Crystalline Forms of Estrogen Receptor Antagonists

Abstract

The present disclosure provides crystalline solid forms of estrogen receptor (ER) inhibitors, compositions thereof, and methods of treating ER-mediated disorders. In some embodiments, the present disclosure provides methods of treating estrogen receptor (ER)-related diseases, disorders, and conditions (e.g., cancer) and / or otherwise modulating (e.g., inhibiting) estrogen receptors in the brain, the methods comprising administering an estrogen receptor antagonist (e.g., Compound 1 fumarate Form E).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority and benefit of PCT Application No. PCT / CN2022 / 094231, filed on May 20, 2022, the entire content of which is incorporated herein by reference.

Background Art

[0002] Estrogen receptor (ER) plays an important role in various cancers including breast cancer. Various treatments targeting estrogen receptor and / or its activity have been developed.

Summary of the Invention

[0003] There is still a need for anti - estrogen agents that can completely inhibit estrogen receptors, including those encoded by both wild - type and mutant (e.g., those containing activating mutations) genes of estrogen receptor alpha (ERα), which encodes estrogen receptor 1 (ESR1). Selective estrogen receptor modulators (SERMs) or degraders (SERDs) are particularly useful or promising tools for such therapies. Recently, a type of estrogen receptor antagonist called complete estrogen receptor antagonist (CERAN) has emerged as a promising therapy for completely inhibiting estrogen receptors.

[0004] CERAN is thought to be "complete" compared to other estrogen receptor antagonists because it inactivates two distinct transcriptional activation functions (AF1 and AF2) of the estrogen receptor. Previous therapies that are not CERAN fail when activating mutations in the gene encoding estrogen receptor 1 allow both AF1 and AF2 to be activated even in the absence of estrogen. The present disclosure provides salts, solid forms, and compositions of compounds useful for complete antagonism of the estrogen receptor and their use, and provides treatment options for subjects suffering from cancer and / or subjects carrying a mutation in estrogen receptor 1 (ESR1).

[0005] 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):

Chemical formula

[0006] During the process development of Compound 1, the Applicant recognized that when preparing solid dosage forms (e.g., tablets or capsules) containing Compound 1, the amorphous form of Compound 1 exhibits certain properties, such as flow properties, bulk density, and handleability, which make the process of generating solid dosage forms containing Compound 1 difficult.

[0007] Furthermore, several attempts were made to formulate Compound 1 into a form that is more easily manufacturable and formulatible, but this resulted in a form of Compound 1 that was solvated with a potentially somewhat toxic organic solvent. The Applicant recognized that Compound 1 exhibits a high solvation tendency in both the free base and salt forms, which presented several problems in attempts to develop a non-solvated or hydrated form of Compound 1. As shown in Examples 6-9, in polymorph screening experiments, a non-solvated or hydrated form of the free base of Compound 1 was not identified, and the non-solvated or hydrated salt forms of Compound 1 were minor.

[0008] However, the present disclosure solves the problems identified above and, in some embodiments, provides forms that exhibit desired characteristics such as improved stability, hygroscopicity, flow properties, compressibility, ease of processing, consistency in manufacturing, particle size distribution, bulk density, pharmacokinetics, bioavailability, and ease of formulatibility. For example, the present disclosure encompasses the recognition that a particular crystalline solid form of Compound 1 as the fumarate salt (“Compound 1 fumarate”) may be useful in the compositions and methods described herein:

Chemical formula

[0009] In some embodiments, the present disclosure provides a non-solvated crystalline solid form of Compound 1 fumarate. In some embodiments, the present disclosure provides a hydrated crystalline solid form of Compound 1 fumarate.

[0010] In some embodiments, the present disclosure provides Form E of Compound 1 fumarate described herein.

[0011] In some embodiments, the present disclosure provides a method of inhibiting an estrogen receptor or a mutation thereof in a biological sample, the method comprising contacting the biological sample with an estrogen receptor antagonist (e.g., Compound 1 fumarate Form E).

[0012] In some embodiments, the present disclosure provides a composition comprising one or more forms of Compound 1 or Compound 1 fumarate provided herein. In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more forms of Compound 1 or Compound 1 fumarate provided herein and a pharmaceutically acceptable carrier.

[0013] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer associated with an estrogen receptor or a mutation of an estrogen receptor, the method comprising administering an estrogen receptor antagonist (e.g., Compound 1 fumarate Form E).

[0014] In some embodiments, the present disclosure provides a method of treating estrogen receptor (ER)-related diseases, disorders, and conditions (e.g., cancer) and / or alternatively regulating (e.g., inhibiting) estrogen receptors in the brain, the method comprising administering an estrogen receptor antagonist (e.g., Compound 1 fumarate Form E).

[0015] In some embodiments, the present disclosure achieves preferential accumulation in tumors compared to a patient's plasma of an ER-related disease disorder or condition (e.g., an ER-related cancer including but not limited to those that are or include tumors (plural) in the brain such as brain metastases), i.e., achieves accumulation in the tumor to a concentration that exceeds the concentration in plasma, by administering a specific complete estrogen receptor antagonist (e.g., Compound 1 fumarate Form E) according to a regimen. BRIEF DESCRIPTION OF THE DRAWINGS

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Figure 9

DETAILED DESCRIPTION OF THE INVENTION

[0025] Compound 1 Compound 1 is a complete estrogen receptor antagonist disclosed in PCT Publication No. WO2017 / 059139, which is incorporated herein by reference in its entirety, and is referred to as Compound B. Exemplary methods for using Compound 1 are described in PCT Publications No. WO2021 / 007146 and No. WO2021 / 178846, each of which is incorporated herein by reference in its entirety.

[0026] The synthesis of Compound 1 is detailed in Example 10 of WO2017 / 059139 and Example 1 herein.

[0027] Compound 1 fumarate In some embodiments, the present disclosure provides a crystalline solid form of Compound 1 fumarate, such as Compound 1 fumarate Form E. Compound 1 fumarate Form E is one of a plurality of polymorphic solid forms of Compound 1 fumarate. As used herein, the term "polymorph" refers to the ability of a compound to exist in one or more different crystal structures. For example, one or more polymorphs may have different pharmaceutically relevant physical properties, such as solubility, stability, and / or hygroscopicity, between one form and another.

[0028] In some embodiments, Compound 1 fumarate Form E exists in a non-solvated form. A crystalline solid form in which no water or solvent is incorporated into the crystal structure is "non-solvated". In some embodiments, Compound 1 fumarate Form E exists as an anhydrate. A crystalline solid form in which no water is incorporated into the crystal structure is an "anhydrate". In some embodiments, Compound 1 fumarate Form E is a non-solvated anhydrate.

[0029] In some embodiments, the crystalline form of Compound 1 fumarate exists as a solvate and / or hydrate. As used herein, the term "solvate" refers to a solid form in which one or more stoichiometric or non-stoichiometric amounts of a solvent are incorporated into the crystal structure. For example, a solvate polymorph or hetero-solvate polymorph may independently contain one or more equivalents of a solvent such as 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc. incorporated into the crystal lattice. As used herein, the term "hydrate" refers to a solvate in which the solvent incorporated into the crystal structure is water.

[0030] It will be understood that "Compound 1 fumarate" refers to a complex form comprising Compound 1 non-covalently associated with fumaric acid, which is a coformer. Such non-covalent associations include, by way of example, ionic interactions, dipole-dipole interactions, π-stacking interactions, hydrogen bond interactions, and the like. It will be understood that the term "Compound 1 fumarate" encompasses salt forms resulting from ionic interactions between Compound 1 and fumaric acid, as well as salt forms resulting from non-ionic associations between Compound 1 and fumaric acid.

[0031] As provided herein, Compound 1 fumarate Form E has distinct XRPD peaks not reported in previous disclosures of Compound 1. As used herein, the term "about", when used with respect to a value of the 2θ angle, refers to ±0.2 degrees of 2θ of the stated value.

[0032] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and fumaric acid (i.e., Compound 1 fumarate), wherein the complex form is Compound 1 fumarate Form E. In some embodiments, Compound 1 fumarate Form E comprises fumaric acid:Compound 1 in a 1:1 ratio. In some embodiments, Compound 1 fumarate Form E is an anhydrate.

[0033] In some embodiments, the provided form (e.g., the form of Compound 1 and Compound 1 fumarate) is characterized by having peaks in its XRPD pattern at 2θ within ±0.2 degrees of optionally specified values selected from “substantially all” of the provided list. An XRPD pattern having “substantially all” of the provided peak list is understood to refer to an XRPD pattern that includes at least 80% (e.g., 80%, 85%, 90%, 95%, 99% or 100%) of the listed peaks. In some embodiments, the XRPD pattern includes at least 90% of the listed peaks. In some embodiments, the XRPD pattern includes all of the listed peaks. In some embodiments, the XRPD pattern includes all but one of the listed peaks. In some embodiments, the XRPD pattern includes all but two of the listed peaks. In some embodiments, the XRPD pattern includes all but three of the listed peaks.

[0034] In some embodiments, the provided form (e.g., the form of Compound 1 and Compound 1 fumarate) is characterized by having a pattern or spectrum “substantially similar” to the figures provided herein. A pattern or spectrum having “substantial similarity” to the figures provided herein includes one or more features of the provided figure (e.g., values of position (2θ angle), values of temperature, values of weight loss rate, intensity, shape of the curve, etc.), whereby it is understood that the form (e.g., solid and / or salt form) characterized by that pattern or spectrum is the same as the form characterized in the figure. For example, in some embodiments, an XRPD pattern having substantial similarity to the provided figure includes substantially all of the same peaks and, optionally, is at 2θ within ±0.2 degrees of the peaks of the reference figure. In some embodiments, an XRPD pattern having substantial similarity to the provided figure includes substantially all of the same peaks, is at 2θ within ±0.2 degrees of the peaks of the reference figure, and has approximately the same intensity, optionally.

[0035] In some embodiments, Compound 1 fumarate Form E is characterized in its XRPD pattern by one or more peaks selected from the 2θ peaks of about 5.83 degrees, about 7.03 degrees, about 8.69 degrees, about 12.88 degrees, about 13.43 degrees, about 14.68 degrees, about 15.65 degrees, about 16.65 degrees, and about 18.46 degrees. In some embodiments, Compound 1 fumarate Form E is characterized in its XRPD pattern by two or more peaks selected from the 2θ peaks of about 5.83 degrees, about 7.03 degrees, about 8.69 degrees, about 12.88 degrees, about 13.43 degrees, about 14.68 degrees, about 15.65 degrees, about 16.65 degrees, and about 18.46 degrees. In some embodiments, Compound 1 fumarate Form E is characterized in its XRPD pattern by three or more peaks selected from the 2θ peaks of about 5.83 degrees, about 7.03 degrees, about 8.69 degrees, about 12.88 degrees, about 13.43 degrees, about 14.68 degrees, about 15.65 degrees, about 16.65 degrees, and about 18.46 degrees.

[0036] In some embodiments, Compound 1 fumarate Form E is characterized in its XRPD pattern by the 2θ peaks of about 5.83 degrees, about 7.03 degrees, about 8.69 degrees, about 12.88 degrees, about 13.43 degrees, about 14.68 degrees, about 15.65 degrees, about 16.65 degrees, and about 18.46 degrees. In some embodiments, Compound 1 fumarate Form E is characterized in its XRPD pattern by the peaks in substantially all of the following: [Table 26]

[0037] In some embodiments, Compound 1 fumarate Form E is characterized by one or more of the following: (i) an XRPD pattern substantially similar to that shown in FIG. 1 and / or FIG. 3; (ii) a TGA pattern substantially similar to that shown in FIG. 2 and / or FIG. 4; and (iii) A DSC pattern substantially similar to that shown in FIG. 2 and / or FIG. 5.

[0038] Preparation of the provided form In some embodiments, the present disclosure provides a method for preparing a provided solid form, e.g., Compound 1 fumarate Form E. In some embodiments, Compound 1 fumarate Form E is prepared by contacting Compound 1 (e.g., amorphous Compound 1, crystalline Compound 1, or a mixture thereof) with fumaric acid. In some embodiments, the present disclosure provides a method for preparing Compound 1 fumarate Form E, the method comprising providing Compound 1 and optionally mixing Compound 1 with fumaric acid in a suitable solvent to provide Compound 1 fumarate Form E. In some embodiments, about 1.0, about 1.1, about 1.2, or about 2.0 equivalents of fumaric acid are added.

[0039] In some embodiments, Compound 1 fumarate Form E is prepared by dissolving Compound 1 fumarate (e.g., amorphous Compound 1 fumarate, crystalline Compound 1 fumarate, or a mixture thereof) in a suitable solvent and then returning the Compound 1 fumarate to the solid phase. In some embodiments, Compound 1 fumarate Form E is prepared by mixing Compound 1 fumarate (e.g., amorphous Compound 1 fumarate, crystalline Compound 1 fumarate, or a mixture thereof) in a suitable solvent under suitable conditions and isolating Compound 1 fumarate Form E.

[0040] In some embodiments, suitable solvents are selected from 2-butanol, dichloroethane, ethanol, heptane, isopropanol, N-methylpyrrolidone, and water, or any combination thereof.

[0041] In some embodiments, the method for preparing Compound 1 fumarate Form E includes heating a mixture containing Compound 1 fumarate to a suitable temperature (e.g., about 30°C to about 60°C). In some embodiments, the method for preparing Compound 1 fumarate Form E includes stirring a mixture containing Compound 1 fumarate at ambient temperature. In some embodiments, the method for preparing Compound 1 fumarate Form E includes cooling a mixture containing Compound 1 fumarate to a suitable temperature (e.g., about -20°C to about 0°C).

[0042] In some embodiments, Compound 1 fumarate Form E precipitates from a mixture (e.g., a solution, suspension, or slurry). In some embodiments, Compound 1 fumarate Form E crystallizes from a solution. In some embodiments, Compound 1 fumarate Form E crystallizes from a solution after seeding the solution (e.g., after adding crystals of Compound 1 fumarate Form E to the solution). In some embodiments, Compound 1 fumarate Form E precipitates or crystallizes from a mixture after removal of all or part of the solvent by methods such as cooling, addition of a poor solvent, and / or evaporation, distillation, filtration, reverse osmosis, absorption, or reaction.

[0043] In some embodiments, the method for preparing Compound 1 fumarate Form E includes isolating Compound 1 fumarate Form E. It will be understood that Compound 1 fumarate Form E can be isolated by any suitable means. In some embodiments, Compound 1 fumarate Form E is separated from the supernatant by filtration. In some embodiments, Compound 1 fumarate Form E is separated from the supernatant by decantation.

[0044] In some embodiments, the isolated Compound 1 fumarate Form E is dried (e.g., in air or under reduced pressure, optionally at an elevated temperature).

[0045] In some embodiments, Compound 1 fumarate Form E is prepared by converting a solid form of Compound 1 fumarate to Compound 1 fumarate Form E.

[0046] In some embodiments, Compound 1 fumarate Form E is prepared by a process that includes mixing Compound 1 (e.g., amorphous Compound 1) in a suitable solvent (e.g., isopropanol) while stirring at a suitable temperature (e.g., about 40 °C). In some embodiments, the process further includes adding a first portion (e.g., about 0.5 equivalents) of fumaric acid. In some embodiments, the process further includes adding a seed crystal of Compound 1 fumarate Form E. In some embodiments, the process further includes adding second, third, and / or fourth portions (e.g., about 0.2 - 0.3 equivalents) of fumaric acid. In some embodiments, the process further includes adding a suitable poor solvent (e.g., heptane). In some embodiments, the process further includes cooling the mixture to ambient temperature (e.g., about 25 °C). In some embodiments, the process further includes isolating the solid form of Compound 1 fumarate Form E by a method such as filtration.

[0047] Composition In some embodiments, the disclosure also provides a composition comprising Compound 1 fumarate Form E.

[0048] In some embodiments, the composition provided that comprises Compound 1 fumarate Form E is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition does not contain a significant amount of foreign matter. Such foreign matter can include starting materials, residual solvents, or any other impurities that can arise from the preparation and / or isolation of the crystalline solid form. In some embodiments, the composition comprises at least about 90% by weight of Compound 1 fumarate Form E. In some embodiments, the composition comprises at least about 95% by weight of Compound 1 fumarate Form E. In some embodiments, the composition comprises at least about 99% by weight of Compound 1 fumarate Form E.

[0049] In some embodiments, the composition provided that comprises Compound 1 fumarate Form E is substantially pure (e.g., contains at least about 95%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 99.8% by weight of the crystalline solid form, based on the total weight of the composition). In some embodiments, the composition that comprises Compound 1 fumarate Form E comprises about 5.0 percent or less total organic impurities. In some embodiments, the composition that comprises Compound 1 fumarate Form E comprises about 3.0 percent or less total organic impurities. In some embodiments, the composition that comprises Compound 1 fumarate Form E comprises about 1.5 percent or less total organic impurities. In some embodiments, the composition that comprises Compound 1 fumarate Form E comprises about 1.0 percent or less total organic impurities. In some embodiments, the composition that comprises Compound 1 fumarate Form E comprises about 0.5 percent or less total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0050] In some embodiments, the composition comprises Compound 1 fumarate Form E and an amorphous solid form (e.g., an amorphous solid form of Compound 1 and / or Compound 1 fumarate). In some embodiments, a composition comprising a crystalline solid form substantially does not contain an amorphous solid form. As used herein, the term "substantially free of an amorphous solid form" means that the composition does not contain a significant amount of the amorphous solid form. In some embodiments, the composition comprises at least about 90% by weight of Compound 1 fumarate Form E. In some embodiments, the composition comprises at least about 95% by weight of Compound 1 fumarate Form E. In some embodiments, the composition comprises at least about 99% by weight of Compound 1 fumarate Form E. In some embodiments, the composition comprises up to about 10% by weight of an amorphous solid form (e.g., an amorphous solid form of Compound 1 and / or Compound 1 fumarate). In some embodiments, the composition comprises up to about 5% by weight of an amorphous solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 1 fumarate). In some embodiments, the composition comprises up to about 1% by weight of an amorphous solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 1 fumarate).

[0051] Pharmaceutical composition In some embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 fumarate Form E and a pharmaceutically acceptable carrier.

[0052] In some embodiments, the provided pharmaceutical composition comprises an amount of Compound 1 (e.g., in the form of Compound 1 fumarate Form E) effective to measurably inhibit an estrogen receptor (ER) or a variant thereof in a biological sample or a patient. In some embodiments, the provided pharmaceutical composition is formulated for oral administration.

[0053] In some embodiments, the provided pharmaceutical composition comprises Compound 1 fumarate Form E and one or more bulking agents, disintegrants, lubricants, glidants, anti-adhesion agents, and / or anti-static agents, etc.

[0054] The pharmaceutical compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intraosseously, or by an implantable reservoir. In some embodiments, the pharmaceutical compositions provided are administered orally, intraperitoneally, or intravenously. In some embodiments, the pharmaceutical compositions provided are administered orally.

[0055] In some embodiments, the pharmaceutical compositions provided are in an oral dosage form (e.g., a capsule or a tablet). In some embodiments, the pharmaceutical compositions provided are tablets. In some embodiments, the pharmaceutical compositions provided are capsules.

[0056] In some embodiments, the pharmaceutical compositions provided are solid pharmaceutical compositions (e.g., solid dosage forms such as capsules or tablets).

[0057] In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 3 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 5 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 10 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 15 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 20 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 25 mg / kg in a mouse. In some embodiments, the pharmaceutical composition provided comprises an amount of Compound 1 suitable for providing to a human a dose of Compound 1 corresponding to at least 30 mg / kg in a mouse.

[0058] In some embodiments, the pharmaceutical composition provided is administered once daily (QD). In some embodiments, the pharmaceutical composition provided is administered twice daily (BID). In some embodiments, the pharmaceutical composition provided is administered every other day (QOD). In some embodiments, the pharmaceutical composition provided is administered once a week (QW). In some embodiments, the pharmaceutical composition provided is administered once every four weeks (Q4W).

[0059] In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises from about 15 mg to about 120 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises from about 15 mg to about 100 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises from about 60 mg to about 120 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises 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. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises about 15 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises about 30 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises about 60 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises about 90 mg of Compound 1. In some embodiments, the pharmaceutical composition provided (e.g., unit dosage form) comprises about 120 mg of Compound 1. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0060] For example, it will be understood that reference to the amount of Compound 1 (e.g., in mg) in a pharmaceutical composition, dosing regimen, etc. means the amount of Compound 1 in free base form. Thus, Compound 1 may be provided and / or utilized, for example, in salt form, and the amount of the salt (or other form) is an amount equivalent to the "free base equivalent" of Compound 1.

[0061] In some embodiments, the pharmaceutical composition provided is prepared by (i) providing Compound 1 fumarate Form E and (ii) formulating Compound 1 fumarate Form E with suitable excipients to provide the pharmaceutical composition.

[0062] Use The compounds and compositions described herein are generally useful for inhibiting estrogen receptor (ER) and its variants. In some embodiments, the present disclosure encompasses the insight that the compounds and compositions described herein are useful for the treatment of ER-related disorders (such as ER-related cancers such as breast cancer including metastatic brain cancer), the detection of such disorders, and / or the characterization of certain tumors.

[0063] For example, in some embodiments, the present disclosure provides a particular method of treatment in a subject having an ER-related disease, disorder, or condition. In some embodiments, the ER-related disease, disorder or condition is cancer. In some embodiments, the ER-related disease, disorder or condition is selected from breast cancer, bone cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, vaginal cancer, endometriosis, and uterine cancer. In some embodiments, the ER-related disease, disorder, or condition is breast cancer.

[0064] In some embodiments, the subject has been determined or suspected to have metastatic cancer (e.g., cancer metastasized to the brain, bone, lung, liver, or central nervous system). In some embodiments, the subject has been determined or suspected to have a brain metastasis. In some embodiments, the subject has developed a brain metastasis related to an ER-related cancer, such as breast cancer, or a mutation in the estrogen receptor.

[0065] In some embodiments, the provided method comprises administering Compound 1 (e.g., as Compound 1 fumarate Form E) to a subject previously treated with an ER inhibitor. In some such embodiments, the provided method comprises administering Compound 1 (e.g., as Compound 1 fumarate Form E) to a subject previously treated with a selective estrogen receptor modulator (SERM) including, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0066] In some embodiments, the provided method comprises administering Compound 1, or a crystalline or complex form thereof, to a subject suffering from an ER-related disorder (e.g., breast cancer) that does not respond to treatment with SERMs, such as, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0067] In some embodiments, the subject has relapsed during or after treatment with a SERM, such as, for example, tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0068] In some embodiments, the provided method comprises administering Compound 1 (e.g., as Compound 1 fumarate Form E) to a subject having an estrogen receptor positive (ER+) and human epidermal growth factor receptor negative (HER-) disease. In some embodiments, the provided method comprises administering Compound 1 (e.g., as Compound 1 fumarate Form E) to a subject having an estrogen receptor positive (ER+) and human epidermal growth factor receptor positive (HER+) disease.

[0069] In some embodiments, Compound 1 (e.g., as Compound 1 fumarate Form E) is administered to a subject in an amount of about 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg. In some embodiments, Compound 1 is administered to a subject in an amount of 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. 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. In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 90 mg. In some embodiments, Compound 1 is administered to a subject in an amount of about 120 mg.

[0070] In some embodiments, Compound 1 (e.g., as Compound 1 fumarate Form E) is administered to a subject in an amount of about 15 mg to about 360 mg per day (QD). In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 360 mg per day (QD). In some embodiments, Compound 1 is administered to a subject in an amount of about 30 mg to about 300 mg per day (QD). In some embodiments, Compound 1 is administered to a subject in an amount of about 60 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to a subject in an amount of about 15 mg to about 100 mg QD. In some embodiments, Compound 1 is administered to a subject in an amount of 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. 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.

[0071] In some embodiments, Compound 1 (e.g., as Compound 1 fumarate Form E) is administered to a subject in a unit dosage form. In some embodiments, the unit dosage form is a capsule or a tablet. In some embodiments, the unit dosage form contains from about 15 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form contains from about 15 mg to about 100 mg of Compound 1. In some embodiments, the unit dosage form contains from about 60 mg to about 120 mg of Compound 1. In some embodiments, the unit dosage form contains 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. In some embodiments, the unit dosage form contains about 15 mg of Compound 1. In some embodiments, the unit dosage form contains about 30 mg of Compound 1. In some embodiments, the unit dosage form contains about 60 mg of Compound 1. In some embodiments, the unit dosage form contains about 90 mg of Compound 1. In some embodiments, the unit dosage form contains about 120 mg of Compound 1. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0072] In some embodiments, the total daily dose of Compound 1 administered to a subject is in an amount of about 15 mg to about 360 mg per day (QD). In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg to about 360 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 30 mg to about 300 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 60 mg to about 120 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is in an amount of about 15 mg to about 100 mg QD. In some embodiments, the total daily dose of Compound 1 administered to a subject is in an amount of 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. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is in an amount of about 30 mg QD. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 60 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 90 mg. In some embodiments, the total daily dose of Compound 1 administered to a subject is about 120 mg.

[0073] Combination therapy The present disclosure encompasses the recognition that certain combinations of agents can be beneficially utilized to fully antagonize estrogen receptors. Thus, in some embodiments, the present disclosure provides a method of treating a subject afflicted with an ER-related disorder (e.g., cancer, such as breast cancer), the method comprising administering a complete estrogen receptor antagonist and a second anti-cancer agent. For example, in some embodiments, the complete estrogen receptor antagonist is Compound 1 (e.g., in the form of Compound 1 fumarate Form E). In some embodiments, the second anti-cancer agent is a CDK 4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

[0074] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, e.g., in the form of Compound 1 fumarate E) and a CDK4 / 6 inhibitor (i.e., an agent that inhibits one or both of CDK4 and CDK6). In some embodiments, the anti-cancer agent is a CDK4 / 6 inhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclib, 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 lerociclib. In some embodiments, the CDK4 / 6 inhibitor is trilaciclib. In some embodiments, the CDK4 / 6 inhibitor is SHR6390.

[0075] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, e.g., in the form of Compound 1 fumarate E) and 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.

[0076] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1, e.g., in the form of Compound 1 fumarate Form E) and 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.

[0077] In some embodiments, the present disclosure provides a method of treating a subject having an ER+ and HER+ disease with a complete estrogen receptor antagonist (e.g., Compound 1, e.g., in the form of Compound 1 fumarate Form E) and a HER2 inhibitor. In some embodiments, the HER2 inhibitor is selected from tucatinib, pertuzumab, lapatinib, trastuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, and neratinib.

[0078] It is understood that the combination therapies comprising the complete estrogen receptor antagonists and anti-cancer agents described herein may include administering the agents simultaneously or separately. For example, in some embodiments, the complete estrogen receptor antagonist and the anti-cancer agent are administered simultaneously. In some embodiments, the anti-cancer agent is administered prior to the administration of the complete estrogen receptor antagonist. In some embodiments, the anti-cancer agent is administered after the administration of the complete estrogen receptor antagonist.

Example

[0079] The examples provided in this specification document and support specific aspects of the present disclosure, but are not intended to limit the scope of any claims. The following non-limiting examples are provided to further illustrate specific teachings provided by the present disclosure. Those skilled in the art will understand that, in light of this application, various changes can be made to the specific embodiments illustrated in these examples without departing from the spirit and scope of the present teachings.

[0080] In the following examples, the following abbreviations may be used: aq. (aqueous solution); ACN (acetonitrile); CSA (camphorsulfonic acid); d (day); DCM (dichloromethane); DEA (diethylamine); DHP (dihydropyran); DMF (N,N-dimethylformamide); DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); EA (ethyl acetate); ee (enantiomeric excess); equiv. (equivalent); ethanol (EtOH); h (hour); Hex (hexane); HPLC (high performance liquid chromatography); IPA (isopropyl alcohol); KHMDS (potassium bis(trimethylsilyl)amide); LAH (lithium aluminum hydride); LCMS (liquid chromatography - mass spectrometry); LDA (lithium diisopropylamide); LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); min (minute); NMR (nuclear magnetic resonance); Pd / C (palladium on carbon); PPh3O (triphenylphosphine oxide); Pt / C (platinum on carbon); rb (round bottom); Rf (retention factor); rt or RT (room temperature); SM (starting material); TEA (triethylamine); THF (tetrahydrofuran); THP (tetrahydropyran); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid or tosylic acid); and UV (ultraviolet).

[0081] Materials and Methods X-ray Powder Diffraction (XRPD) XRPD was performed using a PANalytical X’Pert PRO MPD or Empyrean diffractometer, with an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays onto the detector via the sample. Prior to analysis, a silicon sample (NIST SRM 640f) was analyzed to verify that the observed position of the Si 111 peak was in agreement with the NIST-certified position. The sample specimens were sandwiched between Kapton films and analyzed in transmission geometry. A beam stop, short anti-scatter extension, and anti-scatter knife edge were used to minimize the background generated by air. Solar slits were used on both the incident and diffracted beams to minimize broadening from axial divergence. A scanning position-sensitive detector (X’Celerator) located 240 mm from the sample and Data Collector software v.5.5 were used to collect the diffraction patterns.

[0082] Alternatively, XRPD was performed using a Bruker D8 Focus X-ray diffractometer equipped with a LynxEye detector. The samples were scanned from 3° to 42° (2θ) with a step size of 0.02° (2θ). The tube voltage and current were 40 kV and 40 mA, respectively.

[0083] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) TGA / DSC analyses were performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy calibrations were performed using indium, tin, zinc, aluminum, gold, and phenyl salicylate and then verified with indium. The balance was verified with calcium oxalate. The samples were placed in open aluminum pans, sealed, pierced in the lid, and then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference pedestal. The furnace was heated under nitrogen.

[0084] Alternatively, TGA was performed using a TGA Q500 (TA Instruments, US). Approximately 1 - 5 mg of the sample was placed in a tared open aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated to the final temperature (about 300 °C) at a rate of 10 °C / min. DSC property evaluation was performed using a DSC 250 (TA Instruments, US). Approximately 1 - 5 mg of the sample was placed in a DSC pinhole pan. The sample was heated to the final temperature (about 300 °C) at a rate of 10 °C / min. The change in heat flux due to temperature was recorded.

[0085] Dynamic vapor sorption (DVS) DVS was performed using an Intrinsic DVS (System Measurement System, UK). Approximately 30 - 50 mg of the sample was placed in a sample cage and suspended in the measurement chamber. For the isothermal test, the chamber temperature was kept constant at 25 ± 1 °C by a water bath. The sample was tested in step mode with a full cycle of target RH 0 - 90%. The analysis was performed in 10% RH increments. The duration at each RH was set to 60 minutes so that the sample could reach equilibrium with the chamber environment. Data was collected in 20 - second intervals.

[0086] Gas chromatography (GC) GC analysis was performed using a GC8890 (Agilent, US) equipped with an FID detector, using helium gas as the carrier gas and nitrogen gas as the makeup gas. The sample was made to be 10 mg / mL in dimethylacetamide. The vaporized sample was carried to the chromatography column by the carrier gas (mobile phase). The parameters are summarized below:

Table 27

[0087] Example 1: 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 is presented below.

[0088] Preparation of 4-((1-propylazetidin-3-yl)oxy)benzaldehyde:

Chemical formula

Chemical formula

[0089] 11H NMR (300 MHz, CDCl3) δ: 4.80 (d, J = 5.6 Hz, 4H), 2.29 (q, J = 7.5 Hz, 2H), 2.01 (s, 3H), 1.18 (t, J = 7.5 Hz, 3H).

[0090] Step 2.1 - Preparation of propylazetidin-3-ol

Chemical Structure

[0091] 1 1H NMR (300 MHz, CDCl3) δ: 4.39 (quintet, J = 6 Hz, 1H), 3.62 - 3.56 (m, 2H), 2.90 - 2.85 (m, 2H), 2.41 (t, J = 7.5 Hz, 2H), 1.34 (sextet, J = 7.2 Hz, 2H), 0.87 (t, J = 7.8 Hz, 3H).

[0092] Step 3.4 - Preparation of ((1-propylazetidin-3-yl)oxy)benzaldehyde

Chemical Structure

[0093] 1 HNMR (300 MHz, CDCl3), δ 9.87 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.86 (quintet, J = 5.7 Hz, 1H), 3.85 - 3.80 (m, 2H), 3.13 - 3.08 (m, 2H), 2.48 (t, J = 7.2 Hz, 2H), 1.46 - 1.34 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H).

[0094] (R)-1-(1H-Indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine preparation:

Chemical formula

[0095] 1 H NMR (CDCl3, 300 MHz) R,R diastereomer: δ 0.96 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H), 2.68 (q, J = 7.2 Hz, 1H), 2.97 (m, 2H) 4.00 (q, J = 6.3 Hz, 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 that of the R,R diastereomer due to low purity.

[0096] LCMS: ES+ [M+H]+ 279.0.

[0097] Preparation of (2R)-1-(1H-indol-3-yl)propan-2-amine:

Chemical formula

[0098] 1 1H NMR (CDCl3, 300 MHz) δ 1.17 (d, J = 6.6 Hz, 3H), 2.66 (dd, J = 8.4, 14.7 Hz, 1H), 2.88 (dd, J = 5.4, 14.1 Hz, 1H), 3.27 (sextet, J = 1.5 Hz, 1H), 7.05 - 7.22 (m, 3H), 7.37 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 8.00 (br s, 1H).

[0099] LCMS: ES+ [M+H]+ 174.9.

[0100] Preparation of 2-fluoro-2-methylpropanol:

Chemical Structure

[0101] 1 H NMR (300 MHz, 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).

[0102] Preparation of 2-fluoro-2-methylpropyl trifluoromethanesulfonate:

Chemical formula

[0103] 1 1H NMR (300 MHz, CDCl3) δ 1.46 (d, J = 20.4 Hz, 6H), 4.41 (d, J = 18.6 Hz, 2H). 19 19F NMR (282 MHz, CDCl3) δ -147.1, -74.5.

[0104] (R)-N-(1-(1H-Indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine Preparation:

Chemical Structure

[0105] 11H NMR (300 MHz, CDCl3) δ 1.10 (d, J = 6.3 Hz, 3H), 1.34 (dd, J = 3.0, 21.9 Hz, 6H), 2.68 - 2.95 (m, 4H), 3.02 (sextet, J = 6.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 7.26 - 7.11 (m, 2H), 7.36 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 8.18 (br s, 1H). 19 19F NMR (282 MHz, CDCl3) δ -144.2. m / z: ES+ [M+H]+ 249.0.

[0106] 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 at 80 °C in the dark under N2 for 8 h. The reaction solution was diluted with DCM, filtered, and washed with saturated Na2CO3 solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4. The solution was filtered and concentrated. The residue was dissolved in acetonitrile (2 mL), filtered through a syringe filter, and then purified by preparative LC (18 min with 40 - 90% ACN:H2O, followed by 7 min isocratic 90% ACN). The 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.

[0107] 11H NMR (300 MHz, CDCl3) δ 0.90 (t, J = 7.5 Hz, 3H), 1.09 (d, J = 7.2 Hz, 3H), 1.26 - 1.50 (m, 8H), 2.45 - 2.77 (m, 6H), 3.01 (t, J = 7.2 Hz, 2H), 3.34 (m, 1H), 3.77 (m, 2H), 4.60 (quintet, J = 5.7 Hz, 1H), 5.03 (s, 1H), 6.64 (d, J = 8.1 Hz, 2H), 7.10 - 7.21 (m, 5H), 7.54 (d, J = 7.5 Hz, 1H), 8.19 (br s, 1H). m / z: ES+ [M+H]+ 450.2.

[0108] Example 2: Preparation and Characterization of Compound 1 Fumarate Form E Compound 1 fumarate form E was obtained according to the following exemplary procedure: Compound 1 fumarate form A (about 30 - 100 mg) was slurried in isopropanol at ambient temperature for 20 days. The solid was isolated to obtain Compound 1 fumarate form E. Compound 1 fumarate form A was prepared as follows: Fumaric acid (52.6 mg) was weighed into a 20 mL glass vial. A 40 mg / mL solution of amorphous Compound 1 in ethyl acetate (15 mL) was added to the vial and the mixture was stirred at room temperature. A sample taken after 1 day of stirring was confirmed by XRPD to be Compound 1 fumarate form A. The resulting suspension was filtered and the wet cake was dried under vacuum at 50 °C for 5 hours. The solid was recovered to obtain Compound 1 fumarate form A (231.9 mg, yield about 92.2%).

[0109] The XRPD pattern of Compound 1 fumarate form E is shown in Figure 1.

[0110] As shown by the DSC curve in Figure 2, the sample showed one endothermic peak at 147 °C (onset) / 156 °C (peak). The TGA curve is also shown in Figure 2, indicating no weight loss up to 180 °C. Compound 1 fumarate form E was determined to be non-solvated.

[0111] 1 Analysis by HNMR indicated that the stoichiometry of fumaric acid:Compound 1 was approximately 1:1.

[0112] Also, Compound 1 fumarate Form E was prepared as follows: Amorphous Compound 1 (80.5 mg) and fumaric acid (24.4 mg) were mixed and suspended in isopropanol (2 mL) while stirring with a magnetic stirrer. Heptane (1 mL) was added to the clear solution and the sample was placed in a freezer. After about 1 day, the solid was isolated by centrifugation with filtration and analyzed by XRPD.

[0113] Also, Compound 1 fumarate Form E was prepared as follows: Amorphous Compound 1 (2.0 g) and isopropanol (30 mL) were placed in a 50 mL reaction vessel. Compound 1 was dissolved at 40 °C and the stirring speed was maintained at 300 rpm (two-blade paddle). Fumaric acid (0.5 equivalent) was added and, after stirring for 5 minutes, it dissolved. Then, a seed crystal (1.0 wt%) of Compound 1 fumarate Form E was added. After stirring for 1 hour, fumaric acid (0.2 equivalent) was added. After stirring for a further 1 hour, fumaric acid (0.2 equivalent) was added. After stirring for a further 1 hour, fumaric acid (0.3 equivalent) was added. Then, heptane (30 mL) was added in 4 hours or less. The mixture was maintained at 40 °C for 1 hour, then cooled to 25 °C in 3 hours or less, then stirred for 10 hours. The suspension was filtered and the wet cake was dried in a vacuum oven at 40 °C for 16 hours to obtain Compound 1 fumarate Form E (2.2 g, 90% yield).

[0114] Also, Compound 1 fumarate Form E was prepared as follows: Amorphous Compound 1 (20.0 g) and isopropanol (300 mL) were placed in a 1000 mL reaction vessel. Compound 1 was dissolved at 40 °C while maintaining the stirring speed at 300 rpm (retreating curve impeller, RCI). Fumaric acid (0.5 equivalent) was added and stirred for 20 minutes. Then, seed crystals (1.0 wt%) of Compound 1 fumarate Form E were added. After stirring for 1 hour, fumaric acid (0.2 equivalent) was slowly added. After stirring for another 1 hour, fumaric acid (0.2 equivalent) was slowly added. After stirring for another 1 hour, fumaric acid (0.3 equivalent) was slowly added. Then, heptane (300 mL) was added within 4 hours. The mixture was maintained at 40 °C for 1 hour, then cooled to 25 °C within 3 hours, and then stirred for 10 hours. The suspension was filtered, and the wet cake was dried in a vacuum oven at 40 °C for 16 hours to obtain Compound 1 fumarate Form E (23.2 g, yield 92%). Analysis by XRPD (Figure 3) confirmed that the substance was Compound 1 fumarate Form E. TGA analysis (Figure 4) showed a weight loss of 0.438% starting from 151.2 °C, and DSC (Figure 5) showed a melting point (peak temperature) of 157.9 °C. Gas chromatography (GC) showed that isopropanol was present at 3264 ppm and heptane was present at 1434 ppm. DVS analysis (Figure 6) showed that Compound 1 fumarate Form E was not hygroscopic.

[0115] Exemplary XRPD data for Compound 1 fumarate Form E are summarized below: [Table 28]

[0116] Example 3: Solubility Test Solubility tests of Compound 1 and Compound 1 fumarate in different solvents at 25 °C were carried out. The solubility was measured by dynamic measurement method and gravimetric measurement method.

[0117] Dynamic method: Under the conditions of a certain amount of solute and a certain temperature, the solvent was gradually added while stirring for 15 minutes until equilibrium was reached. Once the solute was completely dissolved, the amount of the solvent was recorded and the solubility was calculated.

[0118] Gravimetric method: An excess of solid and a certain amount of solvent were added to an 8 mL vial, stirred for 24 hours, and filtered. 1 mL of the upper clear liquid was collected, dried at 50 °C for 24 hours, weighed, and the solubility was calculated.

[0119] Compound 1 fumarate form A anhydrate was prepared as follows: Amorphous compound 1 (1.0 g) and ethyl acetate (25 mL) were added to a 50 mL reaction vessel. Compound 1 was dissolved at 25 °C and the stirring speed was maintained at 300 rpm (two-blade paddle). Fumaric acid (1.2 equivalents) was added all at once. After stirring for 10 minutes, a large amount of solid precipitated. The mixture was stirred for 15 hours. The suspension was filtered and the wet cake was dried in a vacuum oven at 40 °C for 16 hours to obtain compound 1 fumarate form A anhydrate (1.035 g, yield 82%).

[0120] The results are summarized in Table 1. Amorphous compound 1 had high solubility in isopropanol, while fumaric acid had relatively low solubility in isopropanol. Compound 1 fumarate form E had very low solubility in isopropanol at 25 °C, and its solubility decreased significantly as the proportion of heptane increased. Compound 1 fumarate form E had much lower solubility than compound 1 fumarate form A anhydrate, indicating that form E is more stable than form A.

Table 1

[0121] Example 4: Bulk density test The bulk density of compound 1 fumarate form E was measured by gently introducing a known sample mass into a graduated cylinder (50 mL), leveling it without compressing the powder, and recording the apparent loosely packed volume to the nearest scale unit. The experiment was repeated three times and the results are summarized in Table 2.

Table 2

[0122] Example 5: Stability Test The amorphous compound 1, Compound 1 fumarate Form E, and Compound 1 fumarate Form A anhydrate were placed in an oven at 60 °C for 2 weeks, and their stability was evaluated. As shown in Table 3, Compound 1 fumarate Form E and Compound 1 fumarate Form A anhydrate showed improved stability compared to the amorphous compound 1. [Table 3]

[0123] Using Compound 1 fumarate Form E and Compound 1 fumarate Form A anhydrate, the following competitive slurry experiments were conducted:

[0124] Experiment #1: Compound 1 fumarate Form E (100 mg), Compound 1 fumarate Form A anhydrate (100 mg), and isopropanol (2 mL) were added to two 8 mL vials and mixed well on a shaker at 25 °C and 40 °C, respectively. Analytical samples were taken at 24 hours and 72 hours. The results of XRPD analysis are shown in Figure 7. After 24 hours, at both 25 °C and 40 °C, Compound 1 fumarate Form A anhydrate was completely converted to Compound 1 fumarate Form E, indicating that Form E is more stable than Form A anhydrate in isopropanol.

[0125] Experiment #2: Compound 2 fumarate Form E (100 mg), Compound 1 fumarate Form A anhydrate (100 mg), and water (2 mL) were added to two 8 mL vials and mixed well on a shaker at 25 °C and 40 °C, respectively. Analytical samples were taken at 24 hours and 72 hours. The results of XRPD analysis are shown in Figure 8. After 72 hours, at both 25 °C and 40 °C, a mixture of Compound 1 fumarate Form E and Compound 1 fumarate Form A anhydrate remained, indicating that the conversion between forms is very slow in water.

[0126] Experiment #3: Compound 3 fumarate form E (100 mg), compound 1 fumarate form A anhydrate (100 mg), and ethyl acetate (2 mL) were added to two 8 mL vials and mixed well on a shaker at 25 °C and 40 °C, respectively. Analytical samples were taken at 24 hours and 72 hours. The results of XRPD analysis are shown in Figure 9. After 72 hours, a mixture of compound 1 fumarate form E and compound 1 fumarate form A anhydrate remained at both 25 °C and 40 °C, indicating that the conversion between forms is slow in ethyl acetate.

[0127] Example 6: Polymorph Screening of Compound 1 The polymorph screening of compound 1 was carried out starting from amorphous compound 1 under 100 experimental conditions. A total of eight screening methods were used, including addition of poor solvent, addition of antisolvent, slurrying at 5 °C, slurrying at room temperature, slow evaporation, slow cooling, temperature cycling, and solid-vapor diffusion. At least two crystalline forms of compound 1 were identified by polymorph screening, and both were solvates. Form A was found to exist as multiple different isostructural solvates (e.g., acetonitrile, acetone, and tetrahydrofuran solvates). Form B was determined to be a DMSO solvate. The results are summarized in Table 4 below:

Table 4

[0128] The addition of poor solvent experiments were carried out under eight conditions each. Approximately 15 mg of compound 1 was dissolved in 0.4 - 3.0 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and then, for the first 1 mL, 0.1 mL of poor solvent was added per step, and then 0.5 mL at a time until a precipitate appeared or the total amount of poor solvent reached 5.0 mL. The resulting precipitate was isolated for XRPD analysis. As summarized in Table 5, only amorphous compound 1 was observed.

Table 5

[0129] The low-speed evaporation experiments were carried out at room temperature under nine different conditions. Approximately 15 mg of Compound 1 was dissolved in 0.5 mL of solvent. All solutions and suspensions were filtered using a 0.45 μm PTFE membrane, and the filtrate was used in the next step. Visibly clear solutions were covered with HPLC caps equipped with holes made by pipette tips and evaporated at room temperature. The solids were isolated for XRPD analysis. The results summarized in Table 6 showed that Form A was obtained under specific conditions: [Table 6]

[0130] The low-speed cooling experiments were carried out in eleven solvent systems respectively. Approximately 20 mg of Compound 1 was dissolved in 1.0 - 2.0 mL of solvent at 60 °C, filtered into a new vial using a 0.45 μm PTFE membrane. The filtrate was slowly cooled from 60 °C to 5 °C at a rate of 0.05 °C / min. The resulting solid was held at a constant temperature of 5 °C and then isolated for XRPD analysis. To induce precipitation, a poor solvent was added to the clear solution. If no solid was observed after the addition of the poor solvent, low-speed evaporation was carried out. The results summarized in Table 7 showed that Form A was obtained under specific conditions: [Table 7]

[0131] The slurry conversion experiments at room temperature were carried out in 30 solvent systems. Approximately 20 mg of Compound 1 was suspended in 0.3 mL of solvent at room temperature for 4 days. The residual solid was isolated for XRPD analysis. The results summarized in Table 8 showed that Form A and Form B were obtained under specific conditions: [Table 8-1] [Table 8-2]

[0132] The slurry conversion experiment at 5 °C was carried out in 11 solvent systems. Approximately 30 mg of Compound 1 was suspended in 0.3 mL of solvent at 5 °C for 4 days. The residual solid was isolated for XRPD analysis. The results summarized in Table 9 showed that Form A was obtained under specific conditions:

Table 9

[0133] The solid evaporation dispersion experiment was carried out using 12 different solvents respectively. Approximately 15 mg of Compound 1 was weighed into a 3 mL vial and placed into a 20 mL vial together with 4 mL of volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature for 9 days to allow the solvent vapor to interact with the sample. The solid was tested by XRPD. The results summarized in Table 10 showed that Form A and Form B were obtained under specific conditions:

Table 10

[0134] The anti-solvent addition experiment was carried out in 8 solvent systems. First, 1 mL of anti-solvent in a 3 mL glass vial was placed in a refrigerator at 5 °C. Then, approximately 10 mg of Compound 1 was dissolved in 1 mL of solvent in a 2 mL glass vial. After the suspension was magnetically stirred for 2 hours to obtain a clear solution, the solution was quickly filtered into the anti-solvent at 5 °C. Then, the sample was allowed to stand at 5 °C for crystallization. If crystallization did not occur after 1 day, the sample was transferred to -20 °C for precipitation. The residual solid was isolated for XRPD analysis. The results summarized in Table 11 showed that only amorphous Compound 1 was obtained:

Table 11

[0135] The temperature cycle experiment was carried out in 8 solvent systems. Approximately 20 mg of Compound 1 was suspended at room temperature in 0.1 mL of solvent in a 23 mL glass vial. The suspension was then heated to 60 °C and equilibrated for 2 hours. The slurry was slowly cooled to 5 °C at a rate of 0.1 °C / min and then heated to 60 °C for 1 hour. This cycle was repeated once more, and it was cooled to 5 °C at a rate of 0.1 °C / min. After the sample was stored at 5 °C, the solid was isolated and analyzed using XRPD. The results summarized in Table 12 showed that Form A was obtained.

Table 12

[0136] Example 7: Salt Screening of Compound 1 The salt screening was carried out at room temperature (RT). A total of 100 salt screening experiments were carried out using 25 acids in 4 different solvent systems. Specifically, the stock solutions of Compound 1 are summarized in Table 13. The outline of the salt screening is shown in Table 14.

Table 13

Table 14-1

Table 14-2

[0137] All 14 hits were characterized by XRPD, TGA, DSC and solution NMR. The results of the characterization are summarized in Table 15.

Table 15

[0138] For further characterization, three salts of malate, fumarate, and oxalate were selected. The salts were scaled up to several hundred milligrams. The characterization data are summarized in Table 16.

Table 16

[0139] Example 8: Additional Polymorph Screening of Compound 1 Polymorph screening was carried out using amorphous Compound 1. To aid in the experimental design, the kinetic solubility of the compound was estimated. The estimation was performed using the solvent dispensing method, and dissolution was judged by visual observation. The results are shown in Table 17. In Table 17, the solvent ratio (v / v) is an approximate value and the values were rounded to the nearest integer. When complete dissolution was achieved with a single dispensing addition, the solubility was reported as ">", and when no solid was present, it was reported as "<". The actual solubility may be greater than the calculated value due to excessive use of the dispensed amount of the solvent or slow dissolution rate.

Table 17

[0140] Based on the solubility data, crystallization experiments were designed at the microscale (about 5 - 10 mg) and the midscale (about 30 - 80 mg), and techniques such as slow evaporation, slurrying, and vapor stress of the melt were utilized. The addition of crystal seeds and selected salt formers were also explored. The experiments consisted of multiple steps, but the observations in the first step served as a guide for the approach to subsequent steps.

[0141] The generated samples were visually observed by polarized light microscopy and analyzed by XRPD for preliminary evaluation. If the generated solid showed a unique XRPD pattern, solution 1 was further characterized by 1H NMR, and the thermal behavior and the presence of volatile substances were evaluated by TGA and DSC. The screening conditions and results are summarized in Table 18.

Table 18-1

Table 18-2

Table 18-3

Table 18-4

[0142] Table 19 provides a summary of the characterization of the substances generated from this experiment. Refer to Table 15 for the sample numbers.

Table 19

[0143] Example 9: Polymorph Screening of Compound 1 Fumarate Polymorph screening was carried out using Compound 1 fumarate Form A ethyl acetate solvate. The Form A ethyl acetate solvate was prepared as follows: Amorphous Compound 1 (3.0025 g) was suspended in ethyl acetate (60 mL) to obtain a clear solution. When fumaric acid (774.6 mg) was added to the solution, further precipitation was observed. The mixture was stirred at ambient temperature for approximately one week. The solid formed was isolated by filtration using a positive displacement syringe. Approximately 4.5 g of undried solid was recovered.

[0144] The screening mainly consisted of long-term slurry experiments. To assist in the design of the screening experiment, the kinetic solubility of fumarate Form A ethyl acetate solvate was estimated. The estimation was carried out on a 3 - 11 mg scale using the solvent dispensing method, and dissolution was judged by visual observation. The results are shown in Table 20. The solubility was estimated at ambient temperature and reported to the nearest mg / mL; when complete dissolution was achieved with a single dispense addition, the solubility was reported as ">";

Table 20

[0145] The long-term slurry experiments were conducted by stirring suspensions of the ethyl acetate solvate of Compound 1 fumarate Form A (about 30 - 100 mg) in various solvent systems at ambient temperature. The solvent systems were selected based on the estimated solubility. After stirring for 20 days, the solids were isolated by centrifugation with filtration (Table 21). [Table 21]

[0146] Crystallization techniques such as high- and low-speed evaporation; solvent / anti-solvent precipitation with aging; crystallization below ambient temperature; and organic and vapor stress were included in the reaction rate experiments using about 30 - 50 mg of the ethyl acetate solvate of Compound 1 fumarate Form A (Table 22). In the evaporation experiments, the filtered solution of the test substance was left uncovered at ambient temperature for high-speed evaporation or covered with aluminum foil with pinholes for low-speed evaporation. In solvent / anti-solvent precipitation, the solution of the starting material was prepared at ambient temperature or elevated temperature and filtered using a 0.2 μm nylon filter. The solution was mixed with the appropriate anti-solvent either by direct addition or reverse addition. The precipitated solid was isolated immediately by vacuum filtration or left to age at ambient temperature. In crystallization below ambient temperature, the solution of the starting material was prepared at ambient temperature and filtered using a 0.2 μm nylon filter. The filtered solution was then placed under conditions below ambient temperature and allowed to crystallize slowly. The precipitated solid was isolated by centrifugation with filtration. In the vapor stress experiment, the solid of the starting material was sampled into a vial and placed either in an RH chamber (prepared as described in Greenspan, L., Journal of Research of the National Bureau of Standards Section A: Physics and Chemistry, vol. 81A, no. 1, 1977, p. 89, doi:10.6028 / jres.081a.011) at a set temperature or in a secondary container containing water. After the specified period, samples were taken and analyzed. [Table 22-1]

Table 22-2

[0147] The crystallization of the glass and film obtained from the reaction rate experiment was carried out by stirring for approximately 22 days (Table 23). Refer to Table 22 for the sample numbers.

Table 23

[0148] Table 24 provides a summary of the property evaluation of the substances generated from this experiment.

Table 24-1

Table 24-2

Table 24-3

[0149] A salt formation experiment was also carried out by stirring a mixture of amorphous compound 1 and fumaric acid (in a ratio of 1:1.2). The solid precipitated by centrifugation with filtration was isolated. The results are summarized in Table 25.

Table 25

Claims

1. The crystalline solid form of compound 1, fumarate, 【Chemistry 21】 The solid form is the crystalline solid form which is form E.

2. The solid form according to claim 1, wherein the solid form is characterized in its X-ray powder diffraction (XRPD) pattern by one or more peaks selected from 2θ peaks at approximately 5.83°, approximately 7.03°, approximately 8.69°, approximately 12.88°, approximately 13.43°, approximately 14.68°, approximately 15.65°, approximately 16.65°, and approximately 18.46°.

3. The solid form according to claim 1, wherein the solid form is characterized in its XRPD pattern by 2θ peaks at approximately 5.83 degrees, approximately 7.03 degrees, approximately 8.69 degrees, approximately 12.88 degrees, approximately 13.43 degrees, approximately 14.68 degrees, approximately 15.65 degrees, approximately 16.65 degrees, and approximately 18.46 degrees.

4. The solid form according to claim 1, wherein the solid form is characterized in substantially all of the following peaks in its XRPD pattern: Table 29

5. The solid form according to claim 1, characterized by one or more of the following: (i) XRPD patterns substantially similar to those shown in Figure 1 and / or Figure 3; (ii) Thermogravimetric analysis (TGA) patterns substantially similar to those shown in Figure 2 and / or Figure 4; and (iii) A differential scanning calorimetry (DSC) pattern substantially similar to that shown in Figure 2 and / or Figure 5.

6. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a solid.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is formulated for oral administration.

9. A method for inhibiting an estrogen receptor or a variant thereof in a biological sample, comprising contacting the biological sample with a solid form according to any one of claims 1 to 5.

10. A composition for use in a method of inhibiting an estrogen receptor or a variant thereof in a patient, wherein the composition comprises a solid form according to any one of claims 1 to 5, and the method comprises bringing the patient into contact with the composition.

11. A composition for the treatment of a disease, disorder, or condition related to estrogen receptors in a patient, wherein the composition comprises a solid form according to any one of claims 1 to 5.

12. The composition according to claim 11, wherein the disease, disorder, or condition is selected from the group consisting of breast cancer, bone cancer, lung cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, vaginal cancer, endometriosis, and uterine cancer.

13. The composition according to claim 12, wherein the disease, disorder, or condition is breast cancer.

14. The composition according to claim 11, wherein the treatment further comprises administering an anticancer agent in addition to the solid form of compound 1 fumarate.

15. The composition according to claim 14, wherein the anticancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

16. A method for preparing the crystalline solid form of compound 1, fumarate, 【Chemistry 22】 The solid form is form E, The above method involves compound 1: 【Chemistry 23】 The method comprises contacting fumaric acid with a suitable solvent to provide compound 1 fumarate form E.

17. The method according to claim 16, wherein the preferred solvent is isopropanol.

18. The method according to claim 16 or 17, wherein the contact comprises dissolving compound 1 in the preferred solvent to form a solution containing compound 1, and adding fumaric acid in divided portions to the solution.

19. The method according to claim 16 or 17, further comprising adding a seed crystal of compound 1 fumarate form E.

20. The method according to claim 18, wherein at least a portion of the fumaric acid is added before the addition of the seed crystal.

21. The method according to claim 18, wherein at least a portion of the fumaric acid is added after the addition of the seed crystal.

22. A composition comprising the crystalline solid form of compound 1 fumarate, 【Chemistry 24】 The solid form is form E, The composition is substantially free of impurities.

23. A composition comprising the crystalline solid form of compound 1 fumarate, 【Chemistry 25】 The solid form is form E, The composition is substantially pure.

24. A composition comprising the crystalline solid form of compound 1 fumarate, 【Chemistry 26】 The solid form is form E, The composition substantially contains no amorphous solid form of compound 1 and / or compound 1 fumarate.

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