of the invention, the term “enantiomerically enriched” refers to a mixture having at least about 99%. The term “enantiomerically enriched” includes enantiomerically pure mixtures which are mixtures that are substantially free of the species of the opposite optical activity or one enantiomer is present in very low quantities, for example, 0.01%, 0.001% or 0.0001%. The term “IC₅₀” is generally defined as the concentration required to kill 50% of the cells in 24 hours. As used herein, the name "ErSO(OH)" refers to the active compound (S)-ErSO(OH), whereas the inactive compound is specifically referred to as (R)-ErSO(OH) and the racemic mixture is specifically referred to as (R/S)-ErSO(OH). Also, ErSO refers to the more active compound (R)-ErSO where (S)-ErSO is the less active compound. Embodiments of the Invention This disclosure provides a method for treating an alpha estrogen receptor (ERD^ positive cancer that metastasized to the brain comprising administering to a subject having an ERD positive cancer that metastasized to the brain a therapeutically effective amount of a compound of Formula I:

or a salt thereof; wherein X is O, S, or NR^D; Z is O, S, or NR^D; R¹ is trifluoromethyl, trifluoromethoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -OR^A, -SR^A, or -N(R^A)₂; R², R³, and R⁴ are each independently H, halo, -OR^A, -SR^A, -N(R^A)₂, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A¹, A², and A³ are each independently H, OH, halo, or alkyl; G¹ is -OR^B, -SR^B, -S(=O)₂R^B, alkyl, or halo; G² is -OR^C, -SR^C, -S(=O)₂R^C, alkyl, or halo, wherein R^C is trifluoromethyl, H, alkyl, or acyl; G³ is H, -OR^W, -SR^W, -S(=O)₂R^W, halo, or alkyl; and R^A, R^B, R^D, and R^W are each independently H, alkyl, or acyl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents; wherein the subject having ERD positive cancer that metastasized to the brain is (effectively) treated. In some embodiments, effective treatment results in complete elimination of a cancer in the brain (e.g., a cancerous brain tumor). In other embodiments, an effective 2-week treatment results in reducing a cancer in the brain by more than 90% of the initial volume of the cancer in the brain. In yet other embodiments, a 2-week treatment reduces the volume of the cancer in the brain by about 80%, about 70%, about 60%, or about 50%. In some embodiments, and G¹ and G² are not both OH. In various embodiments, G¹, G², or G³ is -OR^B, -OR^C, or -OR^W, respectively, R^B, R^C, and R^W each independently can be an oxygen protecting group. In each formula described herein, when a variable, such as any one of R¹-R⁴, A¹-A³, G¹- G³, R^A, R^B, R^C, R^D, or R^W, is alkyl, the alkyl is optionally substituted with one or more substituents, such as one or more of the substituents described in the definition of substituents herein. Alkyl optionally substituted with one or more substituents can be, for example, alkyl substituted with one to six substituents, one to five substituents, one to four substituents, one to three substituents, one or two substituents, or one substituent. Alkyl optionally substituted with one or more substituents includes, for example, halo-substituted alkyl groups such as CF₃, CHF₂, CH₂F, CH₂CF₃, CF₂CH₃, or CF₂CF₃. In one specific embodiment, R¹ is CF₃. In one specific embodiment, G¹ is CF₃. In another specific embodiment, G¹ is OCF₃. In one specific embodiment, G² is CF₃. In another specific embodiment, G² is OCF3. In one specific embodiment, G³ is CF3. In another specific embodiment, G³ is OCF3. In some embodiments, G¹ is OR^B. In certain embodiments, R^B is H or -(C1-C6)alkyl. In some embodiments, R^B is -(C1)alkyl optionally substituted with one to three substituents. In various embodiments, R^B is -(C₁)alkyl substituted with one to three halo substituents. In one specific embodiment, G¹ is OH. In another specific embodiment, G¹ is methyl or trifluoromethyl. In some embodiments R^B and R^C are each independently –(C₁-C₆)CCR^X wherein R^X is H or –(C₁-C₆)alkyl. In various embodiments, alkyl or –(C₁-C₆)alkyl is saturated, or unsaturated wherein the unsaturated moiety comprises double bonds, triple bonds, or a combination thereof. In some embodiments, G² is OR^C. In certain embodiments, R^C is H or -(C1-C6)alkyl. In some embodiments, R^C is -(C1)alkyl optionally substituted with one to three substituents. In various embodiments, R^C is -(C₁)alkyl substituted with one to three halo substituents. In one specific embodiment, G² is OH. In another specific embodiment, G² is methyl or trifluoromethyl. In some embodiments, G³ is OR^W. In certain embodiments, R^W is H or -(C1-C6)alkyl. In some embodiments, R^W is -(C1)alkyl optionally substituted with one to three substituents. In various embodiments, R^W is -(C1)alkyl substituted with one to three halo substituents. In one specific embodiment, G³ is OH. In another specific embodiment, G³ is methyl or trifluoromethyl. In some embodiments, R^A, R^B, R^C and R^D are each independently H or -(C₁-C₆)alkyl. In certain embodiments, R¹, R², R³ and R⁴ are each independently H, halo, or -(C₁-C₆)alkyl. In various embodiments, A¹, A², and A³ are each independently H or halo, and G¹ is -OR^B, and G² is -OR^C. In some embodiments, X is NR^D and Z is O. In one particular embodiment, R^D is H. In various embodiments, R^A, R^B, R^C, R^D, R^W, R¹, R², R³ and R⁴ are each independently -(C1-C6)alkyl, -(C2-C6)alkyl, -(C3-C6)alkyl, or -(C3-C6)cycloalkyl. In some embodiments, when present, at least one -(C₁-C₆)alkyl, -(C₂-C₆)alkyl, -(C₃-C₆)alkyl, or -(C₃- C₆)cycloalkyl is substituted with one or more halo. In certain specific embodiments, -(C₁- C₆)alkyl is trifluoromethyl. In various embodiments, R¹ is CH₃, CH₂CH₃, CF₃, CHF₂, CH₂CF₃, CF₂CH₃, or CF₂CF₃. In some embodiments, G¹ is OH, G² is -OR^C, and R^C is H, CH3, CH₂CH3, CF3, CHF2, CH₂CF3, CF2CH3, or CF2CF3. In one embodiment, R¹ is CH3 or CF3, R² is H, F, or Cl, R³ and R⁴ are H, X is NH, Z is O, A¹-A³ are H, G¹ is OH, G² is OCF3, and G³ is OH. In some embodiments, the compound of Formula I is the (S)-enantiomer. In other embodiments, the compound of Formula I is the (R)-enantiomer. In additional embodiments, the compound of Formula I is a compound of Formula II:

wherein R¹ is –(C₁-C₆)alkyl; R² is H, halo, –(C1-C6)alkyl, or -OR^A; G² is -OR^C, –(C1-C6)alkyl; and G³ is H, halo, -OR^W; wherein –(C1-C6)alkyl is optionally substituted with one or more halo. In one specific embodiment, R¹ is CF₃, R² is H, G¹ is OH, G² is OCF₃, and G³ is OH. In another embodiment, at least one of G¹, G², and G³ is OP wherein P is an oxygen protecting group selected from allyl, benzyl, thiobenzyl, acetyl, chloroacetyl, trifluoroacetyl, phenacyl, methyl methoxy, PEG (-(OCH₂CH₂)_nOH or (-(OCH₂CH₂)_nO-alkyl wherein n is 2 to about 1,000), an amino acid, and a silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBS), or t-butyl-diphenylsilyl (TBDPS)), or each of G¹ and G³ is OP and their OP groups taken together form a benzylidene group. In various other embodiments, one or more hydrogen atoms is deuterium or tritium, one or more carbon atoms is a carbon isotope, or a combination thereof. In some embodiments, the compound is ErSO: (ErSO). In some other embodiments, the compound is ErSO(OH): (ErSO(OH)). In some additional embodiments, the compound is levorotatory. In other embodiments, the compound is dextrorotatory. In a specific embodiment, the compound is (S)-ErSO(OH). In another specific embodiment, the compound is (R)-ErSO. In one embodiment, the compound is (S)-3-(3,4-dihydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one. In another embodiments, the compound is (R)-3-(3,4-dihydroxyphenyl)-3-(4- (trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one. In one other embodiment, the compound is (R)-3-(4-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7- (trifluoromethyl)indolin-2-one. In yet another embodiment, the compound is (S)-3-(4- hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one. In some embodiments, the compound inhibits (or has a binding affinity for) ERD and has an anticancer cellular IC₅₀ that is less than about 200 nM. In other embodiments, the compound is metabolized by the subject to form an active metabolite that inhibits (or has a binding affinity for) ERD and has an anticancer cellular IC₅₀ that is less than about 200 nM. The compound of Formula I or II, or the metabolized compound (of one enantiomer or racemate) inhibits or has a binding affinity for the alpha estrogen receptor (ERD) wherein the anticancer cellular IC₅₀ is less than about 500 nM. In other embodiments the IC₅₀ for ERD is about 1 pM to about 1000 nM, about 0.1 nM to about 750 nM, about 1 nM to about 250 nM, about 5 nM to about 500 nM, about 10 nM to about 5000 nM, about 10 nM to about 80 nM, or about 20 nM to about 45 nM. The compound can kill or inhibit the growth of cancer cells by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum. The cancer cells can be ERD positive cancer cells. In certain embodiments, the compounds are cytotoxic. In various embodiments, the cancer cells are breast cancer cells, ovarian cancer cells, or endometrial cancer cells. This disclosure also provides a composition comprising the compound disclosed herein and a second drug. The disclosure further provides a pharmaceutical composition comprising an enantiopure or enantioenriched compound disclosed herein in combination with a pharmaceutically acceptable diluent, carrier, excipient, or buffer. In some embodiments of the pharmaceutical composition, the compound is a racemic or scalemic mixture of (R)-ErSO(OH) and (S)-ErSO(OH), or (R)-ErSO and (S)-ErSO. In various embodiments, the mixture is a mixture of enantiomers wherein the mixture of enantiomers has a ratio of about 50:50, about 45:55, about 40:60, about 30:70, about 20:80, about 10:90, or about 5:95. In other embodiments of the pharmaceutical composition, the compound is (S)-ErSO(OH), (R)-ErSO, (R)-ErSO(OH), or (S)-ErSO. The disclosure additionally provides a method of treating a cancer comprising administering to an ERD positive cancer subject in need thereof a therapeutically effective amount of a compound disclosed herein, thereby treating the cancer in the subject. In some embodiments, the compound kills or inhibits growth of ERD positive cancer that metastasized to the brain by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum. In various embodiments, the ERD positive cancer is a breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, or endometrial cancer. The disclosure additionally provides a use of the compound for the treatment of an ERD positive cancer that metastasized to the brain. In various embodiments, the ERD positive cancer that metastasized to the brain can be a cancer metathesized from breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, endometrial cancer, or high-grade glioma. The compound can be administered orally, by injection, subcutaneously, sublingually, rectally, by infusion, intravenously, or by dermal absorption. In other embodiments, the therapeutically effective amount of the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly. In additional embodiments, the compound crosses the blood-brain barrier to enter the subject’s brain in an amount sufficient to effectively treat the subject having ERD positive cancer that metastasized to the brain. In other embodiments, the sufficient amount of compound in the subject’s brain is at least 10 mol% of the therapeutically effective amount of the compound administered orally, intravenously, subcutaneously, transdermally, or intramuscularly. In other embodiments, at least 10 mol% of the compound administered crosses the blood-brain barrier. In other embodiments, the amount of compound that crosses the blood-brain barrier is about 10 mol% to about 20 mol%, about 20 mol% to about 30 mol%, about 30 mol% to about 40 mol%, about 40 mol% to about 50 mol%, about 50 mol% to about 60 mol%, about 60 mol% to about 70 mol%, about 70 mol% to about 80 mol%, about 80 mol% to about 90 mol%, or about 90 mol% to about 100 mol%. In yet other embodiments, the recited mol% is weight%. In additional embodiments, the therapeutically effective amount of the compound administered to a human in a single dose is about 75 mg/kg or less. In other embodiments, the single dose is about 60 mg/kg, about 50 mg/kg, about 40 mg/kg, about 30 mg/kg, about 20 mg/kg, about 10 mg/kg, or about 5 mg/kg. In some other embodiments, the therapeutically effective amount of the compound administered is at least 1 mg/kg/day in a human, or about 200 mg/kg/day or less. In other embodiments, the therapeutically effective amount of the compound administered is about 5 mg/kg/day to about 150 mg/kg/day, about 10 mg/kg/day, about 20 mg/kg/day, about 30 mg/kg/day, about 40 mg/kg/day, about 50 mg/kg/day, about 60 mg/kg/day, about 70 mg/kg/day, about 80 mg/kg/day, about 90 mg/kg/day, about 100 mg/kg/day, about 110 mg/kg/day, about 120 mg/kg/day, about 130 mg/kg/day, about 140 mg/kg/day, about 160 mg/kg/day, about 170 mg/kg/day, about 180 mg/kg/day, about 190 mg/kg/day, or about 200 mg/kg/day to about 400 mg/kg/day. In yet other embodiments, the compound is administered in combination with a pharmaceutically acceptable carrier. In additional embodiments, the method further comprises administering a second active agent. In some embodiments, the second active agent is ErSO. In other embodiments, the second active agent is ErSO(OH). In some embodiments, the second active agent is tamoxifen, fulvestrant (Faslodex/ICI 182,780), an aromatase inhibitor (e.g. anastrozole), or a combination thereof. In other embodiments ErSO and/or ErSO(OH) is combined with endocrine therapy. In other embodiments, the second active agent and the compound are administered sequentially or simultaneously (in a combined mixture or separately). In some other embodiments, the compound is administered before (or after) the second active agent. Also, this disclosure provides a method for treating an alpha estrogen receptor (ERD^ positive breast cancer that metastasized to the brain comprising administering to a human having an ERD positive breast cancer that metastasized to the brain a therapeutically effective amount of ErSO or ErSO(OH):

wherein the therapeutically effective amount of the compound is about 200 mg/kg/day or less and the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly, wherein the cancer is thereby treated. In some embodiments, the therapeutically effective amount of the compound administered is about 1 mg/kg/day to about 150 mg/kg/day. Results and Discussion Metastatic estrogen receptor D (ERD) positive breast cancer is presently incurable, and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ERD to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. To target metastatic ERD positive breast cancer, we exploited our finding that estrogen-ERD activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERD to induce lethal hyperactivation of the anticipatory UPR, triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERDD538G and ERDY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. In mouse xenografts bearing large breast tumors, oral and injected ErSO induced complete regression (>115,000 fold mean regression) in about 45% of mice (18/39). Although durable response without treatment for 4-6 months was common, tumors that did recur remained fully sensitive to ErSO re-treatment. Consistent with the essential nature of the UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. On average, ErSO-treated tumors were >180-fold smaller than vehicle-treated tumors. These xenograft studies used human cancer cells in mice that lack immune cells and therefore did not exploit the known ability of inducers of necrotic cell death to activate immune cells and induce immunogenic cell death. Notably, medium from breast cancer cells killed by ErSO contained high levels of the established immune cell activators, HMGB1 and ATP, robustly activated mouse and human macrophage and increased macrophage migration. Moreover, use of ErSO is not limited to breast cancer. ErSO rapidly kills ERD positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO’s potent activity against advanced primary and metastatic ERĮ-positive breast cancers represents a paradigm shift in leveraging ERĮ for anticancer efficacy. The CRISPR/Cas9 gene editing system was used to replace wild type ERD in T47D human breast cancer cells with the two most common ERD mutations seen in metastatic breast cancer, ERDY537S and ERDD538G. The resulting cell lines TYS-4 (also called TYS) and TDG-1 (also called TDG) (T47DERDY537S clone 4 and T47DERDD538G clone 1) exhibit significant resistance to tamoxifen (the active form of tamoxifen is z-4-hydroxytamoxifen; z-OHT) and to fulvestrant/ICI 182,780. To allow visualization of tumors harboring these mutations in live animal, clonal lines of TYS and TDG cells stably expressing firefly luciferase were isolated. Orthotopic mouse tumors containing these TYS-Luc and TYDG-Luc cells are visualized in live animals by bioluminescent imaging (BLI). Because the In Vivo Imaging System (IVIS) has a detection range of more than 10,000-fold and can be used to visualize progression of both primary tumors and metastatic tumors, BLI using IVIS is considered the most advanced way to evaluate the efficacy of new anticancer drugs in animal models. To the best of our knowledge, no other research team in a university, pharmaceutical, or biotechnology company has developed cell lines combining expression of the breast cancer ERD mutations and luciferase for BLI. Unbiased high throughput screening was used for small molecules that block ERD action to identify novel ERD biomodulators. BHPI was the first generation lead small molecule to emerge from that search. BHPI is a potent first-in-class non-competitive small molecule ERD biomodulator that kills therapy-resistant ERD positive breast and endometrial cancer cells and blocks growth of ovarian cancer cells. BHPI binds at a different site on ERD than tamoxifen and fulvestrant and has a different mechanism of action. It was demonstrated that BHPI works through ERD to induce persistent lethal hyperactivation of the anticipatory pathway of activation of the unfolded protein response (UPR). In cell culture models, BHPI selectively blocks growth of cancer cells. BHPI blocked proliferation of the TYS and TDG cells expressing ERD mutations identified in metastatic breast cancer. In a mouse xenograft model of ERD positive breast cancer, at reasonable doses, BHPI stopped tumor growth and induced rapid and substantial tumor regression. In xenograft studies using TYS-Luc and TDG-Luc cells, after 4 weeks the vehicle control breast tumors had roughly quadrupled in cells. In contrast, the tumors in mice treated with BHPI exhibited 97%-99.5% regression. In an orthotopic ovarian cancer xenograft model using OVCAR-3 cells that are highly resistant to diverse anticancer drugs, the taxane paclitaxel was ineffective. BHPI alone strongly reduced tumor growth. Notably, tumors were undetectable in mice treated with BHPI plus paclitaxel and levels of the circulating cancer biomarker CA125 progressively declined to undetectable. In both studies, BHPI was well tolerated by the mice. New Compounds with Ability to Kill Breast Cancer Cells. Assays were developed for compounds with an improved ability to kill cancer cells. One of the assays is based on the classical criterion for cell death, loss of membrane integrity as measured by uptake of the dye Trypan Blue. This instrument-based assay determines the percentage of cells in a population that have taken up Trypan Blue. All cells that have taken up Trypan Blue are dead. This assay is unique to the disclosed screening workflow. Although Trypan Blue uptake is universally accepted as a measure of cell death, it has not been used by others to test potential anticancer drugs. Additional assays used to evaluate cell death include fluorescence activated cell sorting (FACS) and assays based on inhibition of proliferation and determination of cell number, sometimes in conjunction with raptinal, a compound known to induce 100% cell death. Through synthesis and evaluation, novel compounds that are superior to BHPI in their ability to kill breast cancer cells were identified. This led to the discovery of ErSO, a small molecule with potent anticancer efficacy with significant cancer cell selectivity even at concentrations more than 10 times higher than those needed to eradicate ERĮ positive breast cancer cells. Further exploration of the ErSO pharmacophore, led to our discovery of ErSO-OH, which has similar anticancer activity as compared to ErSO. Moreover, current endocrine therapy drugs tamoxifen and fulvestrant are cytostatic and showed no ability at all to kill TYS and TDG breast cancer cells. Demonstrating target specificity, even at concentrations more than 10 times higher than those that effectively kill ERD positive breast cancer cells, ERSO(OH) had no effect in several ERD negative cell lines. Also, the inactive (R) enantiomer was ineffective and not toxic in ERD positive and ERD negative cell lines. Comparison of inhibition data for racemic and purified enantiomers of ErSO(OH) and other structurally related structures are presented in Tables 1 and 2. Chemical physical properties and in-vivo toxicity of (S)-ErSO(OH) and other structurally related compounds are presented in Table 3. Table 1. ErSO(OH) inhibitory activity in breast cancer cells.

* n = 3; 6,000 MCF-7 cells/well, 6-hour and 24-hour incubation followed by media aspiration and Alamar Blue fluorescence measured. Compare, (R)-ErSO: ^24hrIC₅₀ = 15 ± 2 nM. Table 2. Breast cancer cell inhibitory activity (^6hrIC₅₀) in other tested compounds.*

* n = 3; 6,000 MCF-7 cells/well, 6-hour incubation followed by media aspiration and Alamar Blue fluorescence measured. ^# IC₅₀ based on a single isolated isomer. Table 3. Toxicity in mice with I.V. dosing.*

* CD-1 Female Mice, compounds were formulated in 5% DMSO, 10% Tween-20, 85% PBS and solutions filtered prior to tail-vein injection; 3 mice were treated with each (R)-ErSO dose, 2-3 mice per (S)-ErSO dose level, and 2 mice per (S)-ErSO(OH) dose. The results in Table 3 indicates that decreasing clogP and clogBB is a viable strategy to reduce toxicity. Mechanism of Action of ErSO(OH): The actions of ErSO(OH) include, but are not limited to, inducing lethal hyperactivation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR). The endoplasmic reticulum (EnR) stress sensor of the unfolded protein response (UPR) balances the synthesis of new proteins with the availability of chaperones and other proteins that help fold and transport proteins within cells. The anticipatory UPR pathway is activated in the absence of unfolded proteins and anticipates future needs for new protein folding capacity. To induce lethal hyperactivation of the unfolded protein response ErSO(OH) binds to ERD in cancer cells. This leads to activation of phospholipase C J (PLCJ). Activated PLCJ enzymatically produces inositol triphosphate (IP3). The IP3 binds to and opens endoplasmic reticulum IP3 receptor calcium channels in the EnR. Opening the IP3R calcium channels results in very rapid efflux of calcium stored in the lumen (interior) of the endoplasmic reticulum into the cell body. This hyperactivates the UPR. When activated, one arm of the UPR, the PERK arm, inhibits protein synthesis. Activation of another arm of the UPR, IRE1D, induces formation of the active spliced from of the mRNA encoding the transcription factor XBP-1 (spXBP-1). To restore calcium homeostasis, powerful SERCA pumps in the membrane of the endoplasmic reticulum carry out ATP dependent pumping of calcium from the cell body into the interior of the EnR. Because the IP₃R calcium channels remain open, the calcium pumped into the lumen of the EnR leaks back out. This creates a futile cycle that depletes intracellular ATP. UPR markers and inhibitors: Formation of spXBP-1 mRNA is used as a marker for UPR activation. The widely used small molecule 2-APB locks the IP₃Rs closed and prevents the calcium efflux and UPR hyperactivation. The small molecule thapsigargin (THG) potently inhibits the SERCA pumps and prevents the cell from using up its ATP stores. General Synthetic Methods The invention also relates to methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques of organic synthesis, for example, the techniques described herein (see Scheme 1). Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol.2, Ian T. Harrison and Shuyen Harrison, 1974; Vol.3, Louis S. Hegedus and Leroy Wade, 1977; Vol.4, Leroy G. Wade, Jr., 1980; Vol.5, Leroy G. Wade, Jr., 1984; and Vol.6, Michael B. Smith; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5^th Ed. by M.B. Smith and J. March (John Wiley & Sons, New York, 2001), Comprehensive Organic Synthesis; Selectivity, Strategy & Efficiency in Modern Organic Chemistry, in 9 Volumes, Barry M. Trost, Ed.-in-Chief (Pergamon Press, New York, 1993 printing) ); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Carey and Sundberg (1983); Protecting Groups in Organic Synthesis, Second Edition, Greene, T.W., and Wutz, P.G.M., John Wiley & Sons, New York; and Comprehensive Organic Transformations, Larock, R.C., Second Edition, John Wiley & Sons, New York (1999). A number of exemplary methods for the preparation of the compounds of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically, the temperatures will be -100 °C to 200 °C, solvents will be aprotic or protic depending on the conditions required, and reaction times will be 1 minute to 2 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water / organic layer system (extraction) and separation of the layer containing the product. Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 °C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C. Heating can also be used when appropriate. Solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions. Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 °C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable. Protecting Groups. The term "protecting group" refers to any group which, when bound to a hydroxy or other heteroatom prevents undesired reactions from occurring at this group and which can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl group. The particular removable protecting group employed is not always critical and preferred removable hydroxyl blocking groups include conventional substituents such as, for example, allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidene, phenacyl, methyl methoxy, silyl ethers (e.g., trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), or t-butyldimethylsilyl (TBS)) and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Suitable hydroxyl protecting groups are known to those skilled in the art and disclosed in more detail in T.W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981 ("Greene") and the references cited therein, and Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), both of which are incorporated herein by reference. Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds by the methods of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group ("PG" or "P") will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. Scheme 1. General synthetic route.

Synthesis of other compounds described herein were carried out in a similar manner by selection of appropriate starting materials. Additional data and synthetic details for preparation of similar compounds are provided in International Publication No. WO 2020/009958 (Shapiro et al.) and U.S. Patent Application No.16/801,839 (Shapiro et al.), which applications are incorporated herein by reference. Basis of Assays for Killing of Cancer Cells. ALAMAR BLUE/RAPTINAL ASSAY. Live cells maintain a reducing environment. The non-fluorescent cell permeable ingredient of Alamar Blue^ (resazurin) is taken up by cells. In living cells, it is reduced to the fluorescent compound resorufin. Using a standard curve of cell number versus fluorescence the number of live cells in a test sample can be determined; and the measured fluorescence (^_excit. = 555 nm, ^_emission. = 585 nm) is directly proportional to the number of viable cells in a test sample. At high concentrations raptinal (100μM) kills 100% of cells. The vehicle in which the test compound is dissolved is not toxic (1% DMSO). Thus, after subtracting the blank from medium + 100% dead cells alone, the fluorescence reading for vehicle corresponds to 100% viable cells and the signal for raptinal corresponds to 0% viable cells. 6000 cells were seeded per well in a 96-well plate and allowed to adhere overnight before DMSO solutions of compounds were added to each well. Final concentration of DMSO in each well is 1%, final volume: 100 μL. At the end of 6 or 24 hours, media was aspirated and new media (100 μL) was added. Alamar blue solution was added (10 μL of 1 mg resazurin per 10 mL PBS). After 2-4 hours incubation, fluorescence (^_excit. = 555 nm, ^_emission. = 585 nm) was measured. The fluorescence of each well was read with a SpectraMax M3 plate reader (Molecular Devices). Percent dead cells was determined by comparison to a 100% dead cells control (100 μM raptinal treated cells). IC₅₀ was calculated using Origin Pro V10. While this assay provides a less direct measurement of cell death than the trypan blue assay, it is more easily scaled up to large numbers of samples. Cell lines used for the therapeutic target: ERD positive breast cancer cells MCF-7 (Michigan Cancer Foundation-7). ERD positive, the most widely used ERD positive breast cancer cell line. Estrogen greatly stimulates their growth; sensitive to z-OHT and fulvestrant/ICI. Pharmaceutical Formulations The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, Į-ketoglutarate, and E- glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods. The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration, by intravenous, intramuscular, topical or subcutaneous routes. The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained. The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms. Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions, dispersions, or sterile powders comprising the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by agents delaying absorption, for example, aluminum monostearate and/or gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, optionally followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the solution. For topical administration, compounds may be applied in pure form, e.g., when they are liquids. However, it will generally be desirable to administer the active agent to the skin as a composition or formulation, for example, in combination with a dermatologically acceptable carrier, which may be a solid, a liquid, a gel, or the like. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, or water-alcohol/glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol sprayer. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of dermatological compositions for delivering active agents to the skin are known to the art; for example, see U.S. Patent Nos.4,992,478 (Geria), 4,820,508 (Wortzman), 4,608,392 (Jacquet et al.), and 4,559,157 (Smith et al.). Such dermatological compositions can be used in combinations with the compounds described herein where an ingredient of such compositions can optionally be replaced by a compound described herein, or a compound described herein can be added to the composition. Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No.4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day. The compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form. The compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m², conveniently 10 to 750 mg/m², most conveniently, 50 to 500 mg/m² of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The compounds described herein can be effective anti-tumor agents and have higher potency and/or reduced toxicity as compared to BHPI. Preferably, compounds of the invention are more potent and less toxic than BHPI, and/or avoid a potential site of catabolic metabolism encountered with BHPI, i.e., have a different metabolic profile than BHPI. Furthermore, the compounds described herein cause less severe ataxia than BHPI and other known compounds. The invention provides therapeutic methods of treating cancer in a vertebrate such as a mammal, which involve administering to a mammal having cancer an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like. Cancer refers to any of the various type of malignant neoplasm, which are in general characterized by an undesirable cellular proliferation, e.g., unregulated growth, lack of differentiation, local tissue invasion, and metastasis. Cancers that can be treated by a compound described herein include, for example, cancer that has metastasized to the brain from breast cancer, cervical carcinoma, colon cancer, endometrial cancer, leukemia, lung cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, or uterine cancer, and in particular, any cancer that is ERD positive. The ability of a compound of the invention to treat cancer may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of tumor cell kills, and the biological significance of the use of transplantable tumor screens are known. In addition, ability of a compound to treat cancer may be determined using the Tests as described below. The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention. EXAMPLES Example 1. Methods. BBB Penetrance Study. CD-1 mice were injected with ErSO intravenously (tail vein) at doses indicated and sacrificed 5 and 15 minutes after injection (n=3 for each time point and dose). Mice were sacrificed and blood collected. Residual circulatory volume was removed via perfusion. Blood samples were centrifuged at 13,000 RCF for five minutes and the supernatant was collected and stored at -80°C prior to analysis. Brains were harvested from the cranial vault, weighed, and flash frozen. Thawed brains were then homogenized in 1000 μL of cold methanol using a handheld tissue homogenizer. The resultant slurry was centrifuged twice at 13,000 RCF for 10 minutes per run and the supernatant was collected and frozen at -80°C prior to analysis. Samples were then analyzed by LC-MS/MS (Metabolomics Laboratory of the Roy J Carver Biotechnology Center UIUC) to determine ErSO concentration in both serum and brain. To calculate absolute brain:serum ratios, an approximated mouse blood volume of 58.5 mL/kg was utilized for each mouse (Figure 1). MYS Brain Model. 50,000 MYS-Luc cells are suspended in an injected volume of 0.5 microliters of sterile Hanks balanced salt solution. A 5 mm incision is made in the skin on the head. Stereotaxic coordinates are +0.5 mm anterior to bregma, 2.25 - 2.5 mm to the right of midline, -3.5 to -3.3 mm ventral to the skull surface. A small hole is punctured in the skull using a 27 g needle mounted on the stereotaxic holder. A 0.5 ul Hamilton syringe with a 33 g needle is used for the injection. The needle is lowered into the brain, then the cells are injected over a period of 1 min. Tumors were allowed to grow for 3-weeks. Mice were then randomized into either Vehicle IP (DMSO) treated, 40 mg/kg ErSO Oral, or 40 mg/kg ErSO IP consisting of 5 mice each for ErSO groups and 4 for the vehicle group. Mice received daily treatments of either IP DMSO, 40 mg/kg ErSO oral, or 40 mg/kg ErSO IP for 21 days. BLI imaging of the mice occurred on days 0, 3, 7, and 14 (Figures 2-3). Mouse weights were taken a minimum of once per week throughout the treatment arm of the study. Following the treatment regimen, all mice were euthanized. Brain Tumor Xenograft Method Steps. 1) Intracerebral infusion of 50,000 MYS-Luc (MCF7-ERĮY537S-Luc) cells were performed on NSG mice. (MYS-Luc cells are our most aggressive and most metastatic tumor model. Patients whose metastatic tumors harbor the ERĮY537S mutation have 12 months shorter median survival than patients whose tumors contain wild type ERĮ.). 2) The grafted mice were imaged via IVIS one (1) week post graft. 3) Two weeks after the initial injection tumors exhibited sufficient light output and treatment began. 4) Mice were randomly assigned into 3 groups (Vehicle: 4 mice/group; ErSO treated: 5 mice/group). Vehicle was administered daily for 14 days. ErSO (40 mg/kg) was injected i.p. daily for 14 days. ErSO (40 mg/kg) was administered orally daily for 14 days. 5) Tumors were imaged by whole mouse 2D-imaging at day 0 of treatment and days 7 and 14 after initiating treatment. 6) After euthanizing the mice at day 14 of treatment, brains were excised and imaged ex-vivo (Figures 4-7). The results summarized in Tables 1-3 show that ErSO is effective against breast cancer growing in brain. Table 1. MYS-Luc Brain Tumors, Vehicle Daily IP for 14 Days

Table 2. MYS-Luc Brain Tumors, 40 mg/kg ErSO Daily IP for 14 Days

(Table 1). Table 3. MYS-Luc Brain Tumors, 40 mg/kg ErSO Daily p.o. for 14 Days

Example 2. Synthetic procedures. General Information: Unless otherwise stated, reagents were purchased from commercial sources and used without further drying or purification. Solvents used herein were dried after being passed through activated alumina columns. All reactions were run in flame- dried glassware under a positive pressure of nitrogen gas. ¹H NMR and ¹³C NMR experiments were conducted on a Bruker cryoprobe at 500 MHz and 188 MHz respectively. Spectra obtained in CD₃OD were referenced for 3.31 ppm and 49.00 ppm for ¹H and ¹³C NMR spectra, respectively. NMR multiplicities are reported as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. ¹³C multiplicities are all singlets unless otherwise noted.

Synthesis of (R)- and (S)-ErSO(OH): A round bottom flask was charged with 1-bromo- 4-(trifluoromethoxy)benzene (3.08 mmol) and dissolved in THF (3.0 mL). The reaction mixture was cooled to -78 qC and a solution of n-BuLi (2.77 mmol, 1.7 mL) added dropwise over 10 minutes. The reaction was stirred for 1 hour. In another flask, the desired isatin (1.54 mmol) was added and dissolved in THF (9.4 mL). This solution of isatin was added to the reaction vessel dropwise over 10 minutes. The resultant mixture was stirred at -78 qC for 1 hour, warmed to r.t., and then stirred for 1 hour. The reaction was quenched with water (10 mL). The solution was extracted with ethyl acetate (3x) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. A new round bottom flask was charged with crude tertiary alcohol and catechol (6.95 mmol) and dissolved in dichloromethane (7.7 mL). The reaction mixture was then placed in an ice bath and triflic acid (TfOH, 0.7 mL) was then added dropwise. The reaction vessel was removed from the ice bath and stirred at room temperature for 1 hour. The reaction mixture was then poured into an ice-filled sodium bicarbonate and the aqueous solution was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant oil was then purified via column chromatography and chiral separation.

Chiral Separation of (R)- and (S)-ErSO(OH): (R,S) ErSO(OH) was separated into its respective enantiomers using preparative chiral HPLC separation (Lux® 5 μm Cellulose-1, 250 x 21.2 mm, AXIA^™ Packed, isocratic: 40% i-PrOH/Hexanes. Stereochemistry inferred from WO 2020/009958. This chiral separation yields: (S)-ErSO(OH) – First peak on HPLC, as an amorphous white solid after lyophilization from neat acetonitrile.¹H NMR: (CD3OD, 500 MHz) į: 7.56 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 9.2 Hz, 2H), 7.24 (t, J = 7.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H).¹⁹FNMR: (CD3OD, 471 MHz) į: -59.49, -62.98. HRMS (ESI): m/z calc. for C₂₂H₁₃NO₄F₆ [M+H]+ 470.827, found: 470.0829. (R)-ErSO(OH) – Second peak on HPLC, as an amorphous white solid after lyophilization from neat acetonitrile.

3-(3,4-dihydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)indolin-2-one, (R/S)-ErSO(OH): ¹H NMR (CD3OD, 500 MHz) į: 7.53 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.34 (d, J = 8.9 Hz, 2H), 7.26 – 7.18 (m, 5H), 6.71 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.3, 2.3 Hz, 1H). ¹³C NMR (CD3OD, 126 MHz) į: 181.34,149.79 (q, J = 1.8 Hz), 146.54, 146.31, 142.05, 139.84 (q, J = 1.9 Hz), 136.99, 133.33, 131.29, 131.06, 126.07 (q, J = 4.5 Hz), 125.16 (q, J = 271.1 Hz), 123.49, 121.97, 121.89 (q, J = 256.5 Hz), 120.66, 116.67, 116.25, 113.72 (q, J = 33.38 Hz), 62.29. ¹⁹F NMR (CD3OD, 471 MHz) į: -59.49, -62.98. Intermediates for compounds having a substituted oxindole-core can be prepared from the corresponding starting material for the compound, for example, as follows.

6-chloro-3-hydroxy-7-methyl-3-(4-(trifluoromethoxy)phenyl)indolin-2-one (7): A reaction vessel was charged with substituted aniline (2.82 mmol), 1M HCl (2.82 mL), water (18.8 mL), anhydrous sodium sulfate (16.92 mmol), and hydroxylamine hydrochloride (9.17 mmol). The mixture was heated to boiling and then chloral hydrate was added as one portion. The reaction was kept at reflux for 40 minutes, then cooled to reflux and the aqueous solution was extracted with ethyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Concentrated sulfuric acid (3 mL) was then added to the resultant residue. This solution was heated to 80 qC for 20 minutes, then poured onto ice. The resulting aqueous mixture was extracted with ethyl acetate (3x), and the combined organic layers dried over sodium sulfate, filtered, and concentrated in vacuo. The red-brown solid obtained after concentration proved to be poorly soluble in most organic solvents. To a new reaction vessel, the desired phenyl bromide (3.08 mmol) was added and dissolved in THF (3.0 mL). The reaction mixture was cooled to -78 qC and a solution of n-BuLi (2.77 mmol, 1.73 mL) added dropwise over 10 minutes. The reaction was stirred for 1 hour. In another flask, 6-chloro-7-methylisatin (1.54 mmol) was added and dissolved in THF (9.4 mL). This solution of isatin was added to the reaction vessel dropwise over 10 minutes. The resultant mixture was stirred at -78 qC for 1 hour, warmed to r.t., and then stirred for 1 hour. The reaction was quenched with water (10 mL). The solution was extracted with ethyl acetate (3x) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was run through a silica plug (elution solvent gradient: 10% EtOAc/Hexanes ramped to 100% EtOAc). 7 was isolated in 24% yield over three synthetic steps. ¹H NMR (CD3OD, 500 MHz) į: 7.46 (d, J = 8.85 Hz 2H), 7.23 (d, J = 7.98 Hz, 2H), 7.10 (d, J = 7.97 Hz 1H), 6.98 (d, J = 8.02 Hz, 1H), 2.35 (s, 3H). ¹³C NMR (CD3OD, 188 MHz) į: 181.25, 150.17 (q, J = 1.83 Hz), 143.14, 140.98, 136.68, 132.74, 128.63, 124.53, 124.40, 121.88 (q, J = 255.75 Hz), 121.86, 119.76, 78.91, 14.11. HRMS (ESI): m/z calc. for C₁₆H₁₁NO₃F₃ClNa [M+Na]⁺ 380.0277, found: 380.0284. Example 3. Pharmaceutical Dosage Forms. The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'): (i) Tablet 1 mg/tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg/tablet 'Compound X' 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule 'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/mL) mg/mL 'Compound X' (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg/mL) mg/mL 'Compound X' (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 0.1 N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL (vi) Aerosol mg/can 'Compound X' 20 Oleic acid 10 Trichloromonofluoromethane 5,000 Dichlorodifluoromethane 10,000 Dichlorotetrafluoroethane 5,000 (vii) Topical Gel 1 wt.% 'Compound X' 5% Carbomer 934 1.25% Triethanolamine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100g (viii) Topical Gel 2 wt.% 'Compound X' 5% Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100g (ix) Topical Ointment wt.% 'Compound X' 5% Propylene glycol 1% Anhydrous ointment base 40% Polysorbate 80 2% Methyl paraben 0.2% Purified water q.s. to 100g (x) Topical Cream 1 wt.% 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100g (xi) Topical Cream 2 wt.% 'Compound X' 5% Stearic acid 10% Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5% Isopropyl palmitate 2 % Methyl Paraben 0.2% Purified water q.s. to 100g These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest. While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. CITATIONS 1) Cardoso, F.; et al.4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) Ann. Oncol. 2018, 29, 1634. 2) Williams, M. M.; et al. Intrinsic apoptotic pathway activation increases response to anti- estrogens in luminal breast cancers. Cell Death Dis.2018, 9, 21. 3) Richman, J.; et al. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat. Rev. Clin. Oncol.2019, 16, 296. 4) Puyang, X.; et al. Discovery of Selective ER Covalent Antagonists for the Treatment of ERĮWT and ERĮMUT Breast Cancer. Cancer Discov.2018, 8, 1176. 5) Jeselsohn, R.; et al. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol.2015, 12, 573. 6) Robinson, D. R.; et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 2013, 45, 1446. 7) Andruska, N. D.; et al. ERĮ inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression. PNAS 2015, 112, 4737. 8) Shapiro, D. J.; et al. Anticipatory UPR Activation: A Protective Pathway and Target in Cancer. Trends Endocrinol. Metab.2016, 27(10), 731.

Claims

What is claimed is: 1. A method for treating an alpha estrogen receptor (ERD^ positive cancer that metastasized to the brain comprising administering to a subject having an ERD positive cancer that metastasized to the brain a therapeutically effective amount of a compound of Formula I:

or a salt thereof; wherein X is O, S, or NR^D; Z is O, S, or NR^D; R¹ is trifluoromethyl, trifluoromethoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, -OR^A, -SR^A, or -N(R^A)₂; R², R³, and R⁴ are each independently H, halo, -OR^A, -SR^A, -N(R^A)₂, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; A¹, A², and A³ are each independently H, OH, halo, or alkyl; G¹ is -OR^B, -SR^B, -S(=O)₂R^B, alkyl, or halo; G² is -OR^C, -SR^C, -S(=O)₂R^C, alkyl, or halo, wherein R^C is trifluoromethyl, H, alkyl, or acyl; G³ is H, -OR^W, -SR^W, -S(=O)₂R^W, halo, or alkyl; and R^A, R^B, R^D, and R^W are each independently H, alkyl, or acyl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents; wherein the cancer is thereby treated. 48

2. The method of claim 1 wherein the compound of Formula I is a compound of Formula II:

wherein R¹ is –(C₁-C₆)alkyl; R² is H, halo, –(C₁-C₆)alkyl, or -OR^A; G² is -OR^C, –(C₁-C₆)alkyl; and G³ is H, halo, -OR^W; wherein –(C1-C6)alkyl is optionally substituted with one or more halo.

3. The method of claim 1 or 2 wherein the compound inhibits ERD and has an anticancer cellular IC₅₀ that is less than about 200 nM.

4. The method of claim 1 or 2 wherein the compound is metabolized by the subject to form an active metabolite that inhibits ERD and has an anticancer cellular IC₅₀ that is less than about 200 nM.

5. The method of claim 1 or 2 wherein the compound kills or inhibits growth of ERD positive cancer that metastasized to the brain by hyperactivation of the unfolded protein response (UPR) in the endoplasmic reticulum.

6. The method of claim 1 or 2 wherein the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly.

7. The method of claim 6 wherein at least 10 mol% of the compound administered crosses the blood-brain barrier. 49

8. The method of any one of claims 1-7 wherein the ERD positive cancer that metastasized to the brain is an ERD positive cancer that metastasized from breast cancer, ovarian cancer, uterine cancer, cervical carcinoma, or endometrial cancer.

9. The method of any one of claims 1-8 wherein the compound is levorotatory.

10. The method of any one of claims 1-8 wherein the compound is dextrorotatory.

11. The method of any one of claims 1-8 wherein the compound is ErSO:

12. The method of any one of claims 1-8 wherein the compound is ErSO(OH):

13. The method of any one of claims 1-12 wherein the therapeutically effective amount of the compound administered to a human in a single dose is about 75 mg/kg or less.

14. The method of any one of claims 1-12 wherein the therapeutically effective amount of the compound administered to a human is about 200 mg/kg/day or less.

15. The method of claim 14 wherein the therapeutically effective amount of the compound administered is about 1 mg/kg/day to about 150 mg/kg/day. 50

16. The method of any one of claims 1-15 wherein the compound is administered in combination with a pharmaceutically acceptable carrier.

17. The method of any one of claims 1-16 further comprising administering a second active agent.

18. The method of claim 17 wherein the second active agent and the compound are administered sequentially.

19. A method for treating an alpha estrogen receptor (ERD^ positive breast cancer that metastasized to the brain comprising administering to a human having an ERD positive breast cancer that metastasized to the brain a therapeutically effective amount of ErSO or ErSO(OH):

wherein the therapeutically effective amount of the compound is about 200 mg/kg/day or less and the compound is administered orally, intravenously, subcutaneously, transdermally, or intramuscularly, wherein the cancer is thereby treated.

20. The method of claim 19 wherein the therapeutically effective amount of the compound administered is about 1 mg/kg/day to about 150 mg/kg/day. 51