Estrogen receptor antagonist dosage forms

Abstract

The present disclosure provides compounds 1, 2, 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, 30, 39, 38, 39 JPEG2026500166000038.jpg48165 or a pharmaceutically acceptable salt thereof. The unit dosage forms described herein are suitable for oral administration. There remains a need for anti-estrogen agents that can completely 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 degraders (SERDs) are particularly useful or promising tools for such treatment.

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Application No. 63 / 431,515, filed December 9, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The estrogen receptor (ER) plays an important role in various cancers, including breast cancer. A variety of treatments have been developed to target the estrogen receptor and / or its activity. Summary of the Invention [Means for solving the problem]

[0003] There remains a need for antiestrogens that can completely 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 degraders (SERDs) are particularly useful or promising tools for such treatment. Recently, a class of estrogen receptor antagonists called complete estrogen receptor antagonists (CERANs) has emerged as a promising treatment for completely inhibiting estrogen receptors. To date, the only CERAN approved for treating estrogen receptor-mediated diseases is fulvestrant. However, fulvestrant is administered parenterally, which is invasive and inconvenient. Therefore, there is a need for CERANs that can be administered orally.

[0004] The compound (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 ("Compound 1"): [ka]

[0005] is a full estrogen receptor antagonist disclosed in PCT Publication No. WO2017 / 059139 (the entire contents of which are incorporated herein by reference), and is designated Compound B. The present application provides unit dosage forms suitable for oral administration of Compound 1 and uses thereof.

[0006] In some embodiments, the present disclosure provides Compound 1: [ka] or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and a disintegrant.

[0007] In some embodiments, the present disclosure provides a granule, the granule comprising Compound 1: [ka] or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and a disintegrant.

[0008] In some embodiments, the present disclosure provides a method of treating an estrogen receptor-mediated disease, disorder, or condition, comprising administering to a subject in need thereof a unit dosage form described herein. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a plot showing the dissolution of tablets of Formulation 1 after exposure to specific conditions for the indicated times.

[0010] [Figure 2A] 1 is a plot showing the dissolution of tablets of Formulation 2 after exposure to certain conditions after one month.

[0011] [Figure 2B] 1 is a plot showing the dissolution of tablets of Formulation 2 after exposure to certain conditions after 3 months. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides a unit dosage form comprising Compound 1 or a pharmaceutically acceptable salt thereof and certain pharmaceutically acceptable excipients suitable for oral administration. This disclosure encompasses, among other things, the insight that formulating Compound 1 into a unit dosage form suitable for oral delivery presents particular challenges due, at least in part, to slow dissolution rates during manufacturing and adhesion and solidification of Compound 1 on roller granulators. Without being bound by theory, it is understood that Compound 1, in its free base form, has a low glass transition temperature (about 70 to about 72°C) and undergoes a physical change when exposed to temperatures above its glass transition temperature. It has been discovered by the present applicants that this glass transition temperature decreases when exposed to certain pharmaceutically acceptable excipients commonly used in formulation development, causing Compound 1 to become rubbery and inworkable. The present disclosure reports the discovery of this problem with Compound 1 and provides a specific solution to this problem.

[0013] definition About or Approximately: As used herein, the term "about" or "approximately," when applied to one or more values ​​of interest, refers to a value similar to a stated reference value. Generally, a person skilled in the art familiar with the context will fully understand the relevant degree of difference encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "about" or "approximately" can encompass a range of values ​​within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the reference value.

[0014] Administration: As used herein, the term "administering" or "administration" typically refers to administration of a composition to a subject to achieve delivery of the composition or agent contained therein to a target site or site to be treated. Those skilled in the art will recognize various routes that may be utilized for administration to a subject, e.g., a human, in appropriate circumstances. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some specific embodiments, administration may be bronchial (e.g., by bronchial instillation), oral, cutaneous (e.g., may be or may include one or more of topical to the epidermis, intradermal, interdermal, transdermal, etc.), intestinal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular (intraventricular), within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some specific embodiments, administration may be intravenous. In some specific embodiments, administration may be subcutaneous. In some embodiments, administration may comprise only a single dose. In some embodiments, administration may comprise the application of a set number of doses. In some embodiments, administration may comprise administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common time period). In some embodiments, administration may comprise continuous administration (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime-and-boost protocol. A prime-and-boost protocol may comprise administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine), followed, after a set time interval, by administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol may result in an increased immune response in a patient.

[0015] Antagonist: As understood by those skilled in the art, the term "antagonist" generally refers to an agent whose presence or level is associated with a decreased level or activity of a target compared to that observed in the absence of the agent (or at a different level of the agent). In some embodiments, an antagonist is one whose presence or level correlates with a level or activity of a target that is equal to or less than a particular reference level or activity (e.g., that observed under appropriate reference conditions, e.g., in the presence of a known antagonist, e.g., a positive control). In some embodiments, an antagonist may be a direct antagonist in that it directly affects (e.g., directly interacts with) the target. In some embodiments, an antagonist may be an indirect antagonist in that it indirectly affects (e.g., by acting on, e.g., interacting with, a regulator or some other component or entity of the target).

[0016] Biological sample: As used herein, the term "biological sample" typically refers to a sample obtained from 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 can be or include bone marrow, blood, blood cells, ascites, tissue or fine needle biopsy samples, cell-containing body fluids, suspended nucleic acids, sputum, saliva, urine, cerebrospinal fluid, peritoneal fluid, pleural effusion, feces, lymph, gynecological fluids, skin swabs, vaginal swabs, oral swabs, nasal swabs, washings or lavage fluids, such as ductal lavage or bronchoalveolar lavage, aspirates, scrapings, bone marrow specimens, tissue biopsy specimens, surgical specimens, feces, other body fluids, secretions, and / or excretions, and / or cells derived therefrom, and the like. In some embodiments, a 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, a sample is a "primary sample" obtained directly from a source of interest by any suitable means. For example, in some embodiments, a 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, stool, etc.), and the like. In some embodiments, as will be clear from the context, the term "sample" refers to a preparation obtained by processing a primary sample (e.g., by removing one or more components thereof and / or adding one or more agents thereto), for example, 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 specific components, etc.

[0017] Carrier: As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle used in administering a composition. In some exemplary embodiments, a carrier can comprise sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, a carrier is or comprises one or more solid ingredients.

[0018] 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 or treatment(s)) simultaneously. In some embodiments, 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 administration of any dose of a second regimen); in some embodiments, such agents are administered within overlapping dosing regimens. In some embodiments, "administration" of a combination therapy may include administering one or more agent(s) or modality(s) in combination to a subject receiving other agent(s) or modality(s). For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even 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 entity).

[0019] Comparable: As used herein, the term "comparable" refers to two or more agents, entities, circumstances, sets of conditions, etc. that are not necessarily identical to one another, but that are sufficiently similar to permit a comparison between them so that one of skill in the art would understand that conclusions can be reasonably drawn based on observed differences or similarities. In some embodiments, equivalent sets of conditions, circumstances, individuals, or populations are characterized by multiple substantially identical characteristics and one or a few diverse characteristics. One of skill in the art will understand the degree of identity required for two or more such agents, entities, circumstances, sets of conditions, etc. to be considered comparable in any given situation in context. For example, one of skill in the art will understand that sets of circumstances, individuals, or populations are equivalent to one another when they are characterized by a sufficient number and type of substantially identical characteristics to warrant a reasonable conclusion that differences in results obtained under or with different sets of circumstances, individuals, or populations, or in observed phenomena, are caused by or indicate variations in the diverse characteristics.

[0020] Composition: Those skilled in the art will understand that the term "composition" can be used to refer to a separate physical entity that includes one or more specified components. Generally, unless otherwise specified, a composition can be in any form, for example, a gas, a gel, a liquid, a solid, etc.

[0021] 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 active agent (e.g., a therapeutic or diagnostic agent) to be administered to a subject. Typically, each such unit contains a predetermined amount of 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., in a therapeutic dosing regimen).

[0022] 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 set (typically two or more) unit doses administered individually, typically spaced apart, to a subject. In some embodiments, a given therapeutic agent has a recommended dosing regimen that can include 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 of the same unit dosage amount. In some embodiments, different doses within a dosing regimen are of 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).

[0023] 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.

[0024] Modulator: As used herein, the term "modulator" refers to a compound (e.g., a small molecule) that can alter the activity of another molecule (e.g., a protein). For example, in some embodiments, a modulator can cause an increase or decrease in the magnitude of a particular activity of a molecule compared to the magnitude of that activity in the absence of the modulator. For example, a modulator can be an agonist or antagonist (as those terms are defined herein) of a particular target. For example, in some embodiments, a modulator is an agonist. In some embodiments, a modulator is an antagonist.

[0025] Oral: As used herein, the phrases "oral administration" and "orally administered" have their art-recognized meaning to refer to administration of a compound or composition by mouth.

[0026] Parenteral: As used herein, the phrases "parenteral administration" and "parenterally administered" have their art-understood meaning referring to modes of administration other than enteral 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, intrathecal, intrathecal, and intrasternal injection and infusion.

[0027] Patient or Subject: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions are or can be administered, e.g., for 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 treatment to diagnose and / or treat a disease, disorder, or condition.

[0028] 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 dosage amount suitable for administration in a treatment or dosing regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition may be specially formulated for administration in solid or liquid form, including oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin, lungs, or oral cavity; vaginal or rectal administration, e.g., as a pessary, cream, or foam; sublingual; ophthalmic; transdermal; or compatible with the nose, lungs, and other mucosal surfaces.

[0029] Pharmaceutically acceptable: As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0030] Pharmaceutically acceptable salt: As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is suitable for use in a pharmaceutical context, i.e., a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / 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).

[0031] Prevent or Prevention: As used herein, the terms "prevent" or "prevention," when used in reference to the occurrence of a disease, disorder, and / or condition, refer to a reduction in the risk of the disease, disorder, and / or condition occurring and / or a delay in the onset of one or more characteristics or symptoms of the disease, disorder, or condition. Prevention may be considered complete when the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0032] 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 the onset, reduce the 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 subjects who do not exhibit symptoms of the disease, disorder, and / or condition. In some embodiments, treatment may be administered to subjects who show 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.

[0033] compound 1 Compound 1, also known as (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 ("Compound 1"): [ka]

[0034] Compound 1 is a full estrogen receptor antagonist disclosed in PCT Publication No. WO2017 / 059139 (incorporated herein by reference in its entirety) and is designated Compound B. Exemplary methods for using Compound 1 are described in PCT Publication Nos. WO2021 / 007146 and WO2021 / 178846, each of which is incorporated herein by reference in its entirety. The synthesis of Compound 1 is detailed in Example 10 of WO2017 / 059139.

[0035] Compound 1 unit dosage form In some embodiments, the present disclosure provides unit dosage forms comprising Compound 1. The present disclosure encompasses, inter alia, the surprising discovery that certain excipients, when used to prepare unit dosage forms comprising Compound 1, provide certain desirable properties and avoid problems associated with other formulations and excipients.

[0036] In attempts to develop formulations of Compound 1, it was discovered that Compound 1, being amorphous, has low bulk and tapped densities and poor flow properties. Furthermore, it was discovered that Compound 1 has a low glass transition temperature and undergoes physical changes when exposed to temperatures above about 70° C. Without being bound by theory, it is understood that Compound 1's glass transition temperature decreases when exposed to certain excipients, which causes Compound 1 to become rubbery and makes it difficult to process and incorporate into pharmaceutical formulations suitable for oral delivery.

[0037] The present disclosure provides specific solutions to problems associated with developing a unit dosage form suitable for oral delivery comprising Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprising Compound 1, or a pharmaceutically acceptable salt thereof, is prepared by direct compression. In some embodiments, the unit dosage form comprises granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, and is prepared by roller compaction.

[0038] Additionally, during development of the unit dosage forms described herein, it was discovered that certain unit dosage forms prepared by granulation / roller compaction methods exhibit slow dissolution after storage, particularly when stored at elevated temperatures and humidity. These properties are demonstrated, for example, in Example 2 herein.

[0039] The present disclosure, among other things, solves problems associated with preparing formulations of Compound 1, in some embodiments avoiding the need to use roller granulators and granulation processes, and further surprisingly provides a unit dosage form that exhibits improved stability compared to other formulations of Compound 1. For example, Applicants have discovered that not only reducing the weight percent of Compound 1 in a unit dosage form, but also increasing the amount of a first diluent, e.g., a water-soluble diluent, while simultaneously decreasing the amount of a less water-soluble second diluent, provides a unit dosage form that exhibits acceptable properties and avoids the problems associated with previous formulations.

[0040] Dry Powder Blend Formulation In some embodiments, the present disclosure provides Compound 1: [ka] or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and a disintegrant.

[0041] In some embodiments, the unit dosage form contains about 10% to about 20% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. As used herein, unless otherwise specified, the weight of Compound 1, when incorporated into the unit dosage form described herein, is calculated according to the weight of its free base, regardless of whether Compound 1 is incorporated into the unit dosage form as the free base or as a salt form. It is understood that the molecular weight of Compound 1 as the free base is lower than that of a salt of Compound 1. Those skilled in the art will readily understand how to determine the amount of Compound 1 in the unit dosage forms described herein by using the weight of the free base of Compound 1, regardless of the form in which Compound 1 is used.

[0042] Additionally, references to weight percentages of unit dosage forms described herein do not include the weight of any coatings, i.e., the weight percentages described herein refer to the combination of active ingredient (e.g., Compound 1) and pharmaceutically acceptable excipients, excluding any coatings.

[0043] In some embodiments, the unit dosage form comprises about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, the unit dosage form comprises about 10% by weight to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, the unit dosage form comprises about 10% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, the unit dosage form comprises about 11% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, the unit dosage form comprises about 12% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, the unit dosage form comprises about 13% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprises about 14% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprises about 15% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the unit dosage form contains about 10 mg to about 120 mg of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form contains about 20 mg to about 90 mg of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form contains about 20 mg to about 60 mg of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof. In some embodiments, the unit dosage form comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg of the compound, calculated as the free base, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, Compound 1 is the free base form of Compound 1.

[0046] In some embodiments, the unit dosage form comprises about 10% to about 80% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 20% to about 70% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 30% to about 70% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 40% to about 70% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 50% to about 65% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 55% to about 65% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 50% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 55% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 60% by weight of the first diluent. In some embodiments, the unit dosage form comprises about 65% by weight of the first diluent.

[0047] In some embodiments, the first diluent is selected from lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the first diluent is selected from lactose monohydrate, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the first diluent is selected from lactose monohydrate and calcium phosphate. In some embodiments, the first diluent is lactose monohydrate. In some embodiments, the first diluent is microcrystalline cellulose. In some embodiments, the first diluent is mannitol. In some embodiments, the first diluent is calcium phosphate (e.g., calcium phosphate (dibasic)). In some embodiments, the first diluent is lactose anhydrous. In some embodiments, the first diluent is calcium silicate. In some embodiments, the first diluent is pregelatinized starch.

[0048] In some embodiments, the unit dosage form comprises about 40% to about 70% lactose monohydrate by weight. In some embodiments, the unit dosage form comprises about 50% to about 65% lactose monohydrate by weight. In some embodiments, the unit dosage form comprises about 60% lactose monohydrate by weight. In some embodiments, the unit dosage form comprises about 55% to about 65% lactose monohydrate by weight. In some embodiments, the unit dosage form comprises about 40% to about 70% calcium phosphate by weight. In some embodiments, the unit dosage form comprises about 50% to about 65% calcium phosphate by weight. In some embodiments, the unit dosage form comprises about 55% to about 65% calcium phosphate by weight. In some embodiments, the unit dosage form comprises about 60% calcium phosphate by weight.

[0049] In some embodiments, the unit dosage form comprises about 10% to about 20% by weight of the second diluent. In some embodiments, the unit dosage form comprises about 15% to about 20% by weight of the second diluent. In some embodiments, the unit dosage form comprises about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of the second diluent. In some embodiments, the unit dosage form comprises about 18% to about 20% by weight of the second diluent. In some embodiments, the unit dosage form comprises about 18.0%, about 18.5%, about 19.0%, about 19.5%, or about 20.0% by weight of the second diluent.

[0050] In some embodiments, the second diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the second diluent is selected from the group consisting of microcrystalline cellulose, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the second diluent is microcrystalline cellulose. In some embodiments, the second diluent is microcrystalline cellulose having an average particle size of about 180 μm. In some embodiments, the second diluent is lactose monohydrate. In some embodiments, the second diluent is calcium phosphate. In some embodiments, the second diluent is lactose anhydrous. In some embodiments, the second diluent is calcium silicate. In some embodiments, the second diluent is pregelatinized starch.

[0051] In some embodiments, the unit dosage form comprises about 15% to about 20% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 15% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 16% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 17% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 18% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 18.5% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 19% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 19.5% by weight of microcrystalline cellulose. In some embodiments, the unit dosage form comprises about 20% by weight of microcrystalline cellulose.

[0052] In some embodiments, the weight ratio of the first diluent to the second diluent in the unit dosage form is about 3: 1 to about 4: 1. In some embodiments, the weight ratio of the first diluent to the second diluent is about 3: 1, about 3.1: 1, about 3.15: 1, about 3.2: 1, about 3.25: 1, about 3.3: 1, about 3.35: 1, about 3.4: 1, about 3.45: 1, about 3.5: 1, about 3.55: 1, about 3.6: 1, about 3.65: 1, about 3.7: 1, about 3.75: 1, about 3.8: 1, about 3.85: 1, about 3.9: 1, 3.95: 1, or about 4: 1.

[0053] In some embodiments, the first diluent and the second diluent are different.

[0054] In some embodiments, the unit dosage form contains about 5% to about 10% disintegrant by weight. In some embodiments, the unit dosage form contains about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% disintegrant by weight. In some embodiments, the unit dosage form contains about 5% disintegrant. In some embodiments, the unit dosage form contains about 6% disintegrant. In some embodiments, the unit dosage form contains about 7% disintegrant. In some embodiments, the unit dosage form contains about 8% disintegrant. In some embodiments, the unit dosage form contains about 9% disintegrant. In some embodiments, the unit dosage form contains about 10% disintegrant.

[0055] In some embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the unit dosage form comprises about 5% to about 10% by weight of croscarmellose sodium. In some embodiments, the unit dosage form comprises about 5% to about 10% by weight of sodium starch glycolate.

[0056] In some embodiments, the unit dosage form comprises about 10% to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 10% to about 80% by weight of a first diluent, about 10% to about 20% by weight of a second diluent, and about 5% to about 10% by weight of a disintegrant. In some embodiments, the unit dosage form comprises about 10% to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 40% to about 70% by weight of a first diluent, about 10% to about 20% by weight of a second diluent, and about 5% to about 10% by weight of a disintegrant.

[0057] In some embodiments, the unit dosage form comprises about 10% to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 10% to about 80% by weight of lactose monohydrate, about 10% to about 20% by weight of microcrystalline cellulose, and about 5% to about 10% by weight of croscarmellose sodium. In some embodiments, the unit dosage form comprises about 10% to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, about 40% to about 70% by weight of lactose monohydrate, about 10% to about 20% by weight of microcrystalline cellulose, and about 5% to about 10% by weight of croscarmellose sodium, calculated as the free base.

[0058] In some embodiments, the unit dosage form comprises about 12% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 60% by weight of a first diluent, about 19% by weight of a second diluent, and about 8% by weight of a disintegrant.

[0059] In some embodiments, the unit dosage form comprises about 12% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 60% by weight of lactose monohydrate, about 19% by weight of microcrystalline cellulose, and about 8% by weight of croscarmellose sodium.

[0060] In some embodiments, the unit dosage form further comprises a lubricant. In some embodiments, the unit dosage form comprises from about 0.1% to about 1.5% by weight of a lubricant. In some embodiments, the unit dosage form comprises from about 0.5% to about 1.5% by weight of a lubricant. In some embodiments, the unit dosage form comprises about 0.5%, about 1.0%, or about 1.5% by weight of a lubricant.

[0061] In some embodiments, the lubricant is selected from the group consisting of magnesium stearate and sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the unit dosage form comprises from about 0.1% to about 1.5% by weight of the lubricant. In some embodiments, the unit dosage form comprises from about 0.5% to about 1.5% by weight of the lubricant. In some embodiments, the unit dosage form comprises from about 0.5%, about 1.0%, or about 1.5% by weight of the lubricant. In some embodiments, the unit dosage form comprises from about 0.5% to about 1.5% by weight of the magnesium stearate. In some embodiments, the unit dosage form comprises from about 0.5%, about 1.0%, or about 1.5% by weight of the magnesium stearate.

[0062] In some embodiments, the unit dosage form comprises about 0.1% to about 1% by weight of a glidant. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide.

[0063] In some embodiments, the unit dosage form comprises about 12% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, about 60% by weight of lactose monohydrate, about 19% by weight of microcrystalline cellulose, about 8% by weight of croscarmellose sodium, about 0.5% by weight of silicon dioxide, and about 1% by weight of magnesium stearate.

[0064] In some embodiments, the unit dosage form is in the form of a tablet. In some embodiments, the unit dosage form is a dry powder blend. In some embodiments, the unit dosage form is prepared by a direct compression process. In some embodiments, the unit dosage form is a tablet prepared by direct compression of a dry powder blend. In some embodiments, the unit dosage forms described herein do not include granules. In some embodiments, the unit dosage form is a tablet comprising a film coating.

[0065] The unit dosage forms claimed herein exhibit improved stability and solubility compared to alternative formulations. For example, in some embodiments, the unit dosage forms described herein are characterized by about 80% or greater dissolution in about 30 minutes or less (e.g., about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes) using conditions for assessing dissolution known to those of skill in the art. For example, in some embodiments, suitable conditions for assessing dissolution include USP Apparatus 2 (paddle) at 75 RPM in 900 mL of 50 mM citrate buffer (pH 3.5) containing 0.1% sodium lauryl sulfate maintained at 37±0.5°C, or USP Apparatus 1 (basket) at 50 RPM in 500 mL of 0.01 N HCl maintained at 37±0.5°C.

[0066] Granule formulation In some embodiments, the unit dosage forms described herein comprise granules, the granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and a disintegrant. In some embodiments, the unit dosage forms comprise granules and one or more extragranular excipients.

[0067] In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 20% of the total weight of the unit dosage form, calculated as the free base of Compound 1. As used herein, references to weight percentages refer to the weight percentage of that particular component relative to the total weight of the unit dosage form (e.g., the combination of intragranular and extragranular components), not just the granule itself.

[0068] In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 16% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 17% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 18% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 19% of the total weight of the unit dosage form, calculated as the free base of Compound 1. In some embodiments, the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 20% of the total weight of the unit dosage form, calculated as the free base of Compound 1.

[0069] In some embodiments, the granules comprise the first diluent in an amount of about 5% to about 20% of the total weight of the unit dosage form, hi some embodiments, the granules comprise the first diluent in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of the total weight of the unit dosage form.

[0070] In some embodiments, the first diluent is selected from lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the first diluent is selected from lactose monohydrate and calcium phosphate. In some embodiments, the first diluent is lactose monohydrate. In some embodiments, the first diluent is microcrystalline cellulose. In some embodiments, the first diluent is mannitol. In some embodiments, the first diluent is calcium phosphate (e.g., calcium phosphate (dibasic)). In some embodiments, the first diluent is lactose anhydrous. In some embodiments, the first diluent is calcium silicate. In some embodiments, the first diluent is pregelatinized starch.

[0071] In some embodiments, the granules comprise the second diluent in an amount of about 50% to about 70% of the total weight of the unit dosage form. In some embodiments, the granules comprise the second diluent in an amount of about 50% to about 60% of the total weight of the unit dosage form. In some embodiments, the granules comprise the second diluent in an amount of about 50%, about 50.5%, about 51%, about 51.5%, about 52%, about 52.5%, about 53%, about 53.5%, about 54%, about 54.5%, about 55%, about 55.5%, about 56%, about 56.5%, about 57%, about 57.5%, about 58%, about 58.5%, about 59%, about 59.5%, or about 60% of the total weight of the unit dosage form.

[0072] In some embodiments, the second diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the second diluent is selected from the group consisting of microcrystalline cellulose, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. In some embodiments, the second diluent is microcrystalline cellulose. In some embodiments, the second diluent is lactose monohydrate. In some embodiments, the second diluent is calcium phosphate. In some embodiments, the second diluent is lactose anhydrous. In some embodiments, the second diluent is calcium silicate. In some embodiments, the second diluent is pregelatinized starch.

[0073] In some embodiments, the granules comprise disintegrant in an amount of about 1% to about 5% of the total weight of the unit dosage form. In some embodiments, the granules comprise disintegrant in an amount of about 1% of the total weight of the unit dosage form. In some embodiments, the granules comprise disintegrant in an amount of about 2% of the total weight of the unit dosage form. In some embodiments, the granules comprise disintegrant in an amount of about 3% of the total weight of the unit dosage form. In some embodiments, the granules comprise disintegrant in an amount of about 4% of the total weight of the unit dosage form. In some embodiments, the granules comprise disintegrant in an amount of about 5% of the total weight of the unit dosage form.

[0074] In some embodiments, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is croscarmellose sodium.

[0075] In some embodiments, the unit dosage forms described herein comprise granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 20% of the total weight of the unit dosage form; a first diluent in an amount of about 5% to about 20% of the total weight of the unit dosage form; a second diluent in an amount of about 50% to about 70% of the total weight of the unit dosage form; and a disintegrant in an amount of about 1% to about 5% of the total weight of the unit dosage form.

[0076] In some embodiments, the granules further comprise a lubricant. In some embodiments, the lubricant is magnesium stearate or sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the granules comprise a lubricant in an amount of about 0.1% to about 3% of the total weight of the unit dosage form.

[0077] In some embodiments, the granules further comprise a glidant. In some embodiments, the granules comprise the glidant in an amount of about 1% to about 5% of the total weight of the unit dosage form. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is colloidal silicon dioxide.

[0078] In some embodiments, the unit dosage form comprises one or more extragranular excipients selected from the group consisting of lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, pregelatinized starch, magnesium stearate, sodium stearyl fumarate, sodium starch glycolate, croscarmellose sodium, sodium chloride, and potassium chloride.

[0079] In some embodiments, the unit dosage form comprises granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, in an amount of about 15% to about 20% of the total weight of the unit dosage form; a first diluent in an amount of about 5% to about 20% of the total weight of the unit dosage form; a second diluent in an amount of about 50% to about 70% of the total weight of the unit dosage form; and a disintegrant in an amount of about 1% to about 5% of the total weight of the unit dosage form.

[0080] In some embodiments, the unit dosage form comprises granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, in an amount of about 15% to about 20% of the total weight of the unit dosage form; lactose monohydrate in an amount of about 5% to about 20% of the total weight of the unit dosage form; microcrystalline cellulose in an amount of about 50% to about 70% of the total weight of the unit dosage form; and sodium starch glycolate in an amount of about 1% to about 5% of the total weight of the unit dosage form.

[0081] In some embodiments, the unit dosage form comprises granules comprising Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, in an amount of about 18% of the total weight of the unit dosage form, lactose monohydrate in an amount of about 10% of the total weight of the unit dosage form, microcrystalline cellulose in an amount of about 56.5% of the total weight of the unit dosage form, and sodium starch glycolate in an amount of about 3% of the total weight of the unit dosage form.

[0082] In some embodiments, the unit dosage form comprises granules and one or more extragranular excipients, wherein the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base, in an amount of about 18% of the total weight of the unit dosage form; lactose monohydrate in an amount of about 10% of the total weight of the unit dosage form; microcrystalline cellulose in an amount of about 56.5% of the total weight of the unit dosage form; sodium starch glycolate in an amount of about 3% of the total weight of the unit dosage form; and the one or more extragranular excipients are selected from microcrystalline cellulose, sodium starch glycolate, magnesium stearate, and combinations thereof.

[0083] In some embodiments, the unit dosage form further comprises a coating.

[0084] In some embodiments, the unit dosage form is in the form of a tablet. In some embodiments, the tablet is prepared by roller compaction.

[0085] use The unit dosage forms described herein are generally useful for inhibiting estrogen receptor (ER) and its variants. In some embodiments, the present disclosure encompasses the insight that the unit dosage forms described herein are useful for treating estrogen receptor (ER)-associated disorders (e.g., ER-associated cancers such as breast cancer, including metastatic brain cancer), detecting the disorder, and / or characterizing specific tumors.

[0086] For example, in some embodiments, the present disclosure provides specific methods of treatment in a subject having an ER-associated disease, disorder, or condition. In some embodiments, the ER-associated disease, disorder, or condition is cancer. In some embodiments, the ER-associated disease, disorder, or condition is selected from breast cancer, bone cancer, lung cancer, colon cancer, endometrial cancer, prostate cancer, ovarian cancer, vaginal cancer, endometriosis, and uterine cancer. In some embodiments, the ER-associated disease, disorder, or condition is breast cancer.

[0087] In some embodiments, the subject has been determined to have or is suspected of having cancer that has metastasized (e.g., to the brain, bone, lung, liver, or central nervous system). In some embodiments, the subject has been determined to have or is suspected of having brain metastases. In some embodiments, the subject has developed an ER-associated cancer, e.g., breast cancer, or brain metastases associated with mutations in the estrogen receptor.

[0088] In some embodiments, provided methods comprise administering a unit dosage form described herein to a subject who has been previously treated with another ER inhibitor. In some such embodiments, provided methods comprise administering a unit dosage form described herein to a subject who has been previously treated with a selective estrogen receptor modulator (SERM), including, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0089] In some embodiments, provided methods include administering a unit dosage form described herein to a subject suffering from an ER-associated disorder (e.g., breast cancer) that has not responded to treatment with a SERM, including, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0090] In some embodiments, the subject relapsed during or after treatment with a SERM, including, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0091] In some embodiments, provided methods comprise administering a unit dosage form described herein to a subject with estrogen receptor positive (ER+) and human epidermal growth factor receptor negative (HER-) disease. In some embodiments, provided methods comprise administering a unit dosage form described herein to a subject with estrogen receptor positive (ER+) and human epidermal growth factor receptor negative (HER+) disease.

[0092] In some embodiments, the unit dosage forms described herein are administered to a subject such that the subject receives about 15 mg to about 360 mg of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. In some embodiments, about 30 mg to about 360 mg of Compound 1 is administered to the subject. In some embodiments, about 30 mg to about 300 mg of Compound 1 is administered to the subject. In some embodiments, about 60 mg to about 120 mg of Compound 1 is administered to the subject. In some embodiments, about 15 mg to about 100 mg of Compound 1 is administered to the subject. In some embodiments, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of Compound 1 is administered to the subject. In some embodiments, an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg of Compound 1 is administered to a subject. In some embodiments, an amount of about 20 mg of Compound 1 is administered to a subject. In some embodiments, an amount of about 30 mg of Compound 1 is administered to a subject. In some embodiments, an amount of about 60 mg of Compound 1 is administered to a subject. In some embodiments, an amount of about 90 mg of Compound 1 is administered to a subject. In some embodiments, an amount of about 120 mg of Compound 1 is administered to a subject.

[0093] In some embodiments, the unit dosage forms described herein are administered such that about 15 mg to about 360 mg (QD) of Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject per day, calculated as the free base. In some embodiments, about 20 mg to about 360 mg (QD) of Compound 1 is administered to a subject per day. In some embodiments, about 30 mg to about 300 mg (QD) of Compound 1 is administered to a subject per day. In some embodiments, about 60 mg to about 120 mg (QD) of Compound 1 is administered to a subject per day. In some embodiments, about 15 mg to about 100 mg QD of Compound 1 is administered to a subject. In some embodiments, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg QD of Compound 1 is administered to a subject. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg, about 150 mg, about 210 mg, or about 300 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 90 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg QD.

[0094] Combination therapy In some embodiments, the unit dosage forms described herein are administered to a subject suffering from a disease, disorder, or condition described herein in combination with a second anti-cancer agent, hi some embodiments, the second anti-cancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

[0095] In some embodiments, the second anti-cancer agent is a CDK4 / 6 inhibitor (i.e., an agent that inhibits one or both of CDK4 and CDK6). In some embodiments, the second anti-cancer agent is a CDK4 / 6 inhibitor selected from palbociclib, ribociclib, abemaciclib, relociclib, trilaciclib, and SHR6390. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. 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 CDK 4 / 6 inhibitor is SHR6390.

[0096] In some embodiments, the second anti-cancer 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.

[0097] In some embodiments, the second anti-cancer 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.

[0098] In some embodiments, the second anti-cancer agent is a HER2 inhibitor, hi some embodiments, the HER2 inhibitor is selected from tucatinib, pertuzumab, lapatinib, trastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, and neratinib.

[0099] It is understood that combination therapies comprising a full estrogen receptor antagonist and an anti-cancer agent described herein can include simultaneous or separate administration of the agents. For example, in some embodiments, the full estrogen receptor antagonist and the anti-cancer agent are administered simultaneously. In some embodiments, the anti-cancer agent is administered prior to administration of the full estrogen receptor antagonist. In some embodiments, the anti-cancer agent is administered after administration of the full estrogen receptor antagonist. Illustrative Embodiments Embodiment 1. Compound 1: [ka] or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and A unit dosage form comprising a disintegrant. Embodiment 2. 2. The unit dosage form of embodiment 1, wherein the unit dosage form comprises about 10% to about 20% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. Embodiment 3. 3. The unit dosage form of embodiment 1 or 2, wherein the unit dosage form comprises about 10% to about 15% by weight of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. Embodiment 4. 4. The unit dosage form of any one of embodiments 1 to 3, wherein the unit dosage form comprises about 10% to about 80% by weight of the first diluent. Embodiment 5. 5. The unit dosage form of any one of embodiments 1 to 4, wherein the unit dosage form comprises about 10% to about 20% by weight of the second diluent. Embodiment 6. 6. The unit dosage form of any one of embodiments 1 to 5, wherein the weight ratio of the first diluent to the second diluent is from about 3:1 to about 4:1. Embodiment 7. 7. The unit dosage form of any one of embodiments 1-6, wherein the first diluent and the second diluent are different. Embodiment 8. 8. The unit dosage form of any one of embodiments 1 to 7, wherein the unit dosage form comprises about 5% to about 10% by weight of the disintegrant. Embodiment 9. 9. The unit dosage form of any one of embodiments 1-8, wherein the first diluent is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. Embodiment 10. 10. The unit dosage form of any one of embodiments 1-9, wherein the first diluent is selected from the group consisting of lactose monohydrate and mannitol. Embodiment 11. 11. The unit dosage form of any one of embodiments 1-10, wherein the first diluent is lactose monohydrate. Embodiment 12. 12. The unit dosage form of any one of embodiments 1-11, wherein the second diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. Embodiment 13. 13. The unit dosage form of any one of embodiments 1-12, wherein the second diluent is microcrystalline cellulose. Embodiment 14. 14. The unit dosage form of any one of embodiments 1-13, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose. Embodiment 15. 15. The unit dosage form of any one of embodiments 1-14, wherein the disintegrant is croscarmellose sodium. Embodiment 16. The unit dosage form comprises: about 12% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof; about 60% by weight of said first diluent; about 19% by weight of said second diluent; and 16. The unit dosage form of any one of embodiments 1-15, comprising about 8% by weight of said disintegrant. Embodiment 17. 17. The unit dosage form of any one of embodiments 1 to 16, further comprising a lubricant. Embodiment 18. 18. The unit dosage form of embodiment 17, wherein the unit dosage form comprises from about 0.1% to about 1.5% by weight of the lubricant. Embodiment 19. 19. The unit dosage form of embodiment 17 or 18, wherein the lubricant is magnesium stearate. Embodiment 20. 20. The unit dosage form of any one of embodiments 1-19, wherein the unit dosage form comprises from about 20 mg to about 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof, calculated as the free base. Embodiment 21. 21. The unit dosage form according to any one of embodiments 1 to 20, which is in the form of a tablet. Embodiment 22. 22. The unit dosage form of any one of embodiments 1-21, wherein the unit dosage form exhibits greater than 80% dissolution in about 30 minutes or less when stored at 40°C / 75% RH for one month or more, using appropriate dissolution conditions. Embodiment 23. granules, said granules comprising Compound 1: [ka] or a pharmaceutically acceptable salt thereof, a first diluent, a second diluent, and A unit dosage form comprising a disintegrant. Embodiment 24. 24. The unit dosage form of embodiment 23, wherein the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 20% of the total weight of the unit dosage form, calculated as the free base of Compound 1. Embodiment 25. 25. The unit dosage form of embodiment 23 or 24, wherein the granules comprise the first diluent in an amount of about 5% to about 20% of the total weight of the unit dosage form. Embodiment 26. 26. The unit dosage form of any one of embodiments 23-25, wherein the granules comprise the second diluent in an amount of about 50% to about 60% of the total weight of the unit dosage form. Embodiment 27. 27. The unit dosage form of any one of embodiments 23-26, wherein the granules comprise the disintegrant in an amount of about 1% to about 5% of the total weight of the unit dosage form. Embodiment 28. 28. The unit dosage form of any one of embodiments 23-27, wherein the first diluent is selected from lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. Embodiment 29. 29. The unit dosage form of any one of embodiments 23-28, wherein the second diluent is selected from microcrystalline cellulose, lactose monohydrate, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch. Embodiment 30. 30. The unit dosage form of any one of embodiments 23-29, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose. Embodiment 31. 31. The unit dosage form of any one of embodiments 23-30, further comprising one or more extragranular excipients. Embodiment 32. 32. The unit dosage form according to any one of embodiments 23 to 31, in the form of a tablet. Embodiment 33. A method of treating an estrogen receptor-mediated disease, disorder, or condition, comprising administering to a subject in need thereof a unit dosage form of any one of embodiments 1-32. Embodiment 34. 34. The method of embodiment 33, wherein said estrogen receptor-mediated disease, disorder, or condition is cancer. Embodiment 35. 35. The method of embodiment 34, wherein the cancer is breast cancer. Embodiment 36. 35. The method of embodiment 34, wherein the cancer is breast cancer that has metastasized to the lung, liver, bone, or brain. Embodiment 37. The method of any one of embodiments 33-36, further comprising administering a second anti-cancer agent. Embodiment 38. 38. The method of embodiment 37, wherein the second anti-cancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor. Embodiment 39. 39. The method of embodiment 38, wherein the second anti-cancer agent is a CDK4 / 6 inhibitor. Embodiment 40. 40. The method of embodiment 39, wherein said CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, relociclib, trilaciclib, and SHR6390. Embodiment 41. 39. The method of embodiment 38, wherein the second anti-cancer agent is a PIK3CA inhibitor. Embodiment 42. The method of embodiment 41, wherein the PIK3CA inhibitor is selected from the group consisting of alpelisib, taselisib, and LY3023414. Embodiment 43. 39. The method of embodiment 38, wherein the second anti-cancer agent is an mTOR inhibitor. Embodiment 44. 44. The method of embodiment 43, wherein said mTOR inhibitor is selected from the group consisting of sirolimus, temsirolimus, everolimus, and LY3023414. Embodiment 45. 39. The method of embodiment 38, wherein the second anti-cancer agent is a HER2 inhibitor. Embodiment 46. 46. ​​The method of embodiment 45, wherein said HER2 inhibitor is selected from the group consisting of tucatinib, pertuzumab, lapatinib, trastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, and neratinib. [Example]

[0100] Certain abbreviations are used in this Examples section, as shown in the table below. [Table 1]

[0101] Example 1 - Development of a Unit Dosage Form of Compound 1 This example describes a unit dosage form of (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 ("Compound 1"). [ka]

[0102] Example 1a - Granules of Compound 1 The initial formulation (Formulation 1) was prepared by a granulation process. [Table 2]

[0103] Tablets of Formulation 1 were prepared by the following process: Compound 1 and microcrystalline cellulose were blended and screened through 20 mesh. The screened material was blended with lactose, colloidal silicon dioxide, and sodium starch glycolate, which had been individually prescreened through 20 mesh. The blend was then blended with magnesium stearate, which had been prescreened through 30 mesh. In-process blend homogeneity samples were collected from three predetermined locations within the blender. Once blend homogeneity was confirmed, the intragranular blend was roller-compacted to produce ribbons, which were then rolled in a Comil mill to produce granules. The extragranular microcrystalline cellulose and sodium starch glycolate were then screened through 20 mesh and blended with the intragranular ones. The blend was then blended with magnesium stearate, which had been prescreened through 30 mesh. In-process control blend homogeneity samples were collected from three predetermined locations within the blender. Once the homogeneity of the blend is confirmed, the blend is compressed into tablets using circular dies for 20 mg tablets or oval dies for 60 mg tablets. After compression, the tablets are passed through a duster and metal checker.

[0104] The tablets are film coated in a coating pan with Opadry AMB II white dispersion to a target core tablet weight gain of 5% by weight.

[0105] Example 1b - Direct Compression Formulation of Compound 1 Formulation 2 is prepared by a direct compression process and is a unit dosage form having the following ingredients: [Table 3]

[0106] Formulation 2 tablets were manufactured using a dry blend / direct compression process. A step-by-step description of the manufacturing process is provided below.

[0107] Lactose monohydrate, microcrystalline cellulose / colloidal silicon dioxide, croscarmellose sodium and magnesium stearate were individually screened through an appropriate mesh (eg, a 30 mesh screen).

[0108] Compound 1 was added to a blender (e.g., a tote blender) along with approximately equal amounts of prescreened lactose monohydrate and mixed in. The Compound 1 / lactose monohydrate mixture was then passed through a suitable mill (e.g., a Comil mill fitted with a 30 mesh mesh).

[0109] The prescreened microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and lactose monohydrate / Compound 1 mixture was transferred to a blender (e.g., a tote blender) and mixed. The mixed mixture was passed through a suitable mill (e.g., a Comil mill fitted with a 30 mesh mesh).

[0110] The above blended mixture and prescreened magnesium stearate were transferred to a blender (e.g., a tote blender) and mixed. In-process blend homogeneity samples were collected from five predetermined locations within the blender and analyzed. The blend was compressed into core tablets using an oval die. After compression, the tablets were passed through a duster and a metal checker.

[0111] The tablets were film coated in a coating pan with Opadry AMB II white dispersion to a target core tablet weight gain of 5% by weight.

[0112] Example 2 - Stability and Dissolution Testing of Unit Dosage Forms Containing Compound 1 Tablets of Formulation 1 and Formulation 2 were subjected to stability testing to test the dissolution characteristics of the tablets under various test conditions. The tablets were analyzed by the methods provided herein.

[0113] HPLC retention time, assay, and organic impurities The tablets were evaluated by high performance liquid chromatography (HPLC) using an HPLC system equipped with a UV-VIS detector under the conditions provided in the table below. Compound 1 elutes at approximately 23-25 ​​minutes. Impurities greater than 0.05% are reported. [Table 4]

[0114] Content uniformity The HPLC conditions for assessing content uniformity are provided in the table below. The analysis was performed using an HPLC system equipped with a UV-VIS detector. Compound 1 elutes at approximately 1.7 minutes. [Table 5]

[0115] Dissolution The conditions for assessing the dissolution of the example tablets are provided in the table below for Formulation 1 and Formulation 2. Dissolution test analysis was performed by the HPLC method provided below. [Table 6] [Table 7] [Table 8]

[0116] Example 2a - Stability and Dissolution Data Formulation 1 In the following examples, 20 mg and 60 mg tablets were tested in heat-sealed, child-resistant lidded HDPE bottles containing 2 g desiccant canisters and subjected to the conditions shown in the table below. [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14]

[0117] Figure 1 is a plot showing the dissolution of tablets of Formulation 1 after exposure to specific conditions at the times indicated. As can be seen, under the conditions provided above, for example, dissolution in 500 mL of 0.01 N HCl using USP Apparatus 1 (basket) at 50 RPM, approximately 80% of Compound 1 dissolved after approximately 45 minutes and maintained at 37±0.5°C.

[0118] Example 2b - Stability and Dissolution Data Formulation 2 In the following examples, tablets were tested in HDPE bottles with heat-sealed, child-resistant lids containing 2g desiccant canisters and subjected to the conditions shown in the table below. [Table 15] [Table 16] [Table 17]

[0119] Figure 2A is a plot showing the dissolution of tablets of Formulation 2 after exposure to specific conditions after one month. As can be seen from the figure, under the conditions provided above, for example, using USP Apparatus 2 (paddles) at 75 RPM in 900 mL of 50 mM citrate buffer (pH 3.5) containing 0.1% sodium lauryl sulfate, approximately 80% or more of Compound 1 dissolved after about 10 minutes and maintained at 37±0.5°C. Figure 2B is a plot showing the dissolution of tablets of Formulation 2 after exposure to specific conditions after three months. As can be seen from the figure, under the conditions provided above, for example, using USP Apparatus 2 (paddles) at 75 RPM in 900 mL of 50 mM citrate buffer (pH 3.5) containing 0.1% sodium lauryl sulfate, approximately 80% or more of Compound 1 dissolved after about 10 minutes and maintained at 37±0.5°C.

[0120] Example 3 - Synthesis of Compound 1 The complete synthesis of Compound 1 is provided in PCT Publication No. WO2017 / 059139, which is incorporated herein by reference and repeated below. Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde: [ka] Step 1: Preparation of 1-propionylazetidin-3-one [ka]

[0121] 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. 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 solid was rinsed with EA (2 × 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) and then 0–10% MeOH over 15 min. The product desorbed from the column early with DCM and continued to elute from the column up to 10% MeOH. TLC was performed with both solvent systems to determine whether any propionyl chloride was present in the early fractions. Product-containing fractions were pooled and concentrated to give the title compound as a yellow liquid (11.610 g, 98.2%).

[0122] 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). Step 2. Preparation of 1-propionylazetidin-3-ol [ka]

[0123] Lithium aluminum hydride (10.397 g, 273.9 mmol, 3.0 equiv) was suspended in THF (200 mL) and cooled in an ice bath. A solution of 1-propionylazetidin-3-one (11.610 g, 91.3 mmol, 1.0 equiv) in THF (100 mL) was added dropwise to the reaction mixture via a pressure-equalizing addition funnel over 30 minutes. 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 portions over 20 minutes. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The mixture was filtered through a 2 cm bed of Celite®, and the solid was rinsed with EA (2 x 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 in the preparation of the following example compounds without further purification.

[0124] 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). Step 3. Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde [ka]

[0125] 4-Fluorobenzaldehyde (15.00 g, 120.9 mmol, 0.9 equiv.), 1-propylazetidin-3-ol (15.00 g, 130.2 mmol, 1.0 equiv.), cesium carbonate (88.40 g, 271.3 mmol, 2.1 equiv.), and N,N-dimethylformamide (284 mL) were mixed together in a 500 mL round-bottom flask with a Teflon® stir bar. The flask was sealed and heated in a heat block at 95° C. for 6 hours. Analysis of the reaction by LCMS indicated that the aldehyde had been consumed. The suspension was filtered through a sintered glass funnel, and the solid was washed with ethyl acetate (100 mL). The filtrate was concentrated to an orange suspension. The suspension was mixed with water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with water (3×200 mL), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to an orange liquid (21.74 g, 76.1%), which was used without further purification.

[0126] 1 HNMR(300MHz,CDCl3),δ 9.87(s,1H),7.82(d,J=9.0Hz,2H),6.86(d,J=8.7Hz,2H),4.86(quintet,J=5.7Hz,1H),3.85-3 .80(m,2H),3.13-3.08(m,2H),2.48(t,J=7.2Hz,2H),1.46-1.34(m,2H),0.91(t,J=7.2Hz,3H). Preparation of (R)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine: [ka]

[0127] 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) at 25 °C under N2, and the mixture was stirred for 1 h. The reaction was cooled to 0-5 °C, and sodium triacetoxyborohydride (100 g, 472 mmol, 3.3 equiv.) was added to the ice-cooled solution via a powder addition funnel over 30 min. The orange solution was stirred at 0 °C for 1 h and then allowed to warm to room temperature. The reaction was stirred at room temperature 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 minutes, and saturated Na2CO3 solution (200 mL) was added over 15 minutes. Solid K2CO3 (9 g) was added in 3 g portions. At this point, the aqueous layer was pH 12 and bubbles had stopped forming. The layers were filtered and separated. The red organic layer was washed with saturated aqueous NaHCO3 (2 × 100 mL). The aqueous layers were combined and extracted with DCM (2 × 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 the major products of the separated diastereomers (Rf = 0.16 and 0.26). The crude material was adsorbed onto silica gel and purified by flash chromatography (330 g cartridge, 0–100% EA:Hex). Fractions containing the R,R diastereomer were pooled and purified twice using the same flash chromatography conditions to yield 24 g of product (approximately 82% ee). Previously successful separations were achieved at a silica gel:crude ratio of 40:1, so the mixture was split into three portions and separated on three 330 g silica gel cartridges (0-40% EA / Hex for 20 min, isocratic 40% EA / Hex for 40 min). All fractions containing the desired product were >99% diastereomeric pure.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%).

[0128] 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 the low purity.

[0129] LCMS: ES+[M+H]+279.0. Preparation of (2R)-1-(1H-indol-3-yl)propan-2-amine: [ka]

[0130] 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 purged with N for 10 minutes. 20% Pd(OH)2 on carbon wetted with water (10.71 g, 76.3 mmol, 1.8 equiv.) was added, the bottle was pressurized with 50 psi of hydrogen, and the Parr apparatus was shaken 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 Na2CO3 solution (50 mL), and the aqueous layer was extracted with DCM (2 x 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.

[0131] 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(Sex Tet, 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).

[0132] LCMS: ES+[M+H]+174.9. Preparation of 2-fluoro-2-methylpropanol: [ka]

[0133] Methyl 2-fluoro-2-methylpropionate (5.01 g, 40.5 mmol, 1.0 equiv.) was added dropwise over 15 min 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. 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®, washing the solid with DCM. The filtrate was concentrated (200 mbar, 25 °C) to give 2-fluoro-2-methylpropanol as a colorless oil (2.09 g, 56.1%).

[0134] 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). Preparation of 2-fluoro-2-methylpropyl trifluoromethanesulfonate: [ka]

[0135] 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, KMnO4 development) indicated the absence of starting material. The reaction mixture was washed with 1 M HCl solution (2 × 20 mL) and saturated NaHCO3 solution (2 × 20 mL). The aqueous layers were back-extracted with DCM (20 mL). 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%).

[0136] 1 H 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. Preparation of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine: [ka]

[0137] The compound 2-fluoro-2-methylpropyl trifluoromethanesulfonate (9.587 g, 42.8 mmol, 1.1 equiv.) (solution in DCM, 16% DCM by weight, 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 equiv.), anhydrous 1,4-dioxane (60.000 mL, 701.4 mmol, 18.3 equiv.), and freshly distilled diisopropylethylamine (8.500 mL, 48.8 mmol, 1.3 equiv.). The dark brown solution was heated at 90 °C for 3 h. After 3 h, LCMS indicated that a small amount of indoleamine starting material was still present. TLC (10% MeOH / DCM) indicated that the triflate (Rf = 0.54) had been consumed. NMR (286-30) of unused triflate SM indicated no decomposition of the triflate overnight, so another 0.1 equivalent (0.9883 g, 13% DCM (wt%), 0.8563 g triflate SM) was added and the reaction 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 with 50% EA / Hex, one spot Rf < = 0.12, another spot 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. Pure fractions were concentrated to give (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.

[0138] 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.

[0139] Preparation of Compound 1 4-((1-Propylazetidin-3-yl)oxy)benzaldehyde (0.096 g, 0.4 mmol, 1.3 equiv.) was added 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.). Molecular sieves were added, and the solution was stirred in the dark at 80 °C 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 purified by 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.

[0140] 1H NMR(300MHz,CDCl3)δ 0.90(t,J=7.5Hz,3H),1.09(d,J=7.2Hz,3H),1.26-1.50(m,8H),2.45-2.77(m,6H),3.01(t,J=7.2Hz,2H),3.34(m,1H),3.7 7(m,2H),4.60(quintet,J=5.7Hz,1H),5.03(s,1H),6.64(d,J=8.1Hz,2H),7.10-7.21(m,5H),7.54(d,J=7.5Hz,1H),8.19(br s,1H). m / z:ES+[M+H] + 450.2.

[0141] The embodiments of the present disclosure described above are intended to be merely exemplary, and many variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.

Claims

1. Compound 1: [Chemistry 18] or a pharmaceutically acceptable salt thereof, a first diluent; a second diluent, and A unit dosage form comprising a disintegrant.

2. 10. The unit dosage form of claim 1, wherein the unit dosage form comprises about 10% to about 20% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof.

3. 3. The unit dosage form of claim 1, wherein the unit dosage form comprises about 10% to about 15% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof.

4. 4. The unit dosage form of any one of claims 1 to 3, wherein the unit dosage form comprises from about 10% to about 80% by weight of the first diluent.

5. 5. The unit dosage form of any one of claims 1 to 4, wherein the unit dosage form comprises from about 10% to about 20% by weight of the second diluent.

6. 6. The unit dosage form of any one of claims 1 to 5, wherein the weight ratio of said first diluent to said second diluent is from about 3:1 to about 4:

1.

7. 7. The unit dosage form of any one of claims 1 to 6, wherein the first diluent and the second diluent are different.

8. 8. The unit dosage form of any one of claims 1 to 7, wherein the unit dosage form comprises from about 5% to about 10% by weight of the disintegrant.

9. 9. The unit dosage form of any one of claims 1 to 8, wherein the first diluent is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch.

10. 10. The unit dosage form of any one of claims 1 to 9, wherein the first diluent is selected from the group consisting of lactose monohydrate and mannitol.

11. 11. The unit dosage form of any one of claims 1 to 10, wherein the first diluent is lactose monohydrate.

12. 12. The unit dosage form of any one of claims 1 to 11, wherein the second diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch.

13. 13. The unit dosage form of any one of claims 1 to 12, wherein the second diluent is microcrystalline cellulose.

14. 14. The unit dosage form of any one of claims 1 to 13, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose.

15. 15. The unit dosage form of any one of claims 1 to 14, wherein the disintegrant is croscarmellose sodium.

16. The unit dosage form comprises: about 12% by weight of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof; about 60% by weight of said first diluent; about 19% by weight of said second diluent; and 16. The unit dosage form of any one of claims 1 to 15, comprising about 8% by weight of said disintegrant.

17. 17. The unit dosage form of any one of claims 1 to 16, further comprising a lubricant.

18. 18. The unit dosage form of claim 17, wherein the unit dosage form comprises from about 0.1% to about 1.5% by weight of the lubricant.

19. 19. The unit dosage form of claim 17 or 18, wherein the lubricant is magnesium stearate.

20. 20. The unit dosage form of any one of claims 1 to 19, wherein the unit dosage form comprises from about 10 mg to about 120 mg of Compound 1, calculated as the free base, or a pharmaceutically acceptable salt thereof.

21. 21. The unit dosage form according to any one of claims 1 to 20, which is in the form of a tablet.

22. 22. The unit dosage form of any one of claims 1 to 21, characterized in that when stored at 40°C / 75% RH for one month or more, it exhibits greater than 80% dissolution in about 30 minutes or less using appropriate dissolution conditions.

23. granules, said granules comprising Compound 1: 【Chemistry 19】 or a pharmaceutically acceptable salt thereof, a first diluent; a second diluent, and A unit dosage form comprising a disintegrant.

24. 24. The unit dosage form of claim 23, wherein the granules comprise Compound 1, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 20% of the total weight of the unit dosage form, calculated as the free base of Compound 1.

25. 25. The unit dosage form of claim 23 or 24, wherein the granules comprise the first diluent in an amount of about 5% to about 20% of the total weight of the unit dosage form.

26. 26. The unit dosage form of any one of claims 23 to 25, wherein the granules comprise the second diluent in an amount of about 50% to about 60% of the total weight of the unit dosage form.

27. 27. The unit dosage form of any one of claims 23 to 26, wherein the granules comprise the disintegrant in an amount of about 1% to about 5% of the total weight of the unit dosage form.

28. 28. The unit dosage form of any one of claims 23 to 27, wherein the first diluent is selected from lactose monohydrate, microcrystalline cellulose, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch.

29. 29. The unit dosage form of any one of claims 23 to 28, wherein the second diluent is selected from microcrystalline cellulose, lactose monohydrate, mannitol, calcium phosphate, lactose anhydrous, calcium silicate, and pregelatinized starch.

30. 30. The unit dosage form of any one of claims 23 to 29, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and hydroxypropyl cellulose.

31. 31. The unit dosage form of any one of claims 23 to 30, further comprising one or more extragranular excipients.

32. 32. The unit dosage form according to any one of claims 23 to 31, which is in the form of a tablet.

33. 33. A method of treating an estrogen receptor mediated disease, disorder, or condition, comprising administering to a subject in need thereof a unit dosage form of any one of claims 1 to 32.

34. 34. The method of claim 33, wherein the estrogen receptor-mediated disease, disorder, or condition is cancer.

35. 35. The method of claim 34, wherein the cancer is breast cancer.

36. 35. The method of claim 34, wherein the cancer is breast cancer that has metastasized to the lung, liver, bone, or brain.

37. The method of any one of claims 33 to 36, further comprising administering a second anti-cancer agent.

38. 38. The method of claim 37, wherein the second anti-cancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

39. 39. The method of claim 38, wherein the second anti-cancer agent is a CDK4 / 6 inhibitor.

40. 40. The method of claim 39, wherein the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, relociclib, trilaciclib, and SHR6390.

41. 39. The method of claim 38, wherein the second anti-cancer agent is a PIK3CA inhibitor.

42. 42. The method of claim 41, wherein the PIK3CA inhibitor is selected from the group consisting of alpelisib, taselisib, and LY3023414.

43. 39. The method of claim 38, wherein the second anti-cancer agent is an mTOR inhibitor.

44. 44. The method of claim 43, wherein the mTOR inhibitor is selected from the group consisting of sirolimus, temsirolimus, everolimus, and LY3023414.

45. 39. The method of claim 38, wherein the second anti-cancer agent is a HER2 inhibitor.

46. 46. ​​The method of claim 45, wherein the HER2 inhibitor is selected from the group consisting of tucatinib, pertuzumab, lapatinib, trastuzumab, trastuzumab emtansine, trastuzumab deruxtecan, and neratinib.

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