Methods of treating estrogen receptor-associated diseases

Abstract

To provide compounds and / or regimens useful for the treatment of estrogen receptor (ER)-associated diseases, disorders, and conditions (e.g., cancer cells), and / or for modulating (e.g., inhibiting) the estrogen receptor in the brain.SOLUTION: In some embodiments, the present disclosure provides compounds that, when administered systemically (e.g., orally), inhibit the estrogen receptor in the brain. Among other things, the present disclosure provides complete estrogen receptor antagonist compounds useful as described herein (e.g., orally bioavailable complete receptor antagonists that cross the blood brain barrier).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 985,929, filed March 6, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Estrogen receptors (ER) play an important role in various cancers, including breast cancer. Various treatments have been developed to target estrogen receptors and / or their activity. Cancer cells in the brain are particularly problematic. In hormone-positive diseases, such as ER-positive breast cancer, the incidence of breast cancer brain metastasis (BCBM) is 14%, and the median overall survival after the development of brain metastasis is 9-10 months. (Brosnan, Ann Transl Med., 2016;6(9):163) [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Brosnan,Ann Transl Med.,2016;6(9):163 Summary of the Invention [Means for solving the problem]

[0004] The present disclosure provides new insights into compounds and / or regimens useful for treating estrogen receptor (ER)-associated diseases, disorders, and conditions (e.g., cancer cells) and / or for modulating (e.g., inhibiting) estrogen receptors in the brain. Among other things, the present disclosure defines particular structural and / or functional attributes that characterize compounds useful for such treatment and / or modulation.

[0005] In some embodiments, the present disclosure provides certain non-invasive techniques for treating ER-related diseases, disorders, and conditions (e.g., cancer cells) and / or otherwise modulating (e.g., inhibiting) estrogen receptors in the brain. For example, in some embodiments, the present disclosure defines compounds that inhibit estrogen receptors in the brain when administered systemically (e.g., orally). In particular, the present disclosure defines full estrogen receptor antagonist compounds (e.g., orally bioavailable full receptor antagonists that cross the blood-brain barrier) useful as described herein.

[0006] There remains a need for antiestrogens that can fully inhibit estrogen receptors, including those encoded by both wild-type and mutant forms (e.g., those containing activating mutations) of the genes encoding estrogen receptor alpha (ERα) and estrogen receptor 1 (ESR1). Selective estrogen receptor modulators (SERMs) or degrading drugs (SERDs) are particularly useful or promising tools for such therapy. Estrogen receptors are tripartite proteins containing two distinct transcriptional activation functions (AF1 and AF2). Full antiestrogenic activity requires inactivation of both AF1 and AF2. Activating mutations in the gene encoding estrogen receptor 1 allow activation of both AF1 and AF2 even in the absence of estrogen.

[0007] Furthermore, there remains a need for the identification, characterization, and / or treatment of certain brain lesions (e.g., brain tumors, such as brain metastases) that do not require invasive techniques such as whole-brain radiation therapy and / or surgery, particularly for estrogen receptor (ER)-related diseases, disorders, or conditions, such as ER-positive cancers. The present application provides techniques related to such identification, characterization, and / or treatment. In some embodiments, the provided techniques involve administering a composition comprising and / or delivering a full estrogen receptor antagonist described herein (e.g., a full receptor antagonist that is orally bioavailable and / or crosses the blood-brain barrier).

[0008] Those skilled in the art recognize that many existing strategies for treating ER-associated diseases, e.g., cancer, involve first-line therapies, such as tamoxifen and / or endoxifen, to which patients eventually develop resistance. While certain second-line therapies, such as fulvestrant, have been developed, research continues to pursue improved treatment strategies.

[0009] Previous therapies, such as tamoxifen, AZD9496, and ARN-810, are not complete estrogen receptor antagonists because they cannot neutralize both activating functions (i.e., they cannot neutralize both AF1 and AF2). Thus, to completely inhibit the estrogen receptor, there remains a need for therapies that neutralize both AF1 and AF2, and there remains a need for therapies that inhibit the estrogen receptor despite activating mutations. The present disclosure demonstrates, inter alia, that certain compounds, alone or in combination with other agents, can be used as treatments for patients or subjects suffering from cancer, where the patient or subject has a mutation in estrogen receptor 1 (ESR1).

[0010] Fulvestrant has been hailed as a so-called "full" estrogen receptor antagonist because, unlike other approved ER antagonists (e.g., antiestrogens), it is characterized by its ability to (1) inhibit both activating function 1 (AF1) and activating function 2 (AF2), since full antiestrogenic activity requires inactivation of both AF1 and AF2, (2) promote ER degradation, and (3) avoid partial ER agonist activity. Fulvestrant is currently the only such "full" ER antagonist approved for use by intramuscular injection in certain hormone receptor (HR)-positive breast cancers, including HR-positive metastatic breast cancer in postmenopausal women whose disease has progressed after endocrine therapy. Fulvestrant can be used in conjunction with cyclin-dependent kinase 4 / 6 inhibitors, such as pablociclib, ribociclib, and abemaciclib, for either initial or post-progression endocrine therapy in metastatic or locally advanced breast cancer.

[0011] However, fulvestrant has poor oral bioavailability and must be administered parenterally. Furthermore, fulvestrant does not cross the blood-brain barrier, making it unusable for treating brain tumors (e.g., metastases).

[0012] The present disclosure provides knowledge regarding blood-brain barrier-crossing and / or orally bioavailable full estrogen receptor antagonists, and further describes the utility of such compounds in the detection, evaluation, and / or treatment of one or more ER-related diseases, disorders, or conditions (e.g., metastatic ER-positive breast cancer, such as metastatic ER-positive breast cancer). The present disclosure specifically exemplifies blood-brain barrier crossing by certain orally bioavailable full estrogen receptor antagonists, and further provides knowledge regarding specific structural features and / or combinations of features that may contribute to and / or be involved in blood-brain barrier crossing and / or full estrogen receptor antagonism activity. Without wishing to be bound by any particular theory, the present disclosure defines structure-function relationships for blood-brain barrier-crossing and / or orally bioavailable full estrogen receptor antagonists.

[0013] Among other things, the present disclosure provides methods of using such full estrogen receptor antagonists (i.e., that cross the blood-brain barrier and / or are orally bioavailable), specifically including detecting, evaluating, and / or treating brain lesions (e.g., tumors, such as metastases). In some embodiments, the present disclosure provides such methods in the context of an ER-associated disease, disorder, or condition (e.g., an ER-associated cancer). In some embodiments, the provided methods comprise administering to a subject suffering from an ER-associated cancer a composition that includes and / or delivers a full estrogen receptor antagonist to the subject's brain (e.g., upon oral administration), wherein the subject has been determined to have or is suspected of having brain metastases.

[0014] The present disclosure defines the structural characteristics of full receptor antagonists that cross the blood-brain barrier (e.g., upon oral administration). For example, in some embodiments, without wishing to be bound by any particular theory, the present disclosure defines structure-function correlation(s) between one or more of full ER antagonism (as defined herein), the ability to cross the blood-brain barrier, and / or oral bioavailability. In some embodiments, the present disclosure defines structure-function correlation(s) (e.g., defines structural property characteristics) for compounds that exhibit all of these. For example, without wishing to be bound by any particular theory, the present disclosure provides the insight that certain structural element(s) contribute to this combination of desirable activities, and in certain embodiments, defines potential structure-function correlations therewith.

[0015] In some embodiments, the present disclosure teaches that compounds having a pyrido[3,4-b]indole group and / or an azetidinyl group, and / or a substituted or unsubstituted phenyl moiety, are particularly useful as full estrogen receptor antagonists that are orally bioavailable and capable of crossing the blood-brain barrier. For example, in some embodiments, the present disclosure teaches that compounds having a pyrido[3,4-b]indole group covalently bonded to a phenyl linker and an azetidinyl moiety bonded to the phenyl linker via a heteroatom or heteroalkyl linker are particularly useful full estrogen receptor antagonists that are orally bioavailable and capable of crossing the blood-brain barrier. In some embodiments, the phenyl moiety is additionally substituted with one or more halogen atoms (e.g., F, Br, Cl, I). In some embodiments, the phenyl moiety is not additionally substituted (e.g., contains no additional substitutions other than the bond to the pyrido[3,4-b]indole group and the heteroatom or heteroalkyl connecting the phenyl group and the azetidinyl moiety). In some embodiments, the azetidinyl moiety is distal to the phenyl group. In some embodiments, the azetidinyl moiety is proximal to the phenyl group. In some embodiments, the azetidinyl moiety is further substituted with alkyl or haloalkyl.

[0016] In some embodiments, the present disclosure teaches that compounds having the structure set forth in Formula I can be particularly useful as described herein: [ka] In the formula, R a , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , X, and Y are as described herein.

[0017] In certain embodiments, the present disclosure provides insight that one or more features of the pyrido[3,4-b]indole group and / or the XY group of Formula I, and / or combination(s) thereof, can provide or participate in the described function(s) (e.g., complete estrogen receptor antagonism, ability to cross the blood-brain barrier, oral bioavailability, and / or combinations thereof).

[0018] In some embodiments, the present disclosure teaches that compounds having a structure as set forth in Formula I, where the compounds include an azetidinyl moiety, can provide or be responsible for a desired function(s) (e.g., complete estrogen receptor antagonism, oral bioavailability, ability to cross the blood-brain barrier, and / or a combination thereof).

[0019] In some embodiments, the present disclosure teaches that compounds having the structure set forth in Formula I, where the compounds do not include a difluorophenyl moiety, can provide or be responsible for a desired function(s) (e.g., complete estrogen receptor antagonism, oral bioavailability, ability to cross the blood-brain barrier, and / or a combination thereof).

[0020] In some embodiments, the present disclosure teaches that compounds having the structure set forth in Formula I, wherein the compounds include a difluorophenyl moiety, can provide or be involved in a desired function(s) (e.g., complete estrogen receptor antagonism, oral bioavailability, ability to cross the blood-brain barrier, and / or a combination thereof).

[0021] In some embodiments, the present disclosure teaches that one or more of the following compounds may be particularly useful, as described herein: GDC-9545, SAR439859, AZD9833, [ka]

[0022] Furthermore, the present disclosure demonstrates that certain full estrogen antagonists described herein (e.g., having a structure within Formula I), when administered according to an appropriate regimen, can accumulate preferentially in tumor(s) relative to plasma, including to a significantly greater extent than that observed for fulvestrant.

[0023] In some embodiments, the present disclosure provides methods of treating an ER-associated disease or condition (e.g., tumor(s) in the brain, such as brain metastases, or an ER-associated cancer, including tumor(s)) by administering certain full estrogen receptor antagonists according to a regimen that achieves preferential accumulation in the tumor relative to the patient's plasma (i.e., achieving accumulation in the tumor to a concentration greater than that in plasma). In some such embodiments, such accumulation is greater than that observed for fulvestrant. Alternatively or additionally, in some embodiments, such accumulation is at least about 30-fold greater than that observed in plasma.

[0024] Still further, the present disclosure provides various effective dosing regimens for certain full estrogen antagonists described herein (e.g., having a structure within Formula I). ​​The present disclosure provides methods of treating an ER-associated disease or condition (e.g., an ER-associated cancer, including, but not limited to, tumor(s) in the brain, such as brain metastases, or tumor(s) in the brain) by administering such certain full estrogen receptor antagonist(s) according to such regime(s). [Brief explanation of the drawings]

[0025] [Figure 1A] Scatter plot measuring MRI volume (mm3) of ST941 brain metastases at enrollment for each mouse within each group A-E.

[0026] [Figure 1B]Scatter plot measuring MRI weight (g) of ST941 brain metastasis at enrollment for each mouse within each group A to E.

[0027] [Figure 2] FIG. 1 is a scatter plot measuring the mean tumor volume for each group A to E over time.

[0028] [Figure 3A] FIG. 1 is a scatter plot measuring the mean body weight of each of groups A to E over time.

[0029] [Figure 3B] FIG. 1 is a scatter plot measuring the rate of change in mean body weight for each of Groups A to E over time.

[0030] [Figure 4] 1 is a Kaplan-Meier plot showing the proportion of surviving mice within each of groups A through E over time. Check marks indicate censored data reflecting that mice were enrolled on different days.

[0031] [Figure 5A] FIG. 1 is a scatter plot measuring percent estrogenic response as a function of Log[M] for certain estrogen receptor antagonist compounds with no added estrogen.

[0032] [Figure 5B] FIG. 1 is a scatter plot measuring percent estrogen response as a function of Log[M] for certain estrogen receptor antagonist compounds with added estrogen.

[0033] [Figure 6] 1 is a chart measuring estrogen receptor protein degradation across multiple cell lines for multiple estrogen receptor antagonists.

[0034] [Figure 7A]FIG. 1 is a scatter plot showing the percent reduction in estrogen response for Compound 1 in combination with various CDK4 / 6 inhibitors. [Figure 7B] FIG. 1 is a scatter plot showing the percent reduction in estrogen response for Compound 1 in combination with various CDK4 / 6 inhibitors. [Figure 7C] FIG. 1 is a scatter plot showing the percent reduction in estrogen response for Compound 1 in combination with various CDK4 / 6 inhibitors.

[0035] [Figure 8A] FIG. 1 is a scatter plot showing the percent reduction in estrogen proliferation on MCF-7 cells when treated with Compound 1 in combination with a PIK3CA inhibitor. [Figure 8B] FIG. 1 is a scatter plot showing the percent reduction in estrogen proliferation on MCF-7 cells when treated with Compound 1 in combination with a PIK3CA inhibitor.

[0036] [Figure 9A] 1 provides one scatter plot showing the dose response of Compound 1 on AF1 inhibition in cell lines with the most common ESR1 mutations versus ERα (wild type). [Figure 9B] 1 provides one scatter plot for an ERα cell line (D538G) showing the dose response of Compound 1 on AF1 inhibition with the most common ESR1 mutation. [Figure 9C] 1 provides one scatter plot showing the dose response of Compound 1 on AF1 inhibition for the ERα cell line (Y537S) with the most common ESR1 mutation. [Figure 9D] 1 provides one scatter plot for an ERα cell line (Y537C) showing the dose response of compound 1 on AF1 inhibition with the most common ESR1 mutation. [Figure 9E] 1 provides one scatter plot showing the dose response of Compound 1 on AF1 inhibition for the ERα cell line (Y537N) with the most common ESR1 mutation. [Figure 9F]1 provides one scatter plot showing the dose response of Compound 1 on AF1 inhibition for the ERα cell line (Y537R) with the most common ESR1 mutation.

[0037] [Figure 10A] FIG. 1 is a scatter plot showing the change in mean tumor volume at various doses of Compound 1 in mice.

[0038] [Figure 10B] FIG. 10B is a series of scatter plots isolated from FIG. 10A showing the mean tumor volumes in mice at various doses of the compound.

[0039] [Figure 11A] Scatter plot measuring drug exposure (ng / ml) over time for mice. [Figure 11B] FIG. 1 is a scatter plot measuring drug exposure (ng / ml) over time for rats. [Figure 11C] FIG. 1 is a scatter plot measuring drug exposure (ng / ml) over time for dogs. [Figure 11D] Scatter plot measuring drug exposure (ng / ml) over time for monkeys.

[0040] [Figure 12A] FIG. 1 is a scatter plot showing the reduction in estrogen concentrations across different cell lines. [Figure 12B] FIG. 1 is a scatter plot showing the reduction in estrogen concentrations across different cell lines. [Figure 12C] FIG. 1 is a scatter plot showing the reduction in estrogen concentrations across different cell lines. [Figure 12D] FIG. 1 is a scatter plot showing the reduction in estrogen concentrations across different cell lines.

[0041] [Figure 13] 1 is a bar graph showing mutant ER that increases ligand-independent alkaline phosphatase activity (AP) in Ishikawa endometrial cancer cells.

[0042] [Figure 14] 1 is a bar graph showing that activation domain 1 (AF1) of ER is required for AP activity.

[0043] [Figure 15] Mammals express two major isoforms of ER, known as ERα and ERβ, each of which is a member of the nuclear hormone receptor family. (This figure is a reproduction of Figure 1A from Patel & Bihani Pharm & Therap 186:1, 2018.) A) The A-F domains that make up the estrogen receptor, including the activation function 1 (AF1) domain, DNA-binding domain (DBD), hinge region, and ligand-binding domain (LBD) / activation function 2 (AF2) domain. B) The effects of endocrine therapies (aromatase inhibitors, SERMs, and SERDs) on the estrogen receptor pathway. Aromatase inhibitors prevent ER signaling by inhibiting estradiol synthesis. SERMs prevent ER signaling by binding to the ER and causing an inactive complex. SERDs prevent ER signaling by causing ER degradation.

[0044] [Figure 16] This is a reproduction of Figure 3 from Hewitt & Korach Endocrine Rev. 39:664-674 (June 12, 2018), showing variations in the underlying mechanisms of the E2 response.

[0045] [Figure 17A] Scatter plots measuring the concentrations of fulvestrant and Compound 1 in tumor versus plasma (logarithmic scale with fitting).

[0046] [Figure 17B] Scatter plots measuring the concentrations of fulvestrant and Compound 1 in tumor versus plasma (logarithmic scale with fitting).

[0047] [Figure 18]FIG. 1 is a scatter plot measuring tumor regression (y-axis) versus plasma concentration (x-axis) for fulvestrant and Compound 1.

[0048] [Figure 19] FIG. 1 is a scatter plot measuring tumor regression (y-axis) versus tumor concentration (x-axis) for fulvestrant and Compound 1.

[0049] [Figure 20A] Scatter plot measuring the weight of each animal at time 0. "Cmpd1" refers to "Compound 1" as described herein.

[0050] [Figure 20B] Scatter plot measuring the weight of each animal at time 0. "Cmpd1" refers to "Compound 1" as described herein.

[0051] [Figure 21] 1 is a Kaplan-Meier plot showing the proportion of surviving mice in each group over time. Check marks indicate censored data reflecting that mice were enrolled on different days. "Cmpd1" refers to "Compound 1" as described herein.

[0052] [Figure 22A] Scatter plot measuring mean tumor volume over time for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0053] [Figure 22B] Scatter plot measuring the rate of change in tumor volume over time for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0054] [Figure 23A] 1 is a waterfall plot measuring the percent change in tumor volume for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0055] [Figure 23B] 23A is a zoomed view of the waterfall plot in FIG. 23A showing the reduction in tumor volume size for certain groups. "Cmpd1" refers to "Compound 1" as described herein.

[0056] [Figure 24] Scatter plots measuring the mean tumor volume of individual animals in each group over time. "Cmpd1" refers to "Compound 1" as described herein.

[0057] [Figure 25] Scatter plots measuring the rate of change in tumor volume over time for individual animals in each group. "Cmpd1" refers to "Compound 1" as described herein.

[0058] [Figure 26] Scatter plot measuring animal weight over time for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0059] [Figure 27] Scatter plot measuring the rate of change in animal weight over time for each group. "Cmpd1" refers to "Compound 1" as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0060] There is a need for a treatment for certain brain metastases, particularly for estrogen receptor (ER)-positive cancer types, that does not require invasive techniques such as whole-brain radiation therapy and surgery. The present application provides a method for treating brain metastases associated with ER-associated diseases (strogen receptors, including cancers associated with mutations to the estrogen receptor) in a subject by administering a composition comprising a full estrogen receptor antagonist.

[0061] definition Administration: As used herein, the term "administration" refers to administering a composition to a subject or system, typically to effect delivery of, for example, an agent that is, is contained in, or is otherwise delivered by, the composition.

[0062] Agent: As used herein, the term "agent" refers to an entity (e.g., a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or a complex, combination, mixture, or system thereof (e.g., cell, tissue, organism) or phenomenon (e.g., heat, current or electric field, magnetic force or electric field, etc.).

[0063] Alkyl: The term "alkyl," used alone or as part of a larger moiety, (unless otherwise specified) refers to an alkyl group having 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms (e.g., C1 to C 12 , C1~C 10 , C1-C8, C1-C6, C1-C4, C1-C3, or C1-C2), saturated, optionally substituted, straight-chain or branched, or cyclic hydrocarbon groups. Exemplary alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, sec-butyl, isobutyl, t-butyl, etc.), pentyl, hexyl, and heptyl. The term "cycloalkyl" refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0064] Alkylene: The terms "alkylene" and "alkylenyl" are used interchangeably and refer to a divalent alkyl group. In some embodiments, an "alkylene" is a divalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, for example, 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are optionally replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups, and also include those described herein. It will be understood that two substituents on an alkylene group can be joined together to form a ring system. In certain embodiments, two substituents can be joined together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms.

[0065] Alkenyl: The term “alkenyl,” used alone or as part of a larger moiety, refers to an alkyl group having at least one double bond (unless otherwise specified) and having 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms (e.g., C2 to C6). 12 , C2~C 10 "Cycloalkenyl" refers to an optionally substituted linear, branched, or cyclic hydrocarbon group (C2-C8, C2-C6, C2-C4, or C2-C3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term "cycloalkenyl" refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having from about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0066] Antagonist: As used herein, the term "antagonist" may refer to an agent or condition whose presence, level, degree, type, or form is related to a decrease in the level or activity of a target. Antagonists may include agents of any chemical class, including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that exhibits relevant inhibitory activity. In some embodiments, an antagonist may be a "direct antagonist" in that it directly binds to its target, and in some embodiments, an antagonist may be an "indirect antagonist" in that it affects the target by means other than directly binding to the target (e.g., by interacting with a modulator of the target, thereby altering the level or activity of the target). In some embodiments, an "antagonist" may be referred to as an "inhibitor."

[0067] Aryl: The term "aryl" refers to an alkyl group having a total of 5 to 14 ring members (e.g., C 5~14 ) refers to monocyclic and bicyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Unless otherwise specified, "aryl" groups are hydrocarbons.

[0068] Associated: Two events or entities are "associated" with one another, as that term is used herein, if the presence, level, degree, type, and / or form of one correlates with the presence, level, degree, type, and / or form of the other. For example, a particular entity (e.g., a polypeptide, gene signature, metabolite, microorganism, etc.) is considered to be associated with a particular disease, disorder, or condition if its presence, level, and / or form correlates with the occurrence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, two or more entities are physically "associated" with one another if they interact, either directly or indirectly, such that they are in and / or remain in physical proximity to one another. In some embodiments, two or more entities that are physically associated with one another are covalently bonded to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently bonded to one another, but are non-covalently associated by, for example, hydrogen bonding, van der Waals interactions, hydrophobic interactions, magnetism, and combinations thereof.

[0069] Biological sample: As used herein, the term "biological sample" typically refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism or cell culture), as described herein. In some embodiments, the source of interest includes an organism, such as an animal or a human. In some embodiments, the biological sample is or includes a biological tissue or biological fluid. In some embodiments, the biological sample may be or include bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy sample, cell-containing body fluid, free-floating nucleic acid, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural effusion, feces, lymphatic fluid, gynecological fluid, skin swab, vaginal swab, oral swab, nasal swab, lavage fluid or washings, such as ductal washings or bronchoalveolar lavage fluid, aspirate, scraping, bone marrow specimen, tissue biopsy specimen, surgical specimen, feces, other body fluids, secretions, and / or excretions, and / or cells therefrom, etc. In some embodiments, the biological sample is or comprises cells obtained from an individual. In some embodiments, the obtained cells are or comprise cells derived from the individual from whom the sample is obtained. In some embodiments, the sample is a "primary sample" obtained directly from the source of interest by any suitable means. For example, in some embodiments, the primary biological sample is obtained by a method selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of bodily fluids (e.g., blood, lymph, feces, etc.), etc. In some embodiments, as the context will make clear, the term "sample" refers to a preparation obtained by processing the primary sample (e.g., by removing one or more components and / or adding one or more agents), e.g., filtration using a semipermeable membrane. Such a "processed sample" may include, for example, nucleic acids or proteins extracted from the sample or obtained by subjecting the primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0070] Combination therapy: As used herein, the term "combination therapy" refers to a situation in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all "doses" of a first regimen are administered before any dose of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may involve administering one or more agent(s) or modality(s) to a subject receiving other agent(s) or modality(s) in combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or necessarily simultaneously), although in some embodiments, two or more agents, or active portions thereof, may be administered together in a combination composition or even in a combination compound (e.g., as part of a single chemical complex or covalent conjugate).

[0071] Dosage form or unit dosage form: Those skilled in the art will understand that the term "dosage form" can be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined amount of the active agent. In some embodiments, such amount is a unit dosage (or a whole fraction thereof) appropriate for administration according to a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., correlates with a therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or agent to be administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0072] Dosage regimen or treatment regimen: Those skilled in the art will understand that the terms "dosage regimen" and "treatment regimen" can be used to refer to a series of unit doses (typically more than one) administered individually to a subject, typically separated by a period of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated in time from the other doses. In some embodiments, the individual doses are separated from each other by periods of equal length, and in some embodiments, a dosing regimen includes multiple doses and at least two different periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose in a first dosage amount, followed by one or more additional doses in a second dosage amount that is different from the first dosage amount. In some embodiments, a dosing regimen includes a first dose in a first dosage amount, followed by one or more additional doses in a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across a relevant population (ie, is a therapeutic dosing regimen).

[0073] Excipient: As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0074] Halo or Halogen: As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine, and iodine. "Halo" can modify another group to indicate the optional replacement of a hydrogen atom with a halogen atom. For example, as used herein, a "haloalkyl" is a branched, straight-chain, or cyclic alkyl group substituted with one or more halogen atoms (e.g., a "C1-C6 haloalkyl" group has 1 to 6 carbon atoms and one or more hydrogen atoms replaced with halogen atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di-, or tri-fluoromethyl, -CH2-CH2-fluoro, -CH2-CH2-CH2-fluoro, -CH2-CH2-CH2-CH2-fluoro, and -CH2-CF3, -CH2-C(CH3)2-F.

[0075] Heteroaryl: The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl), having 6, 10, or 14 pi electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzisoxazolyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, and benzisoxazolyl. Heteroaryl groups can be monocyclic or bicyclic.The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0076] Heteroatom: As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0077] Heterocycle: As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has, in addition to carbon atoms, one or more, such as 1 to 4 heteroatoms. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(such as in N-substituted pyrrolidinyl). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, or polycyclic, preferably monocyclic, bicyclic, or tricyclic, and more preferably monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted. Bicyclic heterocycles also include groups in which a heterocycle is fused to one or more aryl rings. Exemplary bicyclic heterocycle groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, and [ka] The bicyclic heterocycle may also be a spirocyclic ring system (e.g., a 7- to 11-membered spirocyclic fused heterocycle having, in addition to carbon atoms, one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) as defined above).

[0078] Oral: As used herein, the phrases "oral administration" and "orally administered" have their art-recognized meaning to refer to oral administration of a compound or composition.

[0079] Parenteral: As used herein, the phrases "parenteral administration" and "parenterally administered" have their art-understood meaning referring to modes of administration other than oral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0080] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions are or can be administered, for example, experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is human. In some embodiments, the patient or subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, the patient or subject exhibits one or more symptoms of a disorder or condition. In some embodiments, the patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, the patient or subject is undergoing or has undergone a particular therapy to diagnose and / or treat a disease, disorder, or condition.

[0081] Pharmaceutical composition: As used herein, the term "pharmaceutical composition" refers to an active agent formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen to a relevant subject (e.g., in an amount demonstrated to exhibit a statistically significant likelihood of achieving a predetermined therapeutic effect when administered), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in the presence of one or more indicators of a particular disease, disorder, or condition of interest, or in prior exposure to a condition or agent, etc.). In some embodiments, comparative terms refer to a statistically relevant difference (e.g., a difference of sufficient generality and / or magnitude to achieve statistical relevance). One of skill in the art will recognize or be able to readily determine the degree and / or generality of difference necessary or sufficient to achieve such statistical significance in a given context.

[0082] Pharmaceutically acceptable carrier: As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; pH buffers; polyesters, polycarbonates, and / or polyanhydrides, and other non-toxic compatible substances used in pharmaceutical formulations.

[0083] Pharmaceutically acceptable salts: As used herein, the term "pharmaceutically acceptable salts" refers to salts of such compounds that are suitable for use in pharmaceutical contexts, i.e., salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). In some embodiments, pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts. Non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. In some embodiments, pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydrogen phosphate, hydroxybenzoate ... Examples of suitable salts include ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc.In some embodiments, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates, as appropriate.

[0084] Substituted or Optionally Substituted: As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. "Substituted" may be explicit or implicit from the structure (e.g., [ka] At least, [ka] refers to, [ka] At least [ka] (refers to "optionally substituted") applies to one or more hydrogens. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as "substituted" preferably have 1 to 4 substituents, more preferably 1 to 2 substituents. Groups described as "optionally substituted" may be unsubstituted or "substituted" as described above.

[0085] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R o, -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph (optionally substituted with R°); -(CH2)0-4O(CH2)0-1Ph (optionally substituted with R°); -CH=CHPh (optionally substituted with R°); -(CH2)0-4O(CH2)0-1-pyridyl (optionally substituted with R°); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2) 0-4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O )R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4C(O)SR°;-( CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR°;-(CH2)0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-C(S)NR°2;-C(S )SR°;-SC(S)SR°,-(CH2)0-4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2)0-4SSR°;-( CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S( O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C1-4 linear or branched alkylene)ON(R°)2;or -(C1-4 straight or branched alkylene)C(O)ON(R°), wherein each R° may be optionally substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definition, two independent occurrences of R° taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be optionally substituted as defined below;

[0086] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with their intervening atoms) are independently halogen, —(CH2)0-2R●, —(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●), —O(haloR●), —CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, —(CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0- 2NHR●, -(CH2)0-2NR●2, -NO2, -SiR●3, -OSiR●3, -C(O)SR●, -(C1-4 straight or branched alkylene)C(O)OR●, or -SSR● (each R● is unsubstituted or, if preceding, "halo" is substituted only with one or more halogens, independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0087] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O ("oxo"), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where each independent occurrence of R* is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR*2)2-3O-, where each independent occurrence of R* is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] Suitable substituents for an aliphatic group of R* include halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, where each R● is unsubstituted or, if preceded by "halo", substituted only with one or more halogens and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†, where each R† is independently hydrogen, a C1-6 aliphatic group optionally substituted as defined below, a non- a substituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of R† taken together with the intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0090] Suitable substituents for an aliphatic group of R† independently include halogen, -R●, -(haloR●), -OH, -OR●, -O(haloR●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, where each R● is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] Small molecule: As used herein, the term "small molecule" refers to an organic and / or inorganic compound with a low molecular weight. Generally, a "small molecule" is a molecule less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, 2 kD, or 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0092] In some embodiments, a small molecule does not comprise a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; e.g., in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0093] In some embodiments, the small molecule is a modulator (e.g., an inhibitor or activator). In some embodiments, the small molecule is biologically active. In some embodiments, the small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent.

[0094] Those of skill in the art will understand, upon reading this disclosure, that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms, such as, for example, crystalline forms (e.g., polymorphs, solvates, etc.), salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0095] Those skilled in the art will appreciate that certain small molecule compounds have structures that can exist in one or more stereoisomeric forms. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer, or geometric isomer, or in the form of a mixture of stereoisomers; in some embodiments, such small molecules may be utilized in accordance with the present disclosure in the form of a racemic mixture.

[0096] Those skilled in the art will recognize that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such small molecules may be utilized in accordance with the present disclosure in individual tautomeric forms or in forms that interconvert between tautomeric forms.

[0097] One of skill in the art will appreciate that certain small molecule compounds have structures that allow for isotopic substitution (e.g., 2H or 3H for H, 11C, 13C or 14C for C, 13N or 15N for N, 17O or 18O for 16O, 36Cl for XXC, 18F for XXF, 131I for XXXI, etc.). In some embodiments, such small molecules may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0098] In some embodiments, a reference to a particular small molecule compound may refer to a particular form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., an acid addition or base addition salt form, depending on the compound), and in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0099] In some embodiments, if a small molecule compound is naturally occurring or a compound that occurs in nature, the compound may be provided and / or utilized in accordance with the present disclosure in a form that is different from the form in which it exists or occurs in nature. One of skill in the art will understand that in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound or a particular form thereof (e.g., with respect to other components of the preparation, including other forms of the compound) that differs from the absolute or relative amount of the compound or form present in a reference preparation of interest (e.g., a primary sample from a source of interest, such as a biological or environmental source) will differ from the compound present in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a distinct form of the compound from a racemic mixture of the compound, a particular salt of a small molecule compound may be considered to be a distinct form of the compound from another salt form of the compound, a preparation that includes only forms of the compound that contain one stereoisomer of the double bond ((Z) or (E)) may be considered to be a distinct form of the compound from those that contain the other stereoisomer of the double bond ((E) or (Z)), and a preparation in which one or more atoms are isotopes different from those present in a reference preparation may be considered to be distinct forms.

[0100] Therapeutic Agent: As used herein, the term "therapeutic agent" generally refers to any agent that induces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, the appropriate population may be defined by various criteria, such as a particular age group, sex, genetic background, pre-existing clinical condition, etc. In some embodiments, a therapeutic agent is a substance that can be used to alleviate, ameliorate, mitigate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. In some embodiments, a "therapeutic agent" is a drug that has been, or needs to be, approved by a government agency before it can be commercially available for administration to humans. In some embodiments, a "therapeutic agent" is a drug that requires a pharmaceutical prescription for administration to humans.

[0101] Treat: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset, reduce severity, and / or reduce the incidence of one or more symptoms or characteristics of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not show signs of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who shows only early signs of the disease, disorder, and / or condition, for example, to reduce the risk of developing pathology associated with the disease, disorder, and / or condition.

[0102] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a treatment regimen. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition. As one of ordinary skill in the art will appreciate, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, and the target cell or tissue. For example, an effective amount of a compound in a formulation for treating a disease, disorder, and / or condition is an amount that relieves, ameliorate, alleviates, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose, and in some embodiments, multiple unit doses are required to deliver the therapeutically effective amount.

[0103] Symbols used herein [ka] refers to the point of attachment between two atoms.

[0104] The compounds referred to herein may contain deuterium ( 2 It will be understood by one of skill in the art that the compound may be enriched with one or more isotopes, such as H or D.

[0105] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain chiral centers, which may be in either the (R) or (S) configuration, or may include mixtures thereof, unless otherwise specified. Accordingly, the present application includes, where applicable, stereoisomers of the compounds described herein, individually or mixed in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers may be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials or by separating isomers of the compounds of the present application.

[0106] Estrogen receptor-related disorders Estrogen receptors ("ER") are involved in a variety of biological processes, such as those related to the development of the female reproductive system, the maintenance of bone mass, and the protection of cardiovascular and / or central nervous system components (see, e.g., Pearce & Jordan Crit. Rev. Onc / Hem 50:3, 2004; Heldring Phys. Rev. 87:905, 2007). ERs are involved in a variety of cancers. Many tumors express estrogen receptors (i.e., ER + In tumors (e.g., breast tumors), active ERα signaling has been demonstrated to cause cell proliferation (although it has been reported that ERβ signaling can achieve tumor-suppressive effects; see, e.g., Nilsson & Gustafson Clin. Pharmacol. Ther. 89:44, 2011). Typically, tumors (e.g., breast tumors) with only 1% of cells staining positive for ER are characterized as "ERα-positive tumors." + Therapies that target ER are classified as +It is the standard treatment for many patients with tumors (see, for example, Cardoso et al. Annals Onc. https: / / doi.org / 10.1093 / announc / mdmx036, 2017; Rugo et al. J. Clin. Oncol. 34: 3069, 2016; Senkus et al. Annal Onc. 26: v8, 2015; Sareddy & Vadlamudi Clin. J Nat. Med, 13: 801, 2015). For example, for patients with early-stage breast cancer, the recommended therapy typically involves tumor resection followed by ER-targeted therapy (e.g., as discussed below). For advanced breast cancer, including metastatic breast cancer, ER-targeted therapy is the norm.

[0107] Given the importance of ER signaling in many cancers and certain cardiovascular, inflammatory, and neurodegenerative diseases, significant efforts have been invested in the development of ER-targeting therapeutic agents and modalities. While there is some fluidity / flexibility in the terminology used to describe ER-targeting agents, a variety of agents with different mechanisms are being developed and / or investigated.

[0108] Several ER-targeting drugs have been designed and / or demonstrated to reduce the levels of estrogen (ie, 17β-estradiol) production.

[0109] Some ER-targeting drugs have been designed and / or demonstrated to bind directly to the ER, and in some cases, such drugs compete with estrogen for binding to the ER and / or prevent the allosteric changes that naturally occur with estrogen binding. Often, the term "anti-estrogen" is used to refer to drugs that bind to the ER, and in some cases, it is used specifically to refer to drugs that compete with estrogen for ER binding.

[0110] The term "selective estrogen receptor modulator" ("SERM") is used to refer to compounds that are designed and / or demonstrated to alter some aspect of ER activity. Some descriptions refer to "SERM" as representing a specific type of antiestrogens, however, other descriptions use the term "SERM" more generally to refer to compounds that specifically affect some feature of ER (particularly ERα) expression and / or activity.

[0111] The term "selective estrogen receptor degrader" ("SERD") is used to refer to compounds that are designed and / or proven to induce or enhance the degradation of ER. Often, a compound may be referred to as a SERD if its presence correlates with a reduction in the level of ER. Some descriptions categorize compounds as either SERMs or SERDs, while others refer to SERDs as a specific type or species of compound that is a SERM.

[0112] Regardless of the mechanism of action of a particular agent, clinical experience to date has demonstrated that incomplete efficacy (e.g., within individual patients and / or across patient populations) and / or the development of resistance remain problems.

[0113] In particular, the presence or expression of certain ER mutations has been reported to affect the efficacy of various ER-targeted therapies (see, e.g., Jeselsohn et al. Nature Rev. Clin. Onc. 12, 573, 2015; Gelsomino et al. Breast Cancer Res. Treat 157:253, 2016; Toy et al. 2013). Some particularly problematic mutations are those that "activate" one or more aspects of ER expression and / or function, and some activating mutations have been reported to render ER ligand-independent (i.e., constitutively active). For example, certain mutations in the ER ligand-binding domain, including D538G and Y537S, have been demonstrated to constitutively activate ER, and other mutations, including deletions and / or fusions that remove the ligand-binding domain, may have similar effects (see, e.g., Li et al. Cell Replicates 4:1116, 2013; Veeraraghavan et al. Breast Cancer Research and Treatment 158, 219-232, 2016; Veeraraghavan, et al. Nature Comms 5:4577, 2014). Some reports indicate that up to 50% of women with metastatic breast cancer may have activating ER mutations detectable in circulating tumor DNA.

[0114] Brain metastases occur in approximately 10-16% of breast cancer patients and are the second most common cause of brain metastases after lung cancer. (Leone, Exp Hematol Oncol 4, 33 (2015) doi:10.1186 / s40164-015-0028-8) The prognosis is poor, with overall survival from diagnosis ranging from several months to several years. (Frisk, et al., Breast Cancer Res. Treat. 166:887-896 (2017)) In particular, in hormone-positive disease, e.g., ER-positive breast cancer, the incidence of breast cancer brain metastasis (BCBM) is 14%, and the median overall survival after the development of brain metastases is 9-10 months. (Brosnan & Anders, Ann Transl Med., 2016;6(9):163) There are no FDA-approved treatments for breast cancer brain metastases; surgery and radiation therapy, including whole-brain radiation therapy, are the only options.

[0115] A challenge in treating breast cancer brain metastases is providing therapies that can penetrate the blood-brain barrier. As noted by Brosnan & Anders, the BBB exists to selectively regulate what enters the brain and protect it from toxic substances, including chemotherapeutic agents and targeted drugs. In particular, "the unpredictable nature and heterogeneity in the permeability of the BBB, along with inherent drug efflux pumps, make it difficult to effectively deliver sufficient amounts of drugs to brain metastases to achieve apoptosis." Brosnan & Anders, Ann Transl Med., 2016;6(9):163.

[0116] The present disclosure establishes a specific class of compounds that are complete estrogen receptor antagonists capable of crossing the blood-brain barrier, thereby providing a viable mode of treatment for breast cancer brain metastases.

[0117] Estrogen receptor antagonists Enormous investment has been and continues to be made in the pursuit of effective ER-targeted therapies (e.g., reviewed by Patel & Bihani Pharmacol. & Therap. 186:1, 2018).

[0118] The most advanced compounds in clinical development include: a. Tamoxifen, an important breast cancer treatment, is credited with "saving the lives of 500,000 women worldwide" (see "Bringing the Investigational Breast Cancer Drug Endoxifen From Bench to Bedside with NCI Support," available at https: / / www.cancer.gov / news-events / cancer-currents-blog / 2017 / endoxifen-breast-cancer-NCI-support (last accessed July 7, 2019) but is known to be less effective in women with low CYP2D6 activity and to be more susceptible to the development of resistance). b. Endoxifen, the active metabolite of tamoxifen, was originally developed to address tamoxifen failure in women with low CYP2D6 activity, which reduces the ability to convert tamoxifen to endoxifen. (Cancer Currents Blog, National Cancer Institute, August 31, 2017) c.ARN-810 (Brilanestrant, GDC-810), which has been described as a "novel, potent, non-steroidal, orally bioavailable, selective ER antagonist / ER degrader that induces tumor regression in tamoxifen-sensitive and -resistant ER+ BC xenograft models" (see Dickler et al. Cancer Res. 75(15 Suppl):Abstract nr CT231, 2015), has been brought into Phase II clinical trials for the treatment of ER+ breast cancer patients who have failed other hormonal agents but may have subsequently experienced further growth decline (see, e.g., Biospace April 27, 2017). d. AZD9496 has been described as "an oral nonsteroidal small molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα" (see Hamilton et al. Clin Cancer Res 1:3519, 2018). AZD9496 has been reported as "an antagonist[ze] and degrade[e]ER with antitumor activity in both endocrine-sensitive and endocrine-resistant models" and has been described as "comparable to fulvestrant in antagonizing ER and circumventing endocrine resistance" (see Nardone et al. Br. Cancer 120:331, 2019). RAD-1901 (elacestrant) is described as a "novel, nonsteroidal, oral SERD that demonstrated single-agent activity in heavily pretreated patients with ER+ advanced breast cancer" (de See Vries et al., Cancer Res. Abstract P1-10-04, 2018; see also Bardia et al., J. Clin. Onc. 35:15_suppl, 1014, 2017). Preclinical studies also reported that "elacestrant significantly inhibited the growth of xenograft models harboring ESR1 mutations, including those with Y537S or D538G mutations, as well as models that were insensitive to fulvestrant and tamoxifen" (see Patel et al., Cancer Res 79:Abstract nr P6-20-08, 2019). f. Fulvestrant (Faslodex™) was the first FDA-approved SERD and is approved for the treatment of certain ER+ cancers, including in combination with palbociclib or abemaciclib. Fulvestrant is a "selective estrogen receptor degrader that binds to, blocks, and degrades estrogen receptors (ERs), resulting in complete inhibition of estrogen signaling through the ER" (see Nathan & Schmid Oncol Ther 5:17, 2017). Fulvestrant has achieved significant clinical success and is often considered the "gold standard" against which ER-targeted therapies are compared. However, fulvestrant is administered by injection rather than orally, and in practice (after the initial dose) requires monthly intramuscular injections of 500 mg. Also, certain retrospective analyses have offered hope that fulvestrant may have some utility in treating patients with ER-mutant tumors, but have not achieved conclusive evidence of activity (e.g., Fribbens et al. J Clin Oncol. 34:2961,2916; Spoerke et al. Nat Commun 7:11579,2016). [ka]

[0119] Fulvestrant remains the gold standard for treating ER-related diseases and disorders for patients who have developed resistance to currently approved therapies, such as tamoxifen and endoxifen. The present disclosure recognizes that fulvestrant's success stems from its ability to (1) inhibit both AF1 and AF2, thereby inhibiting the AF1 activity that persists in constitutively active ER mutants; (2) promote ER degradation; and (3) function as a full estrogen receptor antagonist ("CERAN"), lacking the partial ER agonist activity observed with certain other drugs. For example, compared with estrogen-limiting therapies (e.g., anastrozole) or partial antagonists (e.g., tamoxifen), fulvestrant exhibits superior activity and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer. See Robertson, et al., The Lancet, 388(10063):2997-3005 (Dec. 17, 2016). Without wishing to be bound by any particular theory, it is proposed that the ability of fulvestrant to inhibit both AF1 and AF2 may be due to its recruitment of corepressors to the ER complex.

[0120] Nevertheless, the present disclosure further recognizes that many other compounds, including, for example, ARN-810, AZD9496, tamoxifen, and others, are less effective than fulvestrant, at least in part because they only partially antagonize ER, specifically inhibiting the activation of AF2 but not AF1. However, it is further known that fulvestrant suffers from a number of deficiencies, including poor oral bioavailability and an inability to cross the blood-brain barrier.

[0121] The present disclosure encompasses the insight that the treatment of ER-associated brain metastases involves the administration of a certain class of full estrogen receptor antagonists that are orally bioavailable and can also cross the blood-brain barrier. Thus, in some embodiments, the present disclosure provides a method for treating cancer, the method comprising administering to a subject suffering from an ER-associated cancer a composition that delivers a full estrogen receptor antagonist to the subject's brain, wherein the subject has been determined to have brain metastases or is suspected of having brain metastases.

[0122] Estrogen receptor antagonists In some embodiments, the present disclosure teaches the particular utility of a compound(s) that is a complete estrogen receptor antagonist. In some embodiments, a "complete estrogen receptor antagonist," as that term is used herein, is characterized by complete antagonism of the estrogen receptor without residual estrogen receptor agonist activity. For example, a complete estrogen antagonist is understood to be a drug (e.g., a small molecule compound) that does not exhibit ER antagonism or ER agonism in one or more of the following assays: ERα protein level assay, MCF-7 cell line assay, Ishikawa cell line assay (measuring wild-type ER and specific mutants, including specific mutants lacking the aAF1 and / or AF2 domains), and rodent uterine weight gain assay. See generally WO2017 / 059139 and US9,018,244. Alternatively or additionally, in some embodiments, a full estrogen receptor antagonist has three characteristics: (1) it inhibits both activating function 1 (AF1) and activating function 2 (AF2), since full anti-estrogen activity requires inactivation of both AF1 and AF2; (2) it promotes ER degradation; and (3) it lacks the partial ER agonist activity observed with certain other agents. Without being bound by theory, it is understood that complete inhibition of both AF1 and AF2 is required for full estrogen receptor activity, and that activating mutations in the gene encoding estrogen receptor 1 allow activation of both AF1 and AF2 even in the absence of estrogen.

[0123] Given the importance of ER signaling in many cancers and certain cardiovascular, inflammatory, and neurodegenerative diseases, significant efforts have been invested in the development of ER-targeting therapeutic agents and modalities. While there is some fluidity / flexibility in the terminology used to describe ER-targeting agents, a variety of agents with different mechanisms are being developed and / or investigated.

[0124] Currently, fulvestrant is the only approved therapy with these characteristics. However, as mentioned above, fulvestrant suffers from numerous drawbacks, including poor oral bioavailability and an inability to cross the blood-brain barrier, making it completely ineffective for treating brain metastases associated with ER-related diseases or disorders.

[0125] Specific Structural Features of Exemplary Compounds The present disclosure encompasses the insight that certain classes of compounds can fully antagonize estrogen receptors (i.e., are complete estrogen receptor antagonists) while also being able to cross the blood-brain barrier, making them suitable for treating brain metastases associated with ER-related diseases or disorders. For example, among other things, the present disclosure reports certain estrogen receptor antagonists that exhibit complete estrogen receptor antagonism comparable to that of fulvestrant in various assays.

[0126] Suitable full estrogen receptor antagonists include those reported in WO2012 / 084711, WO2014 / 191726, WO2016 / 097072, WO2017 / 059139, and WO2019 / 245974, each of which is incorporated herein by reference. For example, in some embodiments, full estrogen receptor antagonists include GDC-9545, SAR439859, AZD9833, and the compound of Formula I [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, X is -NH-, -CH2-, or -O-; Y is, [ka] and R a is hydrogen or halo, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen and halo; R 5 is hydrogen or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, and C1-C6 heteroalkyl; R 6 is hydrogen or an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl; R 7 and R 8 are each independently hydrogen and optionally substituted It is selected from C1 to C6 alkyl.

[0127] In some embodiments, the full estrogen receptor antagonist is SAR439859. [ka]

[0128] In some embodiments, the full estrogen receptor antagonist is AZD9833.

[0129] In some embodiments, the full estrogen receptor antagonist is GDC-9545.

[0130] In some embodiments, the estrogen receptor antagonist is [ka] is.

[0131] In some embodiments, the estrogen receptor antagonist is [ka] is.

[0132] In some embodiments, the full estrogen receptor antagonist is a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein R a , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , X, and Y are described in classes and subclasses herein.

[0133] In some embodiments, X is -NH-, -CH2-, or -O-, as generally described above. In some embodiments, X is -NH- or -O-. In some embodiments, X is -CH2- or -O-. In some embodiments, X is -NH- or -CH2-. In some embodiments, X is -NH-. In some embodiments, X is -CH2-. In some embodiments, X is -O-.

[0134] In some embodiments, as generally described above, R a is hydrogen or halo. In some embodiments, R a is hydrogen. In some embodiments, R a is halo. In some embodiments, R はIn some embodiments, R is fluoro, bromo, or chloro. は It's fluoro.

[0135] In some embodiments, as generally described above, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen and halo. 1 , R 2 , R 3 , and R 4 are each hydrogen. In some embodiments, R 1 , R 2 , and R 3 are each hydrogen, and R 4 is halo. In some embodiments, R 1 , R 2 , and R 3 are each hydrogen, and R 4 is fluoro. In some embodiments, R 2 , R 3 , and R 4 are each hydrogen, and R 1 is halo. In some embodiments, R 2 , R 3 , and R 4 are each hydrogen, and R 1 is fluoro. In some embodiments, R 1 , R 3 , and R 4 are each hydrogen, and R 2 is halo. In some embodiments, R 1 , R 3 , and R 4 are each hydrogen, and R 2 is fluoro. In some embodiments, R 1 , R 2 , and R 4 are each hydrogen, and R 3 is halo. In some embodiments, R 1 , R 2 , and R 4 are each hydrogen, and R 3is fluoro. In some embodiments, R 1 and R 2 are each hydrogen, and R 3 and R 4 Each R is halo. 1 and R 2 are each hydrogen, and R 3 and R 4 Each R is fluoro. 3 and R 4 is hydrogen and R 1 and R 2 is halo. In some embodiments, R 3 and R 4 is hydrogen and R 1 and R 2 is fluoro.

[0136] In some embodiments, R 1 and R 2 are each hydrogen, and R 3 and R 4 are each hydrogen or halo, and R 3 or R 4 If one of the is a halo, R 3 or R 4 and the other is hydrogen. In some embodiments, R 1 and R 2 are each hydrogen, and R 3 and R 4 are each hydrogen or fluoro, and R 3 or R 4 When one of R is fluoro, 3 or R 4 The other is hydrogen.

[0137] In some embodiments, as generally described above, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] is.

[0138] In some embodiments, as generally described above, R 5 is hydrogen or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, and C1-C6 heteroalkyl. 5 is an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, and C1-C6 heteroalkyl. 5 is an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, and C2-C6 alkenyl. 5 is an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0139] In some embodiments, R 5 is an optionally substituted C1-C6 alkyl. In some embodiments, R 5 is unsubstituted C1-C6 alkyl. In some embodiments, R 5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, n-butyl, n-pentyl, or n-hexyl. 5 is n-propyl.

[0140] In some embodiments, R 5 is an optionally substituted C1-C6 haloalkyl. In some embodiments, R 5is -CH-halo, -CH-CH-halo, -CH-CH-CH-halo, or -CH-CH-CH-CH-CH-halo. In some embodiments, R 5 is -CH-fluoro, -CH-CH-fluoro, -CH-CH-CH-fluoro, or -CH-CH-CH-CH-CH-fluoro. In some embodiments, R 5 is -CH2-F or -CH2-CH2-CH2-F. In some embodiments, R 5 is -CH2-F. In some embodiments, R 5 is -CH2-CH2-CH2-F.

[0141] In some embodiments, Y is [ka] where R 5 is C1-C6 alkyl. In some embodiments, Y is [ka] In some embodiments, Y is [ka] where R 5 is C1-C6 haloalkyl. In some embodiments, [ka] is.

[0142] In some embodiments, Y is [ka] where R 5 is C1-C6 haloalkyl. In some embodiments, Y is [ka] is.

[0143] In some embodiments, as generally described above, R 6 is hydrogen or an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl.

[0144] In some embodiments, R 6 is an optionally substituted C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more groups selected from halogen and —(CH2)0-4OR°. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more groups selected from halogen and -OR°. In some embodiments, R 6 is C1-C6 alkyl substituted with one or more groups selected from halogen and —OH. In some embodiments, R 6 teeth, [ka] is.

[0145] In some embodiments, R 6 is C1-C6 haloalkyl. In some embodiments, R 6 is C1-C4 haloalkyl. In some embodiments, R 6 is —CH2—C(CH3)2—F or —CH2—CF3.

[0146] In some embodiments, R 7 and R 8are each independently selected from hydrogen and optionally substituted In some embodiments, R 7 and R 8 is hydrogen and R 7 and R 8 and the other is C1-C6 alkyl. In some embodiments, R 7 and R 8 is hydrogen and R 7 and R 8 and the other is methyl. In some embodiments, R 7 is hydrogen and R 8 is R-methyl (i.e., methyl with the stereochemical orientation shown as R). In some embodiments, R 7 is hydrogen and R 8 is S-methyl (i.e., methyl with the stereochemical orientation shown as S).

[0147] Thus, in some embodiments, the full estrogen receptor antagonist is a compound of formula (I), wherein the full estrogen receptor antagonist is [ka] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the full estrogen receptor antagonist is Compound 1. [ka] is.

[0149] In some embodiments, the full estrogen receptor antagonist is the free base form of Compound 1. [ka] is.

[0150] In some embodiments, the full estrogen receptor antagonist is Compound 2 [ka] is.

[0151] In some embodiments, the full estrogen receptor antagonist is compound 3. [ka] is.

[0152] In some embodiments, the full estrogen receptor antagonist is compound 4. [ka] is.

[0153] In some embodiments, the full estrogen receptor antagonist is compound 5. [ka] is.

[0154] In some embodiments, the full estrogen receptor antagonist is compound 5a: [ka] is.

[0155] In some embodiments, the estrogen receptor antagonist is compound 5b: [ka] is.

[0156] In some embodiments, the full estrogen receptor antagonist is (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1R,3R)-1-(2,6-difluoro-4-((1-propylazetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, and The compound is selected from 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9,-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol.

[0157] In some embodiments, the full estrogen receptor antagonist is a free base. In some embodiments, the full estrogen receptor antagonist is in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is as described herein. In some embodiments, the pharmaceutically acceptable salt is selected from a succinate (e.g., a succinate form), a tartrate (e.g., a tartrate form), and a fumarate (e.g., a fumarate form).

[0158] In some embodiments, the compounds described herein can be optionally labeled with a radiolabel, e.g., an isotope of a particular atom. These radiolabeled compounds can be used to detect certain ER + They are useful for tumor detection and visualization (e.g., via positron emission tomography (PET)). Exemplary radiolabels include: 11 C. 18 F, 15 O. 13 N, and 131 Examples include, but are not limited to, I.

[0159] In particular, it should be understood that certain characteristics of the compounds described herein allow them to be a combination of complete estrogen antagonists, orally bioavailable, and able to cross the blood-brain barrier. However, similar compounds lack these three attributes. For example, AZD9496, a selective estrogen receptor degrader (SERD), is found to be orally bioavailable, but fails to fully antagonize estrogen receptors due to the presence of at least some residual agonist activity. Without being bound by theory, it should be noted that AZD9496 lacks the heterocyclic moiety (e.g., azetidinyl moiety) present in the compounds described herein. In particular, without being bound by theory, it is theorized that the combination of a heterocyclic moiety (e.g., azetidinyl moiety) and a pyrido[3,4-b]indole provides a compound with certain desirable properties.

[0160] It is also theorized that the lack of halogen substitution on the phenyl bridge contributes to the ability of certain compounds to cross the blood-brain barrier.

[0161] Evaluation of ER antagonists Among other things, the present disclosure teaches that useful ER antagonist agents are those that have CERAN activity as described herein.

[0162] One aspect of the present disclosure is the insight that previous strategies for evaluating or characterizing ER antagonist (and / or potential antagonist) agents have been deficient, at least in that they typically do not distinguish between SERD and CERAN. In particular, most such previous strategies do not evaluate the ability of agents to specifically affect AF1.

[0163] Among other things, the present disclosure teaches that particularly useful ER antagonist agents are those that can inhibit ligand-independent ER activity, which in some embodiments includes activity observed with constitutive ER variant(s), such as, for example, AF2 deletions or truncations, and / or LBD mutants (e.g., D538G and Y537S).

[0164] Additionally, the present disclosure provides that particularly useful ER antagonist agents are: a. Inhibition of AF1 (e.g., inhibition of at least one, and preferably all, known constitutive ER variants) b. Inhibition of AF2 (e.g., inhibition of ligand-dependent ER activity) c. Promotion of ER degradation.

[0165] Additionally, in some embodiments, particularly useful ER antagonist agents include: a. Oral bioavailability and long half-life. b. Penetration of the blood-brain barrier.

[0166] In certain embodiments, the activity of the ER antagonist agent(s) may be evaluated in comparison with the activity of one or more of ARN-810, AZD9496, endoxifen, fulvestrant, RAD1901, tamoxifen, and / or a compound of formula I, and in some such embodiments, the comparison may be made contemporaneously or, in some embodiments, with historical or prospective results.

[0167] How to use The present disclosure encompasses the insight that certain full estrogen receptor antagonists have several uses, including the treatment, detection, and / or clinical evaluation of certain tumors of ER-associated disorders (e.g., ER-associated cancers such as breast cancer, including metastatic brain tumors).

[0168] Treatment method For example, in some embodiments, the present disclosure provides a method for treating a subject with an ER-related disease, disorder, or condition. For example, in some embodiments, the present disclosure provides a method for treating an ER-related disorder in a subject, wherein the subject has been determined to have or is suspected to have brain metastasis. In some embodiments, the subject has developed an ER-related cancer, such as breast cancer, or brain metastasis associated with a mutation in the estrogen receptor.

[0169] In some embodiments, the present disclosure provides a method of treating metastatic breast cancer in a subject comprising administering to the subject a full estrogen receptor antagonist, wherein the subject has previously been treated with a selective estrogen receptor modulator. In some embodiments, the selective estrogen receptor modulator is selected from tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0170] In some embodiments, the disclosure provides a method of treating cancer in a subject afflicted with an ER-associated cancer, wherein the improvement comprises administering to the subject a composition that delivers a full estrogen receptor antagonist to the subject's brain, wherein the subject has been determined to have or is suspected of having brain metastases.

[0171] In some embodiments, the disclosure provides methods of treating cancer in a subject with a full estrogen receptor antagonist, wherein the improvement comprises administering a full estrogen receptor antagonist to the subject, and the subject has been determined to have or is suspected of having brain metastasis.

[0172] In some embodiments, the present disclosure provides methods of treating ER-associated cancer by administering to a population of subjects suffering from brain metastases a composition comprising a full estrogen receptor antagonist, resulting in an average reduction or elimination of brain metastases.

[0173] In some embodiments, the ER-associated disorder is cancer. In some embodiments, the ER-associated disorder is breast cancer. In some embodiments, the subject suffering from an ER-associated disorder develops brain metastasis.

[0174] In some embodiments, the disclosure provides a method for preventing metastatic spread of cancer to the brain in a subject, the method comprising administering Compound 1: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, preventing the metastatic spread of cancer refers to inhibiting the spread of cancer localized to one part of a subject's body to the brain.

[0175] Detection Method The present disclosure further encompasses the insight that certain compounds described herein, e.g., radiolabeled versions of any of the compounds described herein, are useful for detecting certain ER-related diseases, disorders, and conditions. For example, radiolabeled versions of any of the compounds described herein may be useful for detecting certain ER-related diseases, disorders, and conditions. 18 The compounds described herein substituted with F can be used to detect ER-associated tumors, for example, via PET. In some embodiments, the present disclosure provides methods for detecting an ER-associated disorder in a subject, wherein the subject has been determined to have or is suspected of having brain metastasis. That is, in some embodiments, the present disclosure provides methods for detecting ER-associated metastasis in the brain.

[0176] Characterization methods The present disclosure further encompasses the insight that the efficacy of certain compounds described herein is evaluated by in vitro and in vivo model assays.For example, certain compounds described herein are characterized according to any of the model assays described herein, including, for example, ERα protein level assay, MCF-7 cell line assay, Ishikawa cell line assay (measuring wild-type ER and certain mutants, including mutants lacking AF1 and / or AF2 domains), and rodent uterine weight gain assay.Furthermore, in some embodiments, when characterized by any reference assay, compounds described herein exhibit complete estrogen receptor antagonism, as this term is defined herein.

[0177] Administration The present disclosure provides a method for treating a subject suffering from an ER-associated disorder, wherein the subject has or is suspected of having brain metastases, the method comprising administering a composition comprising a full estrogen receptor antagonist. In some embodiments, the composition comprises a full estrogen receptor antagonist and a pharmaceutically acceptable excipient, carrier, or diluent. Depending on the severity of the condition being treated, the composition may be administered orally, parenterally, by inhalation or nasal spray, topically (e.g., by powder, ointment, or drops), rectally, bucally, vaginally, intraperitoneally, intravesically, or via an implanted reservoir. Preferably, the composition is administered orally, intraperitoneally, or intravenously. In certain embodiments, provided compounds are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg of the subject's body weight per day, one or more times daily, to achieve the desired therapeutic effect.

[0178] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch.Such dosage forms can also contain, as is customary, additional substances other than inert diluents, such as lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0179] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above.

[0180] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings (i.e., buffers) and other coatings well known in the pharmaceutical formulating art. These may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0181] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed flour, peanut, corn germ, olive, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0182] Alternatively, the pharmaceutically acceptable compositions disclosed herein can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the compounds of the present application with suitable non-irritating excipients or carriers, which are solid at room temperature but liquid at body temperature (e.g., rectum or vagina), and therefore melt in the rectum or vaginal cavity to release the active compound. Such materials include cocoa butter, suppository waxes (e.g., beeswax), and polyethylene glycol.

[0183] Those skilled in the art will readily understand how to convert a therapeutically effective dose determined for an animal into a corresponding human equivalent dose. Thus, those skilled in the art will understand that specific data provided for an animal (e.g., a mouse) can be used to determine a suitable dose in a human, for example, by using the table provided by Nair & Jacob, J. Basic Clin. Pharm., 7(2):27-31 (2016).

[0184] The present disclosure provides dosing regimens in which the compounds reported herein are administered at levels and / or according to regimens corresponding to those exemplified herein for Compound 1 (see, e.g., Example 4). That is, a dose (i.e., a composition, optionally including additional pharmaceutically acceptable excipients) refers to a specific ratio of compound weight per kilogram of subject. For example, a 3 mg / kg dose refers to a composition, optionally including a pharmaceutically acceptable excipient, in which the compound is administered to a subject in an amount that is 3 mg per kilogram of the subject's body weight. It is understood that the weight of the compound is determined according to the free base weight of the compound (e.g., if the compound is a salt, the corresponding free base weight of the compound is used to determine the amount of compound in the dose). Thus, in some embodiments, a human subject is provided with a dose corresponding to 3 mg / kg to 30 mg / kg in mice. In some embodiments, a human subject is provided with a dose corresponding to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / kg in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 3 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 5 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 10 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 15 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 20 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 25 mg / kg or more in a mouse. In some embodiments, a human subject is provided with a dose corresponding to 30 mg / kg or more in a mouse.

[0185] In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a unit dosage form. In some embodiments, the composition comprising a full estrogen receptor antagonist is administered in the form of a capsule. In some embodiments, the composition comprising a full estrogen receptor antagonist is administered in the form of a tablet. In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a suspension. In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a solution.

[0186] In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a daily dose (QD). In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a twice-daily dose (BID). In some embodiments, the composition comprising a full estrogen receptor antagonist is administered every other day (QOD). In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a weekly dose (QW). In some embodiments, the composition comprising a full estrogen receptor antagonist is administered as a monthly dose (Q4W).

[0187] The present disclosure also encompasses the recognition that Compound 1 can be advantageously used to treat metastatic cancer, for example, cancer that has spread to the brain, bone, lung, liver, or central nervous system.As illustrated in the following table, Compound 1 can penetrate the blood-brain barrier when administered orally at a single dose of 300 mg / kg.Other estrogen receptor antagonists, such as fulvestrant, cannot penetrate the blood-brain barrier at similar doses. [Table 1]

[0188] Combination therapy The present disclosure recognizes that certain drug combinations can be beneficially used to fully antagonize estrogen receptors. Thus, in some embodiments, the present disclosure provides a method for treating a subject suffering from an ER-related disorder (e.g., cancer or breast cancer), comprising administering a full estrogen receptor antagonist and an anticancer agent. For example, in some embodiments, the anticancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

[0189] In some embodiments, the disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a full estrogen receptor antagonist, wherein the anti-cancer agent is a CDK4 / 6 inhibitor (i.e., inhibits one or both of CDK4 and CDK6). In some embodiments, the second agent is a CDK4 / 6 inhibitor selected from palbococilib, ribociclib, abemaciclib, relociclib, trilaciclib, and SHR6390. In some embodiments, the CDK4 / 6 inhibitor is palbococilib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is relociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is SHR6390.

[0190] In some embodiments, the disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a full estrogen receptor antagonist and an anticancer agent, wherein the second agent is a PIK3CA inhibitor. In some embodiments, the PIK3CA inhibitor is selected from alpelisib, taselisib, and LY3023414. In some embodiments, the PIK3CA inhibitor is alpelisib. In some embodiments, the PIK3CA inhibitor is taselisib. In some embodiments, the PIK3CA inhibitor is LY3023414.

[0191] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a full estrogen receptor antagonist and an anticancer agent, wherein the anticancer agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is selected from sirolimus, temsirolimus, everolimus, and LY3023414. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is LY3023414.

[0192] It is understood that the full estrogen receptor antagonist and anti-cancer agent described herein can be administered simultaneously or separately. For example, in some embodiments, the full estrogen receptor antagonist and anti-cancer agent are administered simultaneously. In some embodiments, the anti-cancer agent is administered before the administration of the full estrogen receptor antagonist. In some embodiments, the anti-cancer agent is administered after the administration of the full estrogen receptor antagonist. Illustrative Embodiments Embodiment 1. A method for treating cancer, comprising: The method comprises administering to a subject suffering from an ER-associated cancer a composition that delivers a full estrogen receptor antagonist to the brain of the subject, wherein the subject has been determined to have or is suspected of having brain metastasis. Embodiment 2. The method of embodiment 1, wherein the full estrogen receptor antagonist is GDC-9545. Embodiment 3 The method of embodiment 1, wherein the full estrogen receptor antagonist is SAR439859. Embodiment 4. The method of embodiment 1, wherein the full estrogen receptor antagonist is AZD9833. Embodiment 5. The full estrogen antagonist is a compound of Formula I [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, X is -NH-, -CH2-, or -O-; Y is, [ka] and R a is hydrogen or halo, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen and halo; R 5 is hydrogen or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, and C1-C6 heteroalkyl; R 6 is hydrogen or an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl; R 7 and R 8 are each independently hydrogen and optionally substituted 2. The method of embodiment 1, wherein the alkyl is selected from C1-C6 alkyl. Embodiment 6.R a 6. The method of embodiment 5, wherein is hydrogen. Embodiment 7. The method of embodiment 5 or 6, wherein X is -NH- or -O-. Embodiment 8. The method of embodiment 7, wherein X is -NH-. Embodiment 9. The method of embodiment 7, wherein X is -O-. Embodiment 10.Y is [ka] The method according to any one of embodiments 5 to 9, wherein Embodiment 11.Y is [ka] The method according to any one of embodiments 5 to 9, wherein Embodiment 12.R 5 The method of any one of embodiments 5 to 11, wherein is C1-C6 alkyl or C1-C6 haloalkyl. Embodiment 13.R 5 is C1-C6 alkyl. Embodiment 14.R 5 14. The method of embodiment 13, wherein is n-propyl. Embodiment 15.R 5 is C1-C6 haloalkyl. Embodiment 16.R 5 16. The method of embodiment 15, wherein is —CH2—F or —CH2—CH2—CH2—F. Embodiment 17.R 5 17. The method of embodiment 16, wherein is —CH2—F. Embodiment 18.R 5 17. The method of embodiment 16, wherein is —CH2—CH2—CH2—F. Embodiment 19.R 3 and R 4 19. The method of any one of embodiments 5 to 18, wherein each is hydrogen. Embodiment 20.R 1 and R 2 20. The method of embodiment 19, wherein each is hydrogen. Embodiment 21.R 1 and R 2 and each is halo. Embodiment 22.R 1 and R 2 and each is fluoro. Embodiment 23.R 7 and R 8 is hydrogen and R 7 and R 8 The method of any one of embodiments 5 to 22, wherein the other is C1-C6 alkyl. Embodiment 24.R 7and R 8 is hydrogen and R 7 and R 8 and the other is methyl. Embodiment 25.R 6が、 The method of any one of embodiments 5 to 24, wherein optionally substituted C1-C6 alkyl or C1-C6 haloalkyl. Embodiment 26.R 6 26. The method of embodiment 25, wherein is optionally substituted C1-C6 alkyl. Embodiment 27.R 6 27. The method of embodiment 26, wherein is C1-C6 alkyl substituted with one or more groups selected from halogen and OR°. Embodiment 28.R 6 28. The method of embodiment 27, wherein is C1-C6 alkyl substituted with one or more groups selected from halogen and OH. Embodiment 29.R 6 but, [ka] 29. The method of embodiment 28, wherein Embodiment 30.R 6 is C1-C6 haloalkyl. Embodiment 31.R 6 but, [ka] 31. The method of embodiment 30, wherein Embodiment 32. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 33. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 34. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 35. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 36. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 37. The compound is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 38. The compound is [ka] 33. The method of embodiment 32, wherein Embodiment 39. The compound is: [ka] 33. The method of embodiment 32, wherein Embodiment 40. The method of any one of embodiments 1 to 39, wherein the method further comprises administering an anti-cancer agent. Embodiment 41. The method of embodiment 40, wherein the anticancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor. Embodiment 42. The method of claim 41, wherein the anticancer agent is a CDK4 / 6 inhibitor.Embodiment 43. The method of embodiment 42, wherein the CDK4 / 6 inhibitor is selected from palbococilib, ribociclib, abemaciclib, relociclib, and trilaciclib. Embodiment 44. The method of embodiment 43, wherein the CDK4 / 6 inhibitor is selected from ribociclib, palbococilib, and abemaciclib. Embodiment 45. The method of embodiment 44, wherein the CDK4 / 6 inhibitor is ribociclib. Embodiment 46. The method of claim 41, wherein the anticancer agent is a PIK3CA inhibitor.Embodiment 47. The method of embodiment 46, wherein the PIK3CA inhibitor is selected from alpelisib and taselisib. Embodiment 48. The method of embodiment 41, wherein the anticancer agent is an mTOR inhibitor. Embodiment 49. The method of embodiment 40, wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, and everolimus. Embodiment 50. The method of any one of embodiments 5 to 49, wherein the subject has previously been treated with a selective estrogen receptor modulator. Embodiment 51 The method of embodiment 50, wherein the selective estrogen receptor modulator is an estrogen receptor agonist or a partial estrogen receptor agonist. Embodiment 52. The method of embodiment 51, wherein the estrogen receptor agonist or partial estrogen receptor agonist is tamoxifen, raloxifene, or toremifene. Embodiment 53. The full estrogen receptor antagonist is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 54. The full estrogen receptor antagonist is: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 55. A method of treating metastatic breast cancer in a subject, comprising administering to the subject a full estrogen receptor antagonist, wherein the subject has previously been treated with a selective estrogen receptor modulator. Embodiment 56. A method of treating cancer in a subject suffering from an ER-associated cancer, wherein the improvement comprises administering to the subject a composition that delivers a full estrogen receptor antagonist to the brain of the subject, wherein the subject has been determined to have or is suspected of having brain metastases. Embodiment 57. A method of treating cancer in a subject with a full estrogen receptor antagonist, wherein the improvement comprises administering a full estrogen receptor antagonist to the subject, wherein the subject has been determined to have or is suspected of having brain metastases. Embodiment 58. A method of treating ER-associated cancer, comprising: The method wherein administering to a population of subjects suffering from brain metastases a composition comprising a full estrogen receptor antagonist reduces or eliminates, on average, said brain metastases. Embodiment 59. A method of treating a subject suffering from cancer characterized by a mutation in estrogen receptor 1 (ESR1), comprising administering to the subject Compound 1: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 60. The method of embodiment 59, wherein the mutation is an activating mutation. Embodiment 61. A method of treating a subject suffering from cancer, comprising administering a compound that is an inhibitor of both activation function 1 and activation function 2 of the estrogen receptor. Embodiment 62. The compound is Compound 1: [ka] 62. The method of embodiment 61, wherein said medicament is a medicament for treating atopic dermatitis, or a pharmaceutically acceptable salt thereof. Embodiment 63. A method of treating a subject suffering from cancer, comprising administering a compound that is an inhibitor of activation function 2 and a second agent that is an inhibitor of activation function 1. Embodiment 64. The compound is an estrogen receptor antagonist selected from AZD9496, RAD-1901, ARN-810, endoxifen, fulvestrant, and Compound 1; [ka] or a pharmaceutically acceptable salt thereof. Embodiment 65. The method of embodiment 64, wherein the compound is selected from fulvestrant and Compound 1. Embodiment 66 The method of embodiment 65, wherein the compound is Compound 1. Embodiment 67. The method of any one of embodiments 63 to 65, wherein the second agent is a CDK4 / 6 inhibitor. Embodiment 68. The method of embodiment 67, wherein the CDK4 / 6 inhibitor is selected from palbococilib, ribociclib, abemaciclib, relociclib, and trilaciclib. Embodiment 69. The method of embodiment 68, wherein the CDK4 / 6 inhibitor is selected from palvocociclib and abemaciclib. Embodiment 70. The method of any one of embodiments 63 to 65, wherein the secondary agent is a PIK3CA inhibitor. Embodiment 71. The method of embodiment 70, wherein the PIK3CA inhibitor is selected from alpelisib and taselisib. Embodiment 72. The method of any one of embodiments 63 to 65, wherein the second agent is an mTOR inhibitor. Embodiment 73. The method of embodiment 72, wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, and everolimus. Embodiment 74. A method of treating a subject suffering from cancer that has metastasized to the brain, bone, lung, or liver, said method comprising administering Compound 1: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 75. A method of treating a subject suffering from cancer, said method comprising administering Compound 1, [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. Embodiment 76. The method of embodiment 75, wherein the amount of the composition administered to the subject is 30 mg / kg or less. Embodiment 77. The method of embodiment 76, wherein the amount of the composition administered to the subject is 10 mg / kg or less. Embodiment 78. The method of embodiment 77, wherein the amount of the composition administered to the subject is 1 mg / kg or less. Embodiment 79. The method of embodiment 78, wherein the amount of the composition administered to the subject is 0.1 mg / kg or less. Embodiment 80. The method of any one of embodiments 75 to 79, wherein the composition is administered to the subject once daily. Embodiment 81. The method of any one of embodiments 75 to 79, wherein the composition is administered to the subject once a week. Embodiment 82. The method of any one of embodiments 75 to 79, wherein the composition is administered to the subject once a month. Embodiment 83. The method of any one of claims 75 to 82, wherein the composition is in the form of a unit dosage form. Embodiment 84. The method of any one of embodiments 75 to 82, wherein the composition is in the form of a capsule. Embodiment 85. The method of any one of embodiments 75 to 82, wherein the composition is in the form of a tablet. Embodiment 86. The method of any one of embodiments 75 to 82, wherein the composition is in the form of a solution. Embodiment 87. The method of any one of embodiments 75 to 82, wherein the composition is in the form of a suspension. Embodiment 88. The method of any one of embodiments 75 to 87, wherein the cancer is breast cancer. Embodiment 89. A method of treating an estrogen receptor (ER)-associated disease, disorder, or condition, comprising administering a full estrogen receptor antagonist to the patient's plasma according to a regimen that achieves at least about 30-fold greater accumulation in the tumor than in the plasma. Embodiment 90. The full estrogen receptor antagonist is Compound 1: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 91. A method of preventing metastatic spread of cancer to the brain in a subject, comprising administering to the subject Compound 1: [ka] or a pharmaceutically acceptable salt thereof.

[0193] Example The examples provided herein demonstrate and support certain aspects of the present disclosure, but are not intended to limit the scope of any claims. Unless specifically presented in the past tense, inclusion in an example is not intended to imply that the work described has been completed or even performed. The following non-limiting examples are provided to further illustrate certain teachings provided by the present disclosure. Those skilled in the art will appreciate in light of this application that various changes can be made in the specific embodiments exemplified in the examples without departing from the spirit and scope of the teachings of the present invention.

[0194] In the examples below, the following abbreviations may be used: (aqueous); ACN (acetonitrile); CSA (camphorsulfonic acid); d (day or days); DCM (dichloromethane); DEA (diethylamine); DHP (dihydropyran); DMF (N,N-dimethylformamide); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMSO (dimethylsulfoxide); EA (ethyl acetate); ee (enantiomeric excess); equiv. (equivalents); ethanol (EtOH); h (hour(s)); Hex (hexane); HPLC (high performance liquid chromatography); IPA (isopropyl alcohol); KHMDS (potassium bis(trimethylsilyl)amide); LAH( lithium aluminum hydride); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); min (minutes or minutes); NMR (nuclear magnetic resonance); Pd / C (palladium on carbon); PPhO (triphenylphosphine oxide); Pt / C (platinum on carbon); rb (round bottom); Rf (retention factor); rt or RT (room temperature); SM (starting material); TEA (triethylamine); THF (tetrahydrofuran); THP (tetrahydropyran); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid or tosylic acid); and UV (ultraviolet).

[0195] Example 1: Synthesis of Compound 1 The complete synthesis of Compound 1 is described in PCT Publication No. 2017 / 059139 (referred to as Compound B, or (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole), which is incorporated herein by reference and repeated below.

[0196] Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde [ka] Step 1: Preparation of 1-propionylazetidin-3-one [ka] Compound 3-azetidinone hydrochloride (10.000 g, 93.0 mmol, 1.0 equiv.), anhydrous 1,2-dichloroethane (200 mL), and diisopropylethylamine (38.9 mL, 223 mmol, 2.4 equiv.) were added to a round-bottom flask (500 mL) to give a pale yellow suspension. The suspension was sonicated for 1 hour and then cooled to -10 °C (dry ice / MeOH) for 10 minutes. P-propionyl chloride (9.8 mL, 112 mmol, 1.2 equiv.) was added dropwise to the cooled suspension to give an orange solution. The reaction was removed from the bath and stirred at room temperature for 16 hours. The solvent was removed to give a semisolid. The semisolid was suspended in EA (300 mL) and the suspension was filtered. The semisolid was rinsed with EA (2 x 100 mL). TLC analysis (10% MeOH / DCM, KMnO7 stain / heat) showed three spots: Rf: 0.2, 0.5, 0.7. TLC (50% EA / Hex, KMnO7 stain / heat) showed two spots: Rf: 1, 0.3. The filtrate was concentrated, adsorbed onto silica gel (25 g), and chromatographed through silica gel (100 g cartridge) with DCM (5 min), then 0–10% MeOH over 15 min. The product separated early from the column in DCM and continued to elute from the column with up to 10% MeOH. TLC was performed in both solvent systems to determine whether any propionyl chloride was present in the initial fractions. Product-containing fractions were pooled and concentrated to give the title compound (11.610 g, 98.2%) as a yellow liquid. 1 H NMR(300MHz, CDCl3)δ:4.80(d,J=5.6Hz,4H),2.29(q,J=7.5Hz,2H),2.01(s,3H),1.18(t,J=7.5Hz,3H).

[0197] Step 2. Preparation of 1-propylazetidin-3-ol [ka] Lithium aluminum hydride (10.397 g, 273.9 mmol, 3.0 equiv) was suspended in THF (200 mL) and cooled in an ice bath. To this reaction mixture, a solution of 1-propionylazetidin-3-one (11.610 g, 91.3 mmol, 1.0 equiv) in THF (100 mL) was added dropwise over 30 minutes via a pressure-equalizing addition funnel. The addition funnel was removed. The flask was then fitted with a condenser, and the reaction was heated to reflux in a 75° C. oil bath for 16 hours. The reaction was cooled in an ice bath for 20 minutes, and sodium sulfate decahydrate (Glauber's salt, 25 g) was added in small portions over 20 minutes. After complete addition, the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a bed of Celite® (2 cm), and the solid was rinsed with EA (2×250 mL). The clear solution was concentrated to a pale yellow liquid (9.580 g, 91.1%). NMR indicated the presence of THF and EA. This material was used without further purification in the preparation of the following example compounds. 1 H NMR(300MHz, CDCl3)δ:4.39(quintet, J=6Hz,1H),3.62-3.56(m,2H),2.90-2.85( m, 2H), 2.41 (t, J=7.5Hz, 2H), 1.34 (sextet, J=7.2Hz, 2H), 0.87 (t, J=7.8Hz, 3H).

[0198] Preparation of (R)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine: [ka] Under N2 at 25 °C, indole-3-acetone (25.0 g, 144 mmol, 1.0 equiv.) was added to a solution of (R)-(+)-1-phenylethylamine (23.0 mL, 181 mmol, 1.3 equiv.) in dichloromethane (600 mL), and the mixture was stirred for 1 h. The reaction was cooled to 0-5 °C, and to this ice-cooled solution, sodium triacetoxyborohydride (100 g, 472 mmol, 3.3 equiv.) was added via powder addition funnel over 30 min. The orange solution was stirred at 0 °C for 1 h and then warmed to RT. The reaction was stirred at RT for 19 h, at which point ESI+ indicated the absence of indole starting material. Saturated NaHCO3 solution (100 mL) was added in 5 mL portions over 15 min at 10 °C with vigorous stirring. The solution was stirred for 15 min, and saturated Na2CO3 solution (200 mL) was added over 15 min. Solid K2CO3 (9 g) was added in 3 g portions, at which point the aqueous layer reached pH 12 and bubbling ceased. The aqueous layer was filtered and separated. The red organic layer was washed with saturated aqueous NaHCO3 (2 x 100 mL). The aqueous layers were combined and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product (49 g). TLC (90:10 DCM:MeOH) showed four spots (Rf = 0.63, 0.50, 0.16, 0.26), two of which were separated diastereomeric major products (Rf = 0.16 and 0.26). The crude material was adsorbed onto silica gel and purified via flash chromatography (330 g cartridge, 0-100% EA:Hex). Fractions containing the R,R diastereomer were pooled and purified a second time using the same flash chromatography conditions to yield 24 g of product (approximately 82% ee). Because a previous successful separation was achieved using a 40:1 silica gel:crude ratio, the mixture was split into three portions and separated on three 330 g silica gel cartridges (0-40% EA / Hex, 20 min, isocratic 40% EA / Hex, 40 min). All fractions containing the desired product were >99% diastereomeric purity.The pure fractions were concentrated and pooled to give (R)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)-propan-2-amine as an orange semi-solid (11.91 g, 29.6%).

[0199] 1 H NMR(CDCl3,300MHz)R,R diastereomer:δ 0.96(d,J=6.6Hz,3H),1.30(d,J=6.6Hz,3H),2.68(q,J=7.2Hz,1H),2.97(m,2H)4.00(q,J=6.3Hz,1H),7.43-6.97(m,10H),7.96(br s,1H). R,S diastereomer: δ 1.11 (d, J = 5.7 Hz, 3H), 1.30 (d, J = 5.4 Hz, 3H) 2.80 (m, 3H), 3.92 (q, J = 6.9 Hz, 1H), 6.93-7.40 (m, 10H), 8.13 (br s, 1H); the aromatic region was difficult to distinguish from the R,R diastereomer due to lack of purity. LCMS: ES+[M+H]279.0.

[0200] Preparation of (2R)-1-(1H-indol-3-yl)propan-2-amine [ka] The compound (R)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine (11.91 g, 42.8 mmol, 1.0 equiv.) was dissolved in methanol (250 mL) and added to a 2 L Parr bottle. The solution was sparged with N for 10 minutes. 20% Pd(OH) on water-wet carbon (10.71 g, 76.3 mmol, 1.8 equiv.) was added, the bottle was pressurized with 50 psi of hydrogen, and shaken in a Parr apparatus for 22 hours. LCMS analysis indicated the reaction was complete. The suspension was filtered through Celite® and concentrated to remove MeOH. The crude material was dissolved in DCM and washed with saturated NaCO solution (50 mL), and the aqueous layer was extracted with DCM (2 × 50 mL). The organic layers were combined, dried and concentrated to give (2R)-1-(1H-indol-3-yl)propan-2-amine as a light brown solid (6.68 g, 89.6%) which required no further purification.

[0201] 1 H NMR(CDCl3,300MHz)δ 1.17(d,J=6.6Hz,3H),2.66(dd,J=8.4,14.7Hz,1H),2.88(dd,J=5.4,14.1Hz,1H),3.27(6 Heavy line, J=1.5Hz,1H),7.05-7.22(m,3H),7.37(d,J=7.5Hz,1H),7.62(d,J=8.7Hz,1H),8.00(br s,1H). LCMS: ES+[M+H]+174.9.

[0202] Preparation of 2-fluoro-2-methylpropanol [ka] To a stirred suspension of lithium aluminum hydride (2.50 g, 65.9 mmol, 1.6 equiv) in anhydrous diethyl ether (100 mL) cooled in an ice bath, methyl 2-fluoro-2-methylpropionate (5.01 g, 40.5 mmol, 1.0 equiv) was added dropwise over 15 min. After 2 h, 2.0 mL of water, 2.0 mL of 15% w / v NaOH, and 5.0 mL of water were added dropwise, successively. After 15 min, the white suspension was diluted with DCM and gravity filtered through Celite®, and the solid was washed with DCM. The filtrate was concentrated (200 mbar, 25 °C) to give 2-fluoro-2-methylpropanol (2.09 g, 56.1%) as a colorless oil. 1 H NMR (300MHz, CDCl3) δ 1.34 (d, J = 21.3 Hz, 6H), 1.95 (br t, 1H), 3.56 (dd, J = 6.6, 20.7 Hz, 2H).

[0203] Preparation of 2-fluoro-2-methylpropyl trifluoromethanesulfonate [ka] Trifluoromethanesulfonic anhydride (5.0 mL, 29.7 mmol, 1.3 equiv) was added dropwise over 30 min to a solution of 2-fluoro-2-methylpropanol (2.090 g, 22.7 mmol, 1.0 equiv) and 2,6-lutidine (3.40 mL, 29.4 mmol, 1.3 equiv) in DCM (25 mL) at 0 °C. After 2 h, the red solution turned light brown. TLC (20:80 EA:Hex, KMnO stain) showed the absence of starting material. The reaction mixture was washed with 1 M HCl solution (2 × 20 mL) and saturated NaHCO solution (2 × 20 mL). The aqueous layers were back-extracted with DCM (20 mL) respectively. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure (150 mbar, 25 C) to give 2-fluoro-2-methylpropyl trifluoromethanesulfonate as a red oil (4.39 g, 86.3%).

[0204] 1H NMR (300MHz, CDCl3) δ 1.46 (d, J = 20.4 Hz, 6H), 4.41 (d, J = 18.6 Hz, 2H). 19 F NMR(282MHz, CDCl3)δ -147.1,-74.5.

[0205] Preparation of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine: [ka] The compound 2-fluoro-2-methylpropyl trifluoromethanesulfonate (9.587 g, 42.8 mmol, 1.1 equivalents) (solution in DCM, 16% by weight DCM, 11.4384 g) was added to a solution of (2R)-1-(1H-indol-3-yl)propan-2-amine (6.680 g, 38.3 mmol, 1.0 equivalents), anhydrous 1,4-dioxane (60.000 mL, 701.4 mmol, 18.3 equivalents), and freshly distilled diisopropylethylamine (8.500 mL, 48.8 mmol, 1.3 equivalents). The dark brown solution was heated at 90 °C for 3 hours. After 3 hours, LCMS showed that a small amount of indoleamine starting material was still present. TLC (10% MeOH / DCM) indicated that the triflate (Rf = 0.54) was consumed. NMR of the unused triflate SM (286-30) indicated that the triflate was not decomposed overnight, so another 0.1 equivalent (0.9883 g, 13 wt% DCM, 0.8563 g triflate SM) was added, and the reaction was heated at 90 °C for 2 h. LCMS indicated the reaction was complete, and TLC (10% MeOH / DCM) showed one spot (Rf = 0.24) (TLC using 50% EA / Hex, one streaky spot Rf ≤ 0.12, another spot at Rf = 0). EtOAc (50 mL) was added, the solution was washed with NaHCO (2 × 50 mL), and the combined aqueous layers were washed with EtOAc (50 mL). The combined organic extracts were dried over NaSO and concentrated under reduced pressure. The crude material (brown oil, 14.8 g) was purified by flash silica chromatography (240 g cartridge, 0–100% EA / Hex). The desired product eluted as a long, tailing peak. Concentration of pure fractions gave (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (4.211 g, 17.0 mmol) as a dark yellow oil.

[0206] 1H NMR(300MHz,CDCl3)δ 1.10(d,J=6.3Hz,3H),1.34(dd,J=3.0,21.9Hz,6H),2.68-2.95(m,4H),3.02(Sextet,J=6.6Hz,1H) ,7.05(d,J=2.4Hz,1H),7.26-7.11(m,2H),7.36(d,J=6.9Hz,1H),7.62(d,J=7.5Hz,1H),8.18(br s,1H). 19 F NMR(282MHz, CDCl3)δ -144.2.m / z:ES+[M+H]249.0.

[0207] Preparation of Compound 1 To a solution of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (0.070 g, 0.3 mmol, 1.0 equiv.) in anhydrous toluene (1.50 mL) and glacial acetic acid (0.100 mL, 1.7 mmol, 6.2 equiv.), 4-((1-propylazetidin-3-yl)oxy)benzaldehyde (0.096 g, 0.4 mmol, 1.3 equiv.) was added. Molecular sieves were added, and the solution was stirred at 80 °C in the dark under N for 8 h. The reaction solution was diluted with DCM, filtered, and washed with saturated NaCO solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried over NaSO. The solution was filtered and concentrated. The residue was dissolved in acetonitrile (2 mL), filtered through a syringe filter, and then purified via preparative LC (40–90% ACN:HO for 18 min, followed by isocratic 90% ACN for 7 min). Pure fractions were concentrated and dried to give (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white powder.

[0208] Example 2: Synthesis of Compounds 2 to 4 Specific synthetic methods for each of compounds 2, 3, and 4 can be found in WO2016 / 097072, which is incorporated herein by reference.

[0209] Example 3: Synthesis of Compounds 5-5b Specific synthetic methods for each of compounds 5, 5a, and 5b can be found in WO2019 / 245974, which is incorporated herein by reference.

[0210] Example 4: In vivo evaluation of Compound 1 Model Development Intracranial tumor implantation Tumors from patients with subcutaneous ST941 tumors were used for intracranial inoculation of eight NMRI nude mice.

[0211] Procedures were performed according to Minerva Imaging SOP 18.1.2. Fresh tissue and single cell suspensions from intracranial injections.

[0212] Briefly, subcutaneous ST941PDX tumors grown in NMRI nude mice were harvested. Tumors were cut into small pieces and enzymatically digested to obtain a single-cell suspension. Digestion was terminated, filtered through a 100 μm filter, washed with PBS, and resuspended in PBS. Tumor cell viability was checked by trypan blue staining, and the final concentration was 20 million viable cells / mL. Cells were kept on ice until inoculation.

[0213] Mice were anesthetized with hypnorm / midazolam (1 mL / 100 g body weight) and placed in a stereotaxic frame to immobilize the head. A longitudinal incision was made in the scalp to expose the skull. A hole was drilled in the skull 1.5 mm to the right of the sagittal suture and 1.0 mm posterior to the bregma using a microdrill. 10 μl of the cell suspension (200,000 cells) was injected at a rate of 60 nl / s to a depth of 2–2.5 mm using a 100 μl syringe with a 25-gauge needle mounted on a microinfusion pump. The needle was left in place for 3 minutes and then withdrawn. Bupivacaine (0.2 mg / 100 g body weight) and lidocaine (1 mg / 100 g body weight) were administered to the incision for local anesthesia, and the skin was closed with sutures.

[0214] Mice were marked for identification and returned to their cages where they were monitored until they fully recovered from anesthesia.

[0215] MR imaging, tumor monitoring and euthanasia Tumor growth was monitored by T2-weighted MR imaging. The first scan was performed 1 week after inoculation and twice weekly thereafter. Body weights and scores were performed at least twice weekly. Animals were scored daily if a weight loss of ≥10% was observed.

[0216] When humane endpoints were met, mice were euthanized by cervical dislocation.

[0217] Effectiveness Intracranial tumor implantation Parental tumors bearing subcutaneous ST941 tumors were used for intracranial inoculation of 54 athymic nude mice.

[0218] Procedures were performed according to Minerva Imaging SOP 18.1.2. Fresh tissue and single cell suspensions from intracranial injections. See brief description above.

[0219] MR imaging for inclusion Mice were enrolled in the study sequentially based on MR imaging. The first MR imaging session began 1–3 weeks after implantation, depending on the model establishment results. MR imaging was then performed twice weekly until enrollment.

[0220] Tumor volume 2-5mm 3 Mice were enrolled in the study when they reached a tumor volume of 1000 mg / kg. Enrollment was the day after actual MR imaging. The first 40 mice that met the enrollment criteria were randomized into five groups. See Table 1. Mice were randomized so that all groups had the same mean tumor volume at enrollment. [Table 2]

[0221] Estrogen replacement and depletion Animals were supplemented with 17β-estradiol in their drinking water starting 2 days before intracranial inoculation. Animals were estrogen-depleted when enrolled in the study, with dosing initiated 2 days later.

[0222] Therapy, Weight Monitoring and MR Imaging Mice were treated according to Table 1 (above). Therapy was given by oral gavage between 9:00 and 10:00 AM daily. The first dose was administered two days after enrollment.

[0223] Body weight and visual assessment were monitored daily during therapy. Animals were scored three times per week according to the table below, or more frequently if a 5% weight loss was evident. [Table 3]

[0224] Tumor growth was monitored by MR on days 5, 10, 15, 20 and 25 relative to the day of enrollment.

[0225] Post-therapy monitoring and euthanasia Weight monitoring and scoring were performed three times per week after treatment, and daily if a 5% weight loss was observed. Mice were euthanized by cervical dislocation when humane endpoints were met.

[0226] tissue preservation Brains containing tumor tissue were excised, preserved in 10% neutral buffered formalin for 48 hours (fixation ratio of at least 1:20), and transferred to 70% ethanol. Samples were stored at 4°C until shipment.

[0227] Figure 1A shows the volume (mm ) of ST941 brain metastases by MRI at the time of enrollment for each mouse in each group A to E.3 ) is a scatter plot measuring

[0228] FIG. 1B is a scatter plot measuring MRI-based body weight (g) at enrollment with ST941 brain metastasis for each mouse within each group A to E.

[0229] FIG. 2 is a scatter plot measuring the mean tumor volume for each of Groups A through E over time.

[0230] FIG. 3A is a scatter plot measuring the mean body weight for each of Groups A through E over time.

[0231] FIG. 3B is a scatter plot measuring the rate of change in mean body weight for each of Groups A through E over time.

[0232] Figure 4 is a Kaplan-Meier plot showing the proportion of surviving mice within each of groups A through E over time. Check marks indicate censored data reflecting that mice were enrolled on different days.

[0233] Example 5: Assay of estrogen receptor protein levels This example describes the evaluation of various compounds (ARN-810, AZD9496, Compound 1, endoxifen, and fulvestrant) on ERα protein levels in various cell lines. Depending on the cell type, 90,000–500,000 cells per well were plated in each well of a 12-well dish and incubated for at least 24 hours in phenol red-free medium containing 5% charcoal dextran-stripped fetal bovine serum (stripped FBS) (HyClone). Cells were treated with 300 nM antiestrogens in serum-free medium for 4 hours, and then lysates were lysed in RIPA buffer (ThermoFisher Scientific) supplemented with protease and phosphatase inhibitors. Total protein extracts were separated on a 10% SDS-PAGE TGX gel and transferred to a nitrocellulose membrane (BioRad). Blots were incubated with either mouse monoclonal anti-ERα antibodies, D12 (#sc-8005, SantaCruz Biotechnology) or SP1 (#MA5-14501, ThermoFisher Scientific). β-actin monoclonal antibodies (#MA5-15739 or #MA5-16410 (ThermoFisher Scientific) or #sc-47778 (SantaCruz Biotechnology)) were used as loading controls. Blots were incubated with appropriate secondary antibodies conjugated to horseradish peroxidase (ThermoFisher Scientific). Signals were detected with Super Signal Femto chemiluminescence reagent (ThermoFisher Scientific). The results are shown in Figure 6. As shown in the figure, all compounds except endoxifen demonstrated a significant ability to reduce ER protein levels in most cell lines, with compound 1 and fulvestrant being the most effective at reducing ER protein levels and showing comparable activity in this regard.

[0234] Example 6: Cell proliferation assay In this example, human ER +We describe an assay to evaluate the effects of test compounds on human MCF-7 cells, a breast cancer cell line. Specifically, 1,000 MCF-7 cells (Cheryl Walker, Baylor College of Medicine) per well were plated in 96-well plates in phenol red-free medium (ThermoFisher Scientific) containing 5% treated FBS. After at least 4 hours, cells were treated with an antiestrogen, and the medium was diluted to 2.5% treated FBS in the presence of 100 pM E2 for 6–8 days. Proliferation was measured using a CyQuant fluorescent DNA-binding dye kit (ThermoFisher Scientific) using a 1:200 GR dye and an excitation of 485 nm and a fluorescence readout of 538 nm.

[0235] Example 7: Estrogen Receptor Antagonism Assay Transient transfection of estrogen receptors and variants This example describes a study in which Ishikawa cells, a human endometrial cancer cell line, were transfected with specific estrogen receptor constructs and endogenous alkaline phosphatase assayed. 15,000 Ishikawa cells per well were plated in 96-well plates in phenol red medium containing 5% treated FBS. At the time of plating, cells in each well were transiently transfected with 75–100 ng of estrogen receptor construct (or empty vector, pSG5) using Lipofectamine LTX (ThermoFisher Scientific). Approximately 4 hours later, cells were treated with the indicated amount of antiestrogen (in the absence of E2) or 500 pM E2 (Figure 13), and the medium was diluted in 2.5% treated FBS. Cells were incubated for 3 days, the medium was removed, and the plates were frozen at -80°C. Thawed plates were incubated with p-nitrophenyl phosphate (ThermoFisher Scientific), a chromogenic substrate for AP, thus revealing the level of AP activity. After 40–80 min at 40°C, absorbance was read at 405 nm.

[0236] Compound 1 has ER antagonist, but not agonist, activity. The AP activity of endogenous wild-type ER in untransfected Ishikawa cells was assayed as described above. Cells were treated with the indicated compounds (ARN-810, AZD-9496, Compound 1, endoxifen, or fulvestrant) alone (agonist mode) or in the presence of 500 pM 17-estradiol (E2) (antagonist mode). The results are shown in Figure 5A (agonist mode) and Figure 5B (antagonist mode). As shown in the figures, all compounds exhibited significant antagonist activity, with Compound 1 and fulvestrant being the most potent. All compounds except Compound 1 and fulvestrant also exhibited significant agonist activity.

[0237] Certain mutant ERs increase ligand-independent ER activity Wild-type ER (HEGO), empty vector (pSG5), or the indicated LBD mutant ER were transiently transfected into Ishikawa cells as described above. Empty vector alone was treated with 500 pM 17-estradiol (E2). 72 hours later, cells were assayed for AP activity. The results are shown in Figure 13. Bars represent the mean absorbance at 405 nm from triplicate wells + standard error. As shown in the figure, the various tested ER mutants were observed to be "activating mutants," in that they exhibited more activity than wild-type ER in the absence of ligand.

[0238] Activation domain 1 (AF1) is required for the ligand-independent activity observed with certain ER mutants. AF1 wild-type ER (HEGO, AA1-595), empty vector (pSG5), or the indicated ER lacking activation domain 2 ("AF2") (AA1-282) or lacking activation domain 1 ("AF1") (AA178-595, with or without the Y537S mutation) were transiently transfected into Ishikawa cells as described above. 72 hours later, cells were assayed for AP activity. Bars represent the mean absorbance at 405 nm from quadruplicate wells + standard error. As shown, even in the presence of the activating Y537S mutation (ΔAF1 / Y5372), AF1 is required for the ligand-independent ER activity observed when the ER is truncated (ΔAF2).

[0239] Compound 1 inhibits the activity of ligand-independent ER mutants Wild-type ER or the indicated ER variants were transiently transfected into Ishikawa cells as described above, and activity was assayed in the presence of compound 1 or fulvestrant. Results are shown in Figures 9A-9F. Points represent the mean AP activity normalized to vehicle from duplicate wells + / - standard error. Dose-response curves for compound 1 and fulvestrant were fitted using least-squares fitting, and pIC 50 (-Log IC 50 ) was calculated using a variable slope sigmoidal dose-response model. The lines represent the normalized AP activity of endogenous receptors (transfected with empty vector (pSG5)). As shown in the figure, compound 1 inhibited the activity of each of the ligand-independent ER mutants with an IC50 comparable to that of fulvestrant.

[0240] Certain clinical candidates are unable to inhibit the activity of ligand-independent ER mutants Wild-type ER or the indicated ER variants were transiently transfected into Ishikawa cells as described above and assayed for activity in the presence of Compound 1 or fulvestrant compared to endoxifen, RAD-1901, ARN-810 (GDC-0810), or AZD-9496 (results are shown in Figures 12A-12B, where Compound 1 and fulvestrant are compared to endoxifen and RAD-1901 in Figures 12A and 12B, or to AZD-9496 in Figures 12C-12D). Compared with ARN-810 (GDC-0810) and AZD-9496. Points represent the mean absorbance at 405 nm from triplicate wells + standard error. Lines represent AP activity of endogenous receptors (transfected with empty vector (pSG5)). As shown in the figure, neither endoxifen, RAD-1901, ARN-810 (GDC-0810), nor AZD-9496 are able to inhibit the activity of the ligand-independent ER variants as Compound 1 and fulvestrant do.

[0241] Example 8: Xenograft analysis of Compound 1 in ST941 PDX brain metastases This example describes the effect of Compound 1 on tumors derived from the patient-derived xenograft (PDX) model ST941, which were implanted directly into the mouse brain.

[0242] In particular, this example describes the effect of Compound 1 on estrogen receptor (ER)-positive tumors directly implanted into the brains of mice using patient-derived human breast cancer cells containing an activating mutation in the estrogen receptor, the Y537SESR1 mutation.

[0243] Regimens compared included oophorectomy plus vehicle, fulvestrant, tamoxifen, Compound 1, and a combination of ribociclib and Compound 1 monotherapy versus vehicle in the ST941 intracranial breast cancer brain metastasis model.

[0244] Protocol and Materials In vitro treatments Subcutaneous ST941 tumor-bearing parental tumors were used for intracranial inoculation of 64 athymic nude mice. The procedure was performed according to the following method. Subcutaneous ST941PDX tumors grown in NMRI nude mice were harvested. The tumors were cut into small pieces and enzymatically digested to obtain a single-cell suspension. The digestion was terminated, filtered through a 100 μm filter, washed with PBS, and resuspended in PBS. The viability of tumor cells was checked by trypan blue staining, and the cells were suspended according to the table below. The cells were kept on ice until inoculation. [Table 4]

[0245] In vivo treatment

[0246] Eight female NMRI nude mice (1 week time frame, age ordered at approximately 6 weeks of age) were used for model development.

[0247] Tumor implantation and estrogen administration Tumors were prepared and implanted by the following method.

[0248] The animals were anesthetized with hypnorm / midazolam (1 mL / 100 g body weight) and placed in a stereotaxic frame to immobilize the head. A longitudinal incision was made in the scalp to expose the skull. A hole was drilled in the skull 1.5 mm to the right of the sagittal suture and 1.0 mm posterior to the bregma using a microdrill. 10 μl of the cell suspension (200,000 cells) was injected at a rate of 60 nl / s to a depth of 2–2.5 mm using a 100 μl syringe with a 25-gauge needle mounted on a microinfusion pump. The needle was left in place for 3 minutes before being withdrawn. Bupivacaine (0.2 mg / 100 g body weight) and lidocaine (1 mg / 100 g body weight) were administered to the incision for local anesthesia, and the skin was closed with sutures.

[0249] The animals were chipped for identification and returned to their cages where they were monitored until they fully recovered from anesthesia.

[0250] Mice were followed by MR imaging to determine whether tumor volumes were between 2 and 5 mm 3 Enrollment occurred either 1 or 2 days after MR imaging, which confirmed adequate tumor size. Mice were randomized so that all groups had approximately equal tumor volumes at enrollment. MR imaging was performed according to the following method:

[0251] The first MR imaging session began 2 weeks after implantation. Once the tumor was established, MR imaging was performed weekly or twice weekly. Animals were enrolled when the tumor volume reached 2-5 mm3. Inclusion occurred the day after the actual MR imaging. Animals that met the enrollment criteria were stratified into six groups according to Table 8-1. Animals were stratified so that all groups had the same mean tumor volume at enrollment.

[0252] Estrogen supplementation was provided via 17β-estradiol in drinking water starting 2 days before intracranial inoculation. Once sufficient tumor volume was reached, estrogen supplementation was discontinued in each animal. Treatment of each mouse began 2 days after enrollment.

[0253] Table 8-1 summarizes the treatments applied to the different groups. [Table 5]

[0254] Animals were treated according to Table 8-1. Oral gavage therapy was administered daily between 9:00 and 10:00 AM. The first dose was administered two days after enrollment.

[0255] Compound 1 formulation was prepared by dissolving Compound 1 in DMSO to form a clear solution. This solution was transferred to 0.5% CMC in Millipore water so that the final concentration of DMSO was less than 5% v / v. During the addition of the DMSO solution, Compound 1 precipitated and formed a finely divided suspension in the vehicle. This suspension precipitated over time. Before administering the test substance, sonication and stirring were performed.

[0256] Ribociclib was formulated at 15 mg / mL. 100 mg of ribociclib was suspended in 6.66 mL of vehicle to reach a final concentration of 15 mg / mL.

[0257] The combination formulation of Compound 1 and ribociclib was prepared by mixing 1:1 mL of the solutions prior to administration.

[0258] Ovariectomy

[0259] Animals in Group B were estrogen-deprived by ovariectomy on the day of enrollment. Ovariectomy was performed according to the following method:

[0260] Animals were anesthetized (sevoflurane, 2-4% in ambient air supplemented with 100% O2 at an approximately 4:1 ratio) and placed in a repositioned position on a heating pad. Carprofen (5 mg / kg) was administered subcutaneously preoperatively and daily for 3 days postoperatively.

[0261] The area around the incision was disinfected with iodine. A 1 cm incision was made along the midline, and the muscle layer was separated from the skin using curved scissors. A small incision 1 cm lateral to the midline was made through the muscle to access the abdominal cavity. The white adipose tissue surrounding the ovaries was removed using forceps. The proximal blood vessels and uterine horns were ligated using monofilament sutures. The ovaries were removed using small scissors, and the remaining tissue was returned to the abdominal cavity.

[0262] The muscle layer and skin layer wounds were closed separately with absorbable sutures, and the procedure was repeated on the other side.

[0263] Therapy, Weight Monitoring and MR Imaging

[0264] Body weight and visual assessment were monitored daily during therapy. Animals were scored three times per week according to the table below, or more frequently if a 10% weight loss was evident. [Table 6]

[0265] Tumor growth was monitored by MR on days 5, 10, 15, 20 and 25 relative to the day of enrollment.

[0266] When humane endpoints were met, animals were euthanized by cervical dislocation.

[0267] tissue preservation

[0268] Once the animals reached the humane endpoint, the following sampling was performed: Blood (plasma samples) Four hours after the last dose, whole blood was collected by cardiac puncture and transferred to EDTA tubes. Samples were centrifuged at 2000 x g for 10 minutes at 4°C. Plasma was transferred to 2 mL round-bottom Eppendorf tubes and stored at -80°C. The brain containing the tumor tissue was removed. Four brains from each group were preserved in 10% neutral buffered formalin for 48 hours (fixation ratio of at least 1:20) and then transferred to 70% ethanol. Samples were stored at 4°C until shipment. Four brains from each group were flash-frozen and stored at -80°C until shipment.

[0269] result The results of the xenograft studies described herein are presented in Figures 20A-27. These results show that mice receiving Compound 1 alone and in combination with ribociclib showed improved survival rates compared to other therapies, including fulvestrant. For example, nearly all mice receiving Compound 1 survived the 100-day study period, while at least half of the mice receiving fulvestrant died within 30 days (see Figures 21, 24, and 25). Thus, the present disclosure encompasses the insight that Compound 1, as a full estrogen receptor antagonist, exhibits improved properties over fulvestrant. Tamoxifen was the only other therapy tested that delayed tumor volume change, but not to the same extent as Compound 1 (see Figure 22B). However, animals treated with tamoxifen (Group D) began to show increased tumor volume after 100 days (see, e.g., Figures 22A, 22B, 24, and 25), and survival rates decreased after two members of Group D died (see Figure 21). The present disclosure also encompasses the insight that Compound 1 exhibits improved properties over tamoxifen in its ability to treat brain metastases. Compound 1 is superior to tamoxifen for additional reasons, including, but not limited to, that Compound 1 is a full estrogen receptor antagonist, whereas tamoxifen, as previously mentioned, is a partial estrogen receptor agonist.

[0270] FIG. 20A is a scatter plot measuring the weight of each animal at time 0.

[0271] FIG. 20B is a scatter plot measuring the tumor burden for each animal at time 0.

[0272] Figure 21 is a Kaplan-Meier plot showing the proportion of surviving mice in each group over time. Check marks indicate censored data reflecting that mice were enrolled on different days. "Cmpd1" refers to "Compound 1" as described herein.

[0273] Figure 22A is a scatter plot measuring the mean tumor volume over time for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0274] Figure 22B is a scatter plot measuring the rate of change in tumor volume over time for each group. "Cmpd1" refers to "Compound 1" as described herein.

[0275] Figure 23A is a waterfall plot measuring the percent change in tumor volume for each group.

[0276] FIG. 23B is a zoomed view of the waterfall plot of FIG. 23A showing the reduction in tumor volume size for certain groups.

[0277] FIG. 24 is a scatter plot measuring the mean tumor volume of individual animals in each group over time.

[0278] FIG. 25 is a scatter plot measuring the percent change in tumor volume over time for individual animals in each group.

[0279] FIG. 26 is a scatter plot measuring the weight of the animals over time for each group.

[0280] FIG. 27 is a scatter plot measuring the rate of change in animal weight over time for each group.

[0281] The above is a description of certain non-limiting embodiments of the subject matter described herein. Accordingly, it should be understood that the embodiments described herein are merely illustrative of the subject matter reported therein. Reference to details of the illustrated embodiments is not intended to limit the scope of the claims, which themselves recite features considered essential.

[0282] The systems and methods of the claimed subject matter are intended to encompass variations and adaptations developed using information from the embodiments described therein. Adaptations, modifications, or both of the systems and methods described therein may be implemented by those skilled in the relevant art.

[0283] When a system is described as having, including, or comprising particular components, or a method is described as having, including, or comprising particular steps, it is further contemplated that there are systems encompassed by the inventive subject matter that consist essentially of or consist of the recited components, and there are methods encompassed by the inventive subject matter that consist essentially of or consist of the recited process steps.

[0284] It should be understood that the order of steps or order for performing certain operations is immaterial so long as any embodiment of the subject matter described therein remains operable. Moreover, two or more steps or operations may be conducted simultaneously. The present invention provides, for example, the following items. (Item 1) 1. A method for treating cancer, comprising: The method comprises administering to a subject suffering from an ER-associated cancer a composition that delivers a full estrogen receptor antagonist to the brain of the subject, wherein the subject has been determined to have brain metastasis or is suspected of having brain metastasis. (Item 2) Item 1. The method of item 1, wherein the full estrogen receptor antagonist is GDC-9545. (Item 3) 2. The method of claim 1, wherein the full estrogen receptor antagonist is SAR439859. (Item 4) 2. The method of claim 1, wherein the full estrogen receptor antagonist is AZD9833. (Item 5) The full estrogen antagonist is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, X is -NH-, -CH2-, or -O-; Y is, [ka] and R a is hydrogen or halo, R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen and halo; R 5 is hydrogen or an optionally substituted group selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, and C1-C6 heteroalkyl; R 6 is hydrogen or an optionally substituted group selected from C1-C6 alkyl and C1-C6 haloalkyl; R 7 and R 8 are each independently selected from hydrogen and optionally substituted C1-C6 alkyl. (Item 6) R a is hydrogen. (Item 7) 7. The method according to item 5 or 6, wherein X is -NH- or -O-. (Item 8) 8. The method of claim 7, wherein X is —NH—. (Item 9) 8. The method of claim 7, wherein X is —O—. (Item 10) Y is, [ka] The method according to any one of items 5 to 9, wherein (Item 11) Y is, [ka] The method according to any one of items 5 to 9, wherein (Item 12) R 5 is C1-C6 alkyl or C1-C6 haloalkyl. (Item 13) R 5 is C1-C6 alkyl. (Item 14) R 5 Item 14. The method according to item 13, wherein is n-propyl. (Item 15) R 5 is C1-C6 haloalkyl. (Item 16) R 5 Item 16. The method of claim 15, wherein is -CH2-F or -CH2-CH2-CH2-F. (Item 17) R 5 Item 17. The method according to item 16, wherein is -CH2-F. (Item 18) R 5 Item 17. The method according to item 16, wherein is -CH2-CH2-CH2-F. (Item 19) R 3 and R 4 and each are hydrogen. (Item 20) R 1 and R 2 and each are hydrogen. (Item 21) R 1 and R 2and each is halo. (Item 22) R 1 and R 2 and each is fluoro. (Item 23) R 7 and R 8 is hydrogen and R 7 and R 8 and the other is C1-C6 alkyl. (Item 24) R 7 and R 8 is hydrogen and R 7 and R 8 The method according to item 23, wherein the other is methyl. (Item 25) R 6 25. The method according to any one of items 5 to 24, wherein is optionally substituted C1-C6 alkyl or C1-C6 haloalkyl. (Item 26) R 6 26. The method of claim 25, wherein is optionally substituted C1-C6 alkyl. (Item 27) R 6 27. The method of claim 26, wherein is C1-C6 alkyl substituted with one or more groups selected from halogen and OR°. (Item 28) R 6 28. The method according to item 27, wherein is C1-C6 alkyl substituted with one or more groups selected from halogen and OH. (Item 29) R 6 but, [ka] Item 29. The method according to Item 28, wherein (Item 30) R 6 Item 26. The method according to item 25, wherein is C1-C6 haloalkyl. (Item 31) R 6 but, [ka] Item 31. The method according to Item 30, wherein (Item 32) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 33) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 34) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 35) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 36) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 37) The compound is [ka] or a pharmaceutically acceptable salt thereof. (Item 38) The compound is [ka] Item 33. The method according to Item 32, wherein (Item 39) The compound is [ka] Item 33. The method according to Item 32, wherein (Item 40) 40. The method according to any one of items 1 to 39, wherein the method further comprises administering an anticancer agent. (Item 41) Item 41. The method of item 40, wherein the anticancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor. (Item 42) Item 42. The method of item 41, wherein the anticancer agent is a CDK4 / 6 inhibitor. (Item 43) 43. The method of item 42, wherein the CDK4 / 6 inhibitor is selected from palbococilib, ribociclib, abemaciclib, relociclib, and trilaciclib. (Item 44) 44. The method of item 43, wherein the CDK4 / 6 inhibitor is selected from ribociclib, palbococilib, and abemaciclib. (Item 45) 45. The method of item 44, wherein the CDK4 / 6 inhibitor is ribociclib. (Item 46) Item 42. The method of item 41, wherein the anticancer agent is a PIK3CA inhibitor. (Item 47) 47. The method of claim 46, wherein the PIK3CA inhibitor is selected from alpelisib and taselisib. (Item 48) Item 42. The method of item 41, wherein the anticancer agent is an mTOR inhibitor. (Item 49) 41. The method of claim 40, wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, and everolimus. (Item 50) 50. The method of any one of items 5 to 49, wherein the subject has been previously treated with a selective estrogen receptor modulator. (Item 51) 51. The method of claim 50, wherein the selective estrogen receptor modulator is an estrogen receptor agonist or a partial estrogen receptor agonist. (Item 52) 52. The method of claim 51, wherein the estrogen receptor agonist or partial estrogen receptor agonist is tamoxifen, raloxifene, or toremifene. (Item 53) The full estrogen receptor antagonist is [ka] or a pharmaceutically acceptable salt thereof. (Item 54) The full estrogen receptor antagonist is [ka] or a pharmaceutically acceptable salt thereof. (Item 55) 1. A method of treating metastatic breast cancer in a subject, comprising administering to said subject a full estrogen receptor antagonist, wherein said subject has previously been treated with a selective estrogen receptor modulator. (Item 56) A method for treating cancer in a subject suffering from an ER-associated cancer, wherein the improvement comprises administering to the subject a composition that delivers a full estrogen receptor antagonist to the brain of the subject, wherein the subject has been determined to have or is suspected of having brain metastases. (Item 57) A method of treating cancer in a subject with a full estrogen receptor antagonist, wherein the improvement comprises administering a full estrogen receptor antagonist to the subject, wherein the subject has been determined to have or is suspected of having brain metastases. (Item 58) 1. A method of treating an ER-associated cancer, comprising: The method wherein administering to a population of subjects suffering from brain metastases a composition comprising a full estrogen receptor antagonist reduces or eliminates, on average, said brain metastases. (Item 59) 1. A method of treating a subject suffering from cancer characterized by a mutation in estrogen receptor 1 (ESR1), comprising administering to the subject compound 1: [ka] or a pharmaceutically acceptable salt thereof. (Item 60) 60. The method of item 59, wherein the mutation is an activating mutation. (Item 61) A method for treating a subject suffering from cancer, comprising administering a compound that is an inhibitor of both activation function 1 and activation function 2 of the estrogen receptor. (Item 62) The compound is Compound 1: [ka] 62. The method according to item 61, wherein the medicament is a medicament for treating rhesus malabsorption, or a pharmaceutically acceptable salt thereof. (Item 63) A method of treating a subject suffering from cancer, comprising administering a compound that is an inhibitor of activation function 2 and a second agent that is an inhibitor of activation function 1. (Item 64) the compound is an estrogen receptor antagonist selected from AZD9496, RAD-1901, ARN-810, endoxifen, fulvestrant, and Compound 1; [ka] or a pharmaceutically acceptable salt thereof. (Item 65) Item 65. The method of item 64, wherein the compound is selected from fulvestrant and compound 1. (Item 66) Item 66. The method of item 65, wherein the compound is Compound 1. (Item 67) The method of any one of embodiments 63-65, wherein the secondary agent is a CDK4 / 6 inhibitor. (Item 68) 68. The method of item 67, wherein the CDK4 / 6 inhibitor is selected from palbococilib, ribociclib, abemaciclib, relociclib, and trilaciclib. (Item 69) 69. The method of item 68, wherein the CDK4 / 6 inhibitor is selected from palvocociclib and abemaciclib. (Item 70) 66. The method of any one of items 63 to 65, wherein the secondary agent is a PIK3CA inhibitor. (Item 71) 71. The method of claim 70, wherein the PIK3CA inhibitor is selected from alpelisib and taselisib. (Item 72) 66. The method of any one of items 63 to 65, wherein the secondary agent is an mTOR inhibitor. (Item 73) 73. The method of claim 72, wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, and everolimus. (Item 74) 1. A method of treating a subject suffering from cancer that has metastasized to the brain, bone, lung, or liver, said method comprising administering Compound 1: [ka] or a pharmaceutically acceptable salt thereof. (Item 75) 1. A method of treating a subject suffering from cancer, said method comprising administering to a subject a compound of formula I, [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. (Item 76) 76. The method of claim 75, wherein the amount of the composition administered to the subject is 30 mg / kg or less. (Item 77) 77. The method of claim 76, wherein the amount of the composition administered to the subject is 10 mg / kg or less. (Item 78) 78. The method of claim 77, wherein the amount of the composition administered to the subject is 1 mg / kg or less. (Item 79) 80. The method of claim 78, wherein the amount of the composition administered to the subject is 0.1 mg / kg or less. (Item 80) 80. The method of any one of items 75 to 79, wherein the composition is administered to the subject once daily. (Item 81) 80. The method of any one of items 75 to 79, wherein the composition is administered to the subject once a week. (Item 82) 80. The method of any one of items 75 to 79, wherein the composition is administered to the subject once a month. (Item 83) The method according to any one of Items 75 to 82, wherein the composition is in the form of a unit dosage form. (Item 84) 83. The method according to any one of items 75 to 82, wherein the composition is in the form of a capsule. (Item 85) 83. The method according to any one of items 75 to 82, wherein the composition is in the form of a tablet. (Item 86) 83. The method according to any one of items 75 to 82, wherein the composition is in the form of a solution. (Item 87) The method according to any one of Items 75 to 82, wherein the composition is in the form of a suspension. (Item 88) 88. The method according to any one of items 75 to 87, wherein the cancer is breast cancer. (Item 89) A method for treating an estrogen receptor (ER)-associated disease, disorder, or condition, comprising administering a full estrogen receptor antagonist to the patient's plasma according to a regimen that achieves at least about 30-fold greater accumulation in the tumor than in the plasma. (Item 90) The full estrogen receptor antagonist is Compound 1: [ka] or a pharmaceutically acceptable salt thereof. (Item 91) 1. A method of preventing the metastatic spread of cancer to the brain in a subject, comprising administering to said subject Compound 1: [ka] or a pharmaceutically acceptable salt thereof.

Claims

[Claim 1] The invention described in this specification.

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