Salts and solid forms of an estrogen receptor antagonist

Abstract

The present disclosure provides salt forms of an estrogen receptor (ER) inhibitor, compositions thereof and methods of treating an ER-mediated disorder.

Description

SALTS AND SOLID FORMS OF AN ESTROGEN RECEPTOR ANTAGONISTRELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Application No. 63 / 600,565, filed November 17, 2023, the entire contents of which are hereby incorporated by reference.BACKGROUND

[0002] The estrogen receptor (ER) plays important roles in various cancers, including breast cancers. A variety of treatments have been developed to target the estrogen receptor and / or its activities.SUMMARY

[0003] There remains a need for anti-estrogen agents that can completely inhibit estrogen receptors, including those coded for by both wild-type and mutant versions (e.g., those containing activating mutations) of the gene encoding Estrogen Receptor-alpha (ERa), Estrogen Receptor 1 (ESRI). Selective estrogen receptor modulators (SERMs) or degraders (SERDs) are a particularly useful or promising tools for such therapy. Recently, classes of estrogen receptor antagonists, termed Complete Estrogen Receptor Antagonists (CERANs) have emerged as promising therapies for completely inhibiting the estrogen receptor.

[0004] CERANs are considered “complete” as compared to other estrogen receptor antagonists because they inactivate two distinct transcriptional activation functions (AF 1 and AF2) of the estrogen receptor. Previous therapies that are not CERANs fail when activation mutations in the gene that codes for estrogen receptor 1 allows for activation of both AF1 and AF2 even in the absence of estrogen. The present disclosure provides salts, solid forms, and compositions and uses thereof of a compound useful for complete antagonism of the estrogen receptor, providing an option for treatment for subjects suffering from a cancer, and / or wherein the subject carries a mutation of estrogen receptor 1 (ESRI).

[0005] The compound (lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-l-(4-((l- propylazetidin-3-yl)oxy)phenyl)-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indole (“Compound 1”):Compound 1 is a complete estrogen receptor antagonist published in PCT Publication No. WO 2017 / 059139 (the entire contents of which are hereby incorporated by reference), designated as Compound B. There remains a need for identifying salt, solid, hydrate, and / or solvate forms of Compound 1 useful for various therapeutic applications.

[0006] In some embodiments, the present disclosure provides salt forms of Compound 1, designated as Compound 2:Compound 2 wherein X is a co-former selected from the group consisting of cyclamic acid, l-hydroxy-2- napthoic acid, naphthal ene-2-sulfonic acid, formic acid, sodium bisulfate, and potassium bisulfate.

[0007] In some embodiments, the present disclosure provides one or more solvates of Compound 2 (e.g., a complex of Compound 2 and a solvent, including, for example, 2- methyltetrahydrofuran, isopropyl acetate, and ethanol solvates). In some embodiments, the present disclosure provides one or more hydrates of Compound 2. In some embodiments, the present disclosure provides one or more unsolvated forms of Compound 2.

[0008] In some embodiments, the present disclosure provides one or more crystalline forms of Compound 2.

[0009] In some embodiments, the present disclosure provides methods of inhibiting the estrogen receptor, or a mutation thereof, in a biological sample comprising contacting saidbiological sample with an estrogen receptor antagonist (e.g., a form of Compound 2 provided herein).

[0010] In some embodiments, the present disclosure provides compositions comprising one or more forms of Compound 2 provided herein. In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more forms of Compound 2 provided herein and a pharmaceutically acceptable carrier.

[0011] In some embodiments, the present disclosure provides methods of treating patients or subjects suffering from a cancer related to the estrogen receptor or mutations of the estrogen receptor, comprising administering an estrogen receptor antagonist (e.g., a form of Compound 2 provided herein).

[0012] In some embodiments, the present disclosure provides methods of treating estrogen receptor (ER)-associated diseases, disorders, and conditions (e.g., cancer) and / or for otherwise modulating (e.g., inhibiting) the estrogen receptor in the brain, comprising administering an estrogen receptor antagonist (e.g., a form of Compound 2 provided herein).

[0013] In some embodiments, the present disclosure provides methods of treating an ER- associated disease disorder or condition (e.g., an ER-associated cancer, including but not limited to one that is or comprises tumor(s) in the brain such as brain metastases) by administering a particular complete estrogen receptor antagonist (e.g., a form of Compound 2 provided herein) according to a regimen that achieves preferential accumulation in tumor relative to plasma in the patient (i.e., achieves accumulation in tumor to a concentration above that in plasma).BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is a series of X-ray powder diffraction (XRPD) patterns for amorphous Compound 1 starting material (top), cyclamic acid (second from top), Compound 1 Cyclamate Form A on Kapton film prior to drying (third from top), and air-dried Compound 1 Cyclamate Form A (bottom).

[0015] FIG. 2A is a thermogravimetric analysis (TGA) curve (top) and a differential scanning calorimetry (DSC) curve (bottom) of Compound 1 Cyclamate Form A.

[0016] FIG. 2B is a series of DSC curves of Compound 1 Cyclamate Form A samples isolated from 2-MeTHF (top), IP Ac (second from top), and CPME (bottom).

[0017] FIG. 3A is a series of XRPD patterns for amorphous Compound 1 starting material (top), l-hydroxy-2-naphthoic acid (second from top), and Compound 1 l-Hydroxy-2-napthoate Form A (bottom).

[0018] FIG. 3B is a series of XRPD patterns for Compound 1 l-Hydroxy-2-napthoate Form A prepared in the salt screening described in Example 4 (top) and Compound 1 l-Hydroxy-2- napthoate Form A produced in an additional synthesis as described in Example 5 (bottom).

[0019] FIG. 3C is a series of XRPD patterns for Compound 1 l-Hydroxy-2-napthoate Form A before (top) and after (bottom) DVS.

[0020] FIG. 4A is a TGA curve (top) and a DSC curve (bottom) of Compound 1 1-Hydroxy- 2-napthoate Form A prepared in the salt screening described in Example 4.

[0021] FIG. 4B is a TGA curve (top) and a DSC curve (bottom) of Compound 1 1-Hydroxy- 2-napthoate Form A prepared in an additional synthesis as described in Example 5.

[0022] FIG. 5 is a series of high-performance liquid chromatography (HPLC) chromatograms of Compound 1 starting material (top), l-hydroxy-2-naphthoic acid (second from top), and two chromatograms of Compound 1 l-Hydroxy-2-naphthoate Form A (third from top and bottom).

[0023] FIG. 6 is a DVS isotherm plot of Compound 1 l-Hydroxy-2-naphthoate Form A.

[0024] FIG. 7A is a series of XRPD patterns for amorphous Compound 1 starting material (top), naphthalene-2-sulfonic acid (second from top), and Compound 1 Naphthalene-2-sulfonate Form A (bottom).

[0025] FIG. 7B is a series of XRPD patterns for Compound 1 Naphthalene-2-sulfonate Form A prepared in the salt screening described in Example 4 (top) and Compound 1 Naphthalene-2- sulfonate Form A produced in an additional synthesis as described in Example 5 (bottom).

[0026] FIG. 7C is a series of XRPD patterns for Compound 1 Naphthal ene-2-sulfonate Form A before (top) and after (bottom) DVS.

[0027] FIG. 8A is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Naphthal ene- 2-sulfonate Form A prepared in the salt screening described in Example 4.

[0028] FIG. 8B is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Naphthalene- 2-sulfonate Form A prepared in an additional synthesis as described in Example 5.

[0029] FIG. 9 is a series of HPLC chromatograms of Compound 1 starting material (top), naphthalene-2-sulfonic acid (second from top), and two chromatograms of Compound 1 Naphthalene-2-sulfonate Form A (third from top and bottom).

[0030] FIG. 10 is a DVS isotherm plot of Compound 1 Naphthalene-2-sulfonate Form A.

[0031] FIG. 11 is a series of XRPD patterns for amorphous Compound 1 starting material (top) and Compound 1 Formate Form A (bottom).

[0032] FIG. 12 is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Formate Form A.

[0033] FIG. 13 is a series of XRPD patterns for amorphous Compound 1 starting material (top), sodium bisulfate (second from top), Compound 1 Sodium Bisulfate Form A (third from top), and Compound 1 Sodium Bisulfate Form B (bottom).

[0034] FIG. 14A is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Sodium Bisulfate Form A.

[0035] FIG. 14B is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Sodium Bisulfate Form B.

[0036] FIG. 15A is a series of XRPD patterns for amorphous Compound 1 starting material (top), potassium bisulfate (second from top), and Compound 1 Potassium Bisulfate Form A (bottom).

[0037] FIG. 15B is a series of XRPD patterns for Compound 1 Potassium Bisulfate Form A before (top) and after (bottom) heating to 175 °C.

[0038] FIG. 16 is a TGA curve (top) and a DSC curve (bottom) of Compound 1 Potassium Bisulfate Form A.DETAILED DESCRIPTIONCompound 1

[0039] Compound l is a complete estrogen receptor antagonist, published in PCT Publication No. WO 2017 / 059139 (the entirety of which is incorporated herein by reference), designated as Compound B. Exemplary methods for using Compound 1 are described in PCT Publication Nos. WO 2021 / 007146 and WO 2021 / 178846, the entirety of each of which is incorporated herein by reference.

[0040] A synthesis of Compound 1 is described in detail in Example 10 of WO 2017 / 059139, as well as in Example 1 herein.

[0041] The present disclosure encompasses the recognition that it is desirable to provide a form (e.g., a salt and / or solid form) of Compound 1 that, as compared to another form ofCompound 1 (e.g., an amorphous form), imparts 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 formulation. For example, Applicant recognized that, when developing a solid dosage form (e.g., tablet or capsule) comprising Compound 1, the amorphous form of Compound 1 exhibited certain properties, e.g., flow properties, bulk density, and handleability, which made the process for generating a solid dosage form comprising Compound 1 difficult. Accordingly, the present disclosure provides salts of Compound 1 which overcome the problems identified above.Salt Forms of Compound 1

[0042] In some embodiments, the present disclosure provides complex forms of Compound 1 with a co-former. In some embodiments, the present disclosure provides a complex (otherwise referred to as a “salt” or “salt form”) comprising Compound 1 and a co-former X, designated as Compound 2:Compound 2 wherein X is a co-former selected from the group consisting of cyclamic acid, l-hydroxy-2- naphthoic acid, naphthalene-2-sulfonic acid, formic acid, sodium bisulfate, and potassium bisulfate. In some embodiments, X is cyclamic acid. In some embodiments, X is 1 -hydroxyl- naphthoic acid. In some embodiments, X is naphthalene-2-sulfonic acid. In some embodiments, X is formic acid. In some embodiments, X is sodium bisulfate. In some embodiments, X is potassium bisulfate.

[0043] It is understood that Compound 2 can exist in a neat or unsolvated form, a hydrated form, a solvated form, or a heterosolvated form. In some embodiments, Compound 2 is a neat or unsolvated crystal form and thus does not have any water or solvent incorporated into the crystalstructure (and is referred to herein as an “anhydrate” form). In some embodiments, Compound 2 is a hydrated or solvated form. In some embodiments, Compound 2 is a heterosolvated form (e.g., hydrate / solvate form).

[0044] In some embodiments, the present disclosure provides Compound 2 as an ethanol, methanol, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl acetate solvate. In some embodiments, the present disclosure provides Compound 2 as a hydrate.

[0045] It will be appreciated that certain solvates and / or hydrates of Compound 2 may be isostructural. For example, as described herein, Compound 2 may exist in a variety of different isostructural solvate forms.

[0046] In some embodiments, the term “complex” is used herein to refer to a form comprising Compound 1 non-covalently associated with a co-former (e.g., X). Such non-covalent associations include, by way of example, ionic interactions, dipole-dipole interactions, -stacking interactions, hydrogen bond interactions, etc.

[0047] It will be appreciated that the term “complex” encompasses salt forms resulting from an ionic interaction between Compound 1 and an acid or base, as well as non-ionic associations between Compound 1 and a neutral species.

[0048] In some embodiments, the term “complex” is used herein to refer to a form comprising Compound 1 ionically associated with a co-former (e.g., X). Accordingly, in some such embodiments, the term “complex” is used herein to refer to a salt comprising Compound 1 and an acid or a base.

[0049] In some embodiments, a “complex” is an inclusion complex, a salt form, a co-crystal, or a clathrate, or hydrates and / or solvates thereof, etc. In some embodiments, the term “complex” is used to refer to a 1: 1 ratio of Compound 1 and co-former (e.g., X). In some embodiments, the term “complex” does not necessarily indicate any particular ratio of Compound 1 to co-former (e.g., X). In some embodiments, a complex is a salt form, or a hydrate or solvate thereof. In some embodiments, a complex is a co-crystal form, or a hydrate or solvate thereof. In some embodiments, a complex is an inclusion complex, or a hydrate or solvate thereof. In some embodiments, a complex is a clathrate, or a hydrate or solvate thereof.

[0050] In some embodiments, co-former X and Compound 1 are ionically associated. In some embodiments, Compound 1 is non-covalently associated with co-former X.

[0051] A complex form of Compound 1 can exist in a variety of physical forms. For example, a complex form of Compound 1 can be in solution, suspension, or in solid form. In some embodiments, a complex form of Compound 1 is in solution form. In certain embodiments, a complex form of Compound 1 is in solid form. When a complex of Compound 1 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. In some embodiments, a complex form of Compound 1 is an amorphous solid. In some embodiments, a complex form of Compound 1 is a crystalline solid. Exemplary complex forms of Compound 1 are described in more detail below.

[0052] It will be appreciated that Compound 2 (i.e., a complex comprising Compound 1 and a co-former X) can comprise one equivalent of X. Accordingly, in some embodiments, complexes described herein comprise Compound 1 and one equivalent of X. In some embodiments, complexes described herein comprise Compound 1 and two equivalents of X. In some embodiments, complexes described herein comprise Compound 1 and three equivalents of X. In some embodiments, complexes described herein comprise Compound 1 and 0.5-2.5 equivalents of X (e.g., 0.5, 0.9, 1.2, 1.5, etc., equivalents of X).

[0053] In some embodiments, the present disclosure provides crystalline solid forms of Compound 2, compositions thereof, and methods of using and preparing crystalline solid forms of Compound 2.

[0054] As used herein, the term “about” when used in reference to a degree 2-theta value refers to the stated value ± 0.2 degrees 2-theta.

[0055] In some embodiments, provided forms (e.g., forms of Compound 2) are characterized by having peaks in its XRPD pattern selected from “substantially all” of a provided list, optionally within ± 0.2 degrees 2-theta of the stated value. It will be appreciated that an XRPD pattern having “substantially all” of a provided list of peaks refers to an XRPD pattern that comprises at least 80% (e.g., 80%, 85%, 90%, 95%, 99% or 100%) of the listed peaks. In some embodiments, an XRPD pattern comprises at least 90% of the listed peaks. In some embodiments, an XRPD pattern comprises all of the listed peaks. In some embodiments, an XRPD pattern comprises all but one of the listed peaks. In some embodiments, an XRPD pattern comprises all but two of the listed peaks. In some embodiments, an XRPD pattern comprises all but three of the listed peaks.

[0056] In some embodiments, provided forms (e.g., forms of Compound 2) are characterized by having a pattern or spectrum that is “substantially similar” to a Figure provided herein. It willbe appreciated that a pattern or spectrum having “substantial similarity” to a Figure provided herein is one that comprises one or more features (e.g., position (degrees 2-theta) values, temperature values, % weight loss values, intensity, shape of curve, etc.) of the provided Figure so as to enable identification of the form (e.g., solid and / or salt form) characterized by the pattern or spectrum as being the same as the form characterized in the Figure. For example, in some embodiments, an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ± 0.2 degrees 2-theta of peaks in the reference Figure. In some embodiments, an XRPD pattern having substantial similarity to a provided Figure is one that comprises substantially all of the same peaks, optionally within ± 0.2 degrees 2-theta of peaks in the reference Figure, with about the same intensities.Compound 1 Cyclamate

[0057] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and cyclamic acid (i.e., Compound 2, wherein X is cyclamic acid). In some embodiments, a complex form comprises one equivalent of cyclamic acid. In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and cyclamic acid. Compound 1 can exist in at least one crystalline cyclamate salt form (“Compound 1 Cyclamate Form A”).Compound 1 Cyclamate Form A

[0058] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Cyclamate Form A. In some embodiments, Compound 1 Cyclamate Form A is a solvate. In some embodiments, Compound 1 Cyclamate Form A is a 2-methyltetrahydrofuran solvate. In some embodiments, Compound 1 Cyclamate Form A is a cyclopentyl methyl ether solvate. In some embodiments, Compound 1 Cyclamate Form A is an isopropyl acetate solvate.

[0059] In some embodiments, Compound 1 Cyclamate Form A is characterized by one or more peaks in its XRPD pattern selected from those at about 6.4, about 7.1, about 18.5, about 19.4, about 21.5 degrees 2-theta. In some embodiments, Compound 1 Cyclamate Form A is characterized by two or more peaks in its XRPD pattern selected from those at about 6.4, about 7.1, about 18.5, about 19.4, about 21.5 degrees 2-theta. In some embodiments, Air-Dried Compound 1 Cyclamate Form A is characterized by three or more peaks in its XRPD pattern selected from those at about6.4, about 7.1, about 18.5, about 19.4, about 21.5 degrees 2-theta. In some embodiments, Compound 1 Cyclamate Form A is characterized by four or more peaks in its XRPD pattern selected from those at about 6.4, about 7.1, about 18.5, about 19.4, about 21.5 degrees 2-theta.

[0060] In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0061] In some embodiments, Compound 1 Cyclamate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 1 (bottom trace) and / or FIG. 1 (third from top trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 2A (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 2A (bottom trace), FIG 2B (top trace), FIG 2B (middle trace), and / or FIG. 2B (bottom trace).Compound 1 l-Hydroxy-2-naphthoate

[0062] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and l-hydroxy-2-naphthoic acid (i.e., Compound 2, wherein X is l-hydroxy-2- naphthoic acid). In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and l-hydroxy-2-naphthoic acid. In some embodiments, a complex form comprises one equivalent of 1 -hydroxy -2-naphthoic acid. Compound 1 can exist in at least one crystalline salt form (“Compound 1 l-Hydroxy-2-naphthoate Form A”).Compound 1 l-Hydroxy-2-naphthoate Form A

[0063] In some embodiments, the present disclosure provides Compound 2 as Compound 1 1- Hydroxy-2-naphthoate Form A. In some embodiments, a Compound 1 1 -Hydroxy-2-naphthoate Form A is an anhydrate.

[0064] In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by one or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by two or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by three or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by four or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by five or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by six or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by seven or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by eight or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta. In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by nine or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7,about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2- theta.

[0065] In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by peaks in its XRPD pattern at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2-theta. In some embodiments, Compound 1 1 -Hydroxy -2-naphthoate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0066] In some embodiments, Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 3 A (bottom trace), FIG. 3B (top trace), FIG. 3B (bottom trace), FIG. 3C (top trace), and / or FIG. 3C (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 4A (top trace) and / or FIG. 4B (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 4A (bottom trace) and / or FIG. 4B (bottom trace).Compound 1 Naphthalene-2 -sulfonate

[0067] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and naphthalene-2-sulfonic acid (i.e., Compound 2, wherein X is naphthalene-2- sulfonic acid). In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and 1 -hydroxy -2 -naphthoic acid. Compound 1 can exist in at least one crystalline salt form (“Compound 1 Naphthalene-2-sulfonate Form A”).Compound 1 Naphthalene-2-sulfonate Form A

[0068] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Naphthalene-2-sulfonate Form A. In some embodiments, a Compound 1 Naphthalene-2-sulfonate Form A is an anhydrate.

[0069] In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by one or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthal ene-2-sulfonate Form A is characterized by two or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by three or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by four or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by five or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthal ene-2-sulfonate Form A is characterized by six or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2- sulfonate Form A is characterized by seven or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by eight or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by nine or morepeaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by ten or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta.

[0070] In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by peaks in its XRPD pattern at about 6.5, about 7.6, about 10.8, about 12.9, about 15.0, about 16.0, about 18.5, about 19.0, about 19.3, about 20.1, and about 20.8, about 21.1 degrees 2-theta. In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0071] In some embodiments, Compound 1 Naphthalene-2-sulfonate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 7A (bottom trace), FIG. 7B (top trace), FIG. 7B (bottom trace), FIG. 7C (top trace), and / or FIG. 7C (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 8A (top trace) and / or FIG. 8B (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 8A (bottom trace) and / or FIG. 8B (bottom trace).Compound 1 Formate

[0072] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and formic acid (i.e., Compound 2, wherein X is formic acid). In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and formic acid. Compound 1 can exist in at least one crystalline salt form (“Compound 1 Formate Form A”).Compound 1 Formate Form A

[0073] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Formate Form A. In some embodiments, a Compound 1 Formate Form A is an isopropyl acetate solvate. In some embodiments, Compound 1 Formate Form A is a hydrate.

[0074] In some embodiments, Compound 1 Formate Form A is characterized by one or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by two or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by three or more peaks in its XRPD pattern selected from thoseat about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by four or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by five or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by six or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by seven or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by eight or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta.

[0075] In some embodiments, Compound 1 Formate Form A is characterized by peaks in its XRPD pattern at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta. In some embodiments, Compound 1 Formate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0076] In some embodiments, Compound 1 Formate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 11 (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 12 (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 12 (bottom trace).Compound 1 Sodium Bisulfate

[0077] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and sodium bisulfate (i.e., Compound 2, wherein X is sodium bisulfate). In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and sodium bisulfate. Compound 1 can exist in at least two crystalline salt forms (“Compound 1 Sodium Bisulfate Form A” and “Compound 1 Sodium Bisulfate Form B”).Compound 1 Sodium Bisulfate Form A

[0078] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Sodium Bisulfate Form A. In some embodiments, a Compound 1 Sodium Bisulfate Form A is an ethanol solvate. In some embodiments, Compound 1 Sodium Bisulfate Form A is a hydrate.

[0079] In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by one or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by two or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by three or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by four or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by five or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by six or more peaks in its XRPD pattern selected from those about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta.

[0080] In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by peaks in its XRPD pattern at about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta.

[0081] In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0082] In some embodiments, Compound 1 Sodium Bisulfate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to those depicted in FIG. 13 (third from top trace);(ii) a TGA pattern substantially similar to those depicted in FIG. 14A (top trace); and(iii) a DSC pattern substantially similar to those depicted in FIG. 14A (bottom trace).Compound 1 Sodium Bisulfate Form B

[0083] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Sodium Bisulfate Form B. In some embodiments, a Compound 1 Sodium Bisulfate Form B is a 2-methyltetrahydrofuran solvate. In some embodiments, Compound 1 Sodium Bisulfate Form B is a hydrate.

[0084] In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by one or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by two or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by three or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by four or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by five or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by six or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by seven or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by eight or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by nine or more peaks in its XRPD pattern selected from those about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta.

[0085] In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by peaks in its XRPD pattern at about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta. In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by peaks in its XRPD pattern at substantially all of:

[0086] In some embodiments, Compound 1 Sodium Bisulfate Form B is characterized by one or more of the following:(i) an XRPD pattern substantially similar to those depicted in FIG. 13 (bottom trace);(ii) a TGA pattern substantially similar to those depicted in FIG. 14B (top trace); and(iii) a DSC pattern substantially similar to those depicted in FIG. 14B (bottom trace).Compound 1 Potassium Bisulfate

[0087] In some embodiments, the present disclosure provides a complex form comprising Compound 1 and potassium bisulfate (i.e., Compound 2, wherein X is potassium bisulfate). In some embodiments, the present disclosure provides a crystalline complex form comprising Compound 1 and potassium bisulfate. Compound 1 can exist in at least one crystalline salt forms (“Compound 1 Potassium Bisulfate Form A”).Compound 1 Potassium Bisulfate Form A

[0088] In some embodiments, the present disclosure provides Compound 2 as Compound 1 Potassium Bisulfate Form A. In some embodiments, a Compound 1 Potassium Bisulfate Form A is a 2-methyltetrahydrofuran solvate.

[0089] In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by one or more peaks in its XRPD pattern selected from those about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta. In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by two or more peaks in its XRPD pattern selected from those about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta. In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by three or more peaks in its XRPD pattern selected from those about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta. In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by four or more peaks in its XRPD pattern selected from those about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta. In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by five or more peaks in its XRPD pattern selected from those about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta.

[0090] In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by peaks in its XRPD pattern at about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta. In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by peaks in its XRPD pattern at substantially all of:

[0091] In some embodiments, Compound 1 Potassium Bisulfate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to those depicted in FIG. 15A (bottom trace), FIG. 15B (top trace), and / or FIG. 15B (bottom trace);(ii) a TGA pattern substantially similar to those depicted in FIG. 16 (top trace); and(iii) a DSC pattern substantially similar to those depicted in FIG. 16 (bottom trace).Preparing Provided Forms

[0092] In some embodiments, the present disclosure provides methods of preparing Compound 2 (i.e., salt forms of Compound 1), as well as solid forms of Compound 2. The present disclosure also provides methods of preparing compositions comprising mixtures of Compound 1 and / or Compound 2 in one or more solid forms and / or an amorphous form.Compound 2

[0093] In some embodiments, Compound 2 (e.g., amorphous Compound 2, crystalline Compound 2, or a mixture thereof) is prepared by contacting Compound 1 (e.g., amorphous Compound 1, crystalline Compound 1, or a mixture thereof) with a suitable acid, such as cyclamic acid, l-hydroxy-2-naphthoic acid, naphthal ene-2-sulfonic acid, formic acid, sodium bisulfate, or potassium bisulfate. In some embodiments, the present disclosure provides a method of preparing Compound 2 comprising steps of providing Compound 1; and combining Compound 1 with a suitable acid, optionally in a suitable solvent, to provide Compound 2. In some embodiments, about 1.0, about 1.1, about 1.2, or about 2.0 equivalents of suitable acid are added.

[0094] In some embodiments, a solid form of Compound 2 is prepared by dissolving Compound 2 (e.g., amorphous Compound 2, crystalline Compound 2, or a mixture thereof) in a suitable solvent and then causing Compound 2 to return to the solid phase. In some embodiments, a solid form of Compound 2 is prepared by combining Compound 2 (e.g., amorphous Compound2, crystalline Compound 2, or a mixture thereof) in a suitable solvent under suitable conditions and isolating the solid form of Compound 2.

[0095] In some embodiments, a suitable solvent is selected from ethanol, methanol, 2- methyltetrahydrofuran, cyclopentylmethyl ether, isopropyl acetate, and water, or any combination thereof.

[0096] In some embodiments, a method of preparing Compound 2 (e.g., a solid form of Compound 2) comprises a step of heating a mixture comprising Compound 2 to a suitable temperature (e.g., from about 30 °C to about 60 °C). In some embodiments, a method of preparing Compound 2 (e.g., a solid form of Compound 2) comprises a step of stirring a mixture comprising Compound 2 at ambient temperature. In some embodiments, a method of preparing Compound 2 (e.g., a solid form of Compound 2) comprises a step of cooling a mixture comprising Compound 2 to a suitable temperature (e.g., from about -20 °C to about 5 °C). In some embodiments, a method of preparing Compound 2 (e.g., a solid form of Compound 2) comprises a step of heating a mixture of Compound 2 and a solvent to a suitable temperature such that Compound 2 is dissolved, followed by cooling the mixture of Compound 2 and the solvent to cause crystals of Compound 2 to form and grow.

[0097] In some embodiments, Compound 2 (e.g., a solid form of Compound 2) precipitates from a mixture (e.g., a solution, suspension, or slurry). In some embodiments, Compound 2 crystallizes from a solution. In some embodiments, Compound 2 crystallizes from a solution following seeding of the solution (e.g., adding crystals of Compound 2 to the solution). In some embodiments, Compound 2 precipitates or crystallizes from a mixture after cooling, addition of an anti-solvent, and / or removal of all or part of a solvent through methods such as evaporation, distillation, filtration, reverse osmosis, absorption, or reaction.

[0098] In some embodiments, a method of preparing Compound 2 (e.g., a solid form of Compound 2) comprises a step of isolating Compound 2. It will be appreciated that Compound 2 may be isolated by any suitable means. In some embodiments, Compound 2 (e.g., a solid form of Compound 2) is separated from a supernatant by filtration. In some embodiments, Compound 2 (e.g., a solid form of Compound 2) is separated from a supernatant by decanting.

[0099] In some embodiments, isolated Compound 2 (e.g., an isolated solid form of Compound 2) is dried (e.g., in air or under reduced pressure, optionally at elevated temperature).

[0100] In some embodiments, a solid form of Compound 2 is prepared by converting one solid form of Compound 2 into another solid form of Compound 2.Compositions

[0101] In some embodiments, the present disclosure also provides compositions comprising one or more salt forms of Compound 1. In some embodiments, provided compositions comprise Compound 2, e.g., Compound 1 Cyclamate Form A, Compound 1 l-Hydroxy-2-naphthoate Form A, Compound 1 Naphthalene-2-sulfonate Form A, Compound 1 Formate Form A, Compound 1 Sodium Bisulfate Form A, Compound 1 Sodium Bisulfate Form B, Compound 1 Potassium Bi sulfate Form A, or a mixture thereof.

[0102] In some embodiments, a provided composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2) is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the composition contains no significant amount of extraneous matter. Such extraneous matter may include starting materials, residual solvents, or any other impurities that may result from the preparation of and / or isolation of a crystalline solid form. In some embodiments, the composition comprises at least about 90% by weight of a crystalline solid form. In some embodiments, the composition comprises at least about 95% by weight of a crystalline solid form. In some embodiments, the composition comprises at least about 99% by weight of a crystalline solid form.

[0103] In some embodiments, a provided composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) is substantially pure (e.g., comprises 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, a composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) comprises no more than about1.0 percent of total organic impurities. In some embodiments, a composition comprising a crystalline solid form (e.g., a crystalline solid form of Compound 2) comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

[0104] In some embodiments, a composition comprises a crystalline solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2) and an amorphous solid form (e.g., an amorphous solid form of Compound 1 and / or Compound 2). In some embodiments, a composition comprising a crystalline solid form is substantially free of an amorphous solid form. As used herein, the term “substantially free of an amorphous solid form” means that the composition contains no significant amount of an amorphous solid form. In some embodiments, the composition comprises at least about 90% by weight of a crystalline solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2). In some embodiments, the composition comprises at least about 95% by weight of a crystalline solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2). In some embodiments, the composition comprises at least about 99% by weight of a crystalline solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2). In some embodiments, the composition comprises no more than about 10% by weight of an amorphous solid form (e.g., an amorphous solid form of Compound 1 and / or Compound 2). In some embodiments, the composition comprises no more than about 5% by weight of an amorphous solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2). In some embodiments, the composition comprises no more than about 1% by weight of an amorphous solid form (e.g., a crystalline solid form of Compound 1 and / or Compound 2).

[0105] In some embodiments, a composition comprises a free base form (e.g., Compound 1) and a salt form (e.g., Compound 2). In some such embodiments, a free base form is crystalline, amorphous, or a mixture thereof; in some such embodiments, a salt form is crystalline, amorphous, or a mixture thereof.

[0106] In some embodiments, a composition comprises a mixture of crystalline solid forms (e.g., a mixture of one or more crystalline forms of Compound 1 and / or Compound 2).Uses

[0107] Compounds and compositions described herein are generally useful for the inhibition of the estrogen receptor (ER) and mutants thereof. In some embodiments, the present disclosureencompasses the insight that compounds and compositions described herein are useful for treatment of an ER-associated disorder (e.g., an ER-associated cancer, such as breast cancer, including metastatic brain cancer), detection of the same, and / or characterization of certain tumors.

[0108] For example, in some embodiments, the present disclosure provides certain methods of treatment in a subject having an ER-associated disease, disorder, or condition. In some embodiments, an ER-associated disease, disorder or condition is a cancer. In some embodiments, an ER-associated 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, an ER-associated disease, disorder, or condition is breast cancer.

[0109] In some embodiments, a subject has been determined or is suspected of having a cancer that has metastasized (e.g., to the brain, bones, lungs, liver, or the central nervous system). In some embodiments, a subject has been determined or is suspected of having brain metastases. In some embodiments, the subject has developed brain metastases related to an ER-associated cancer, e.g., breast cancer, or a mutation to the estrogen receptor.

[0110] In some embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex form thereof, to a subject previously treated with an ER inhibitor. In some such embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex form thereof, to a subject previously treated with a Selective Estrogen Receptor Modulator (SERM), including, for example, tamoxifen, endoxifene, raloxifene, toremifene, lasofoxifene, and ospemifene.[oni] In some embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex form thereof, to a subject suffering from an ER-associated disorder (e.g., breast cancer) that is unresponsive to therapy with a SERM, including, for example, tamoxifen, endoxifene, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0112] In some embodiments, a subject has relapsed during or following therapy with a SERM, including, for example, tamoxifen, endoxifene, raloxifene, toremifene, lasofoxifene, and ospemifene.

[0113] In some embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex form thereof, to a subject with estrogen receptor positive (ER+) and human epidermal growth factor receptor negative (HER-) disease. In some embodiments, aprovided method comprises administering Compound 1, or a crystalline form or complex form thereof, to a subject with estrogen receptor positive (ER+) and human epidermal growth factor receptor positive (HER+) disease.

[0114] In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 15 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 30 mg to about 360 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 30 mg to about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about to 60 mg to about 120 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is 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 the subject in an amount that is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 90 mg. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg.

[0115] In some embodiments, Compound 1 is administered to the subject in an amount that is about 15 mg to about 360 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg to about 360 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg to about 300 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is about 60 mg to about 120 mg per day (QD). In some embodiments, Compound 1 is administered to the subject in an amount that is from about 15 mg to about 100 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is 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 the subject in an amount that is about 120 mg, about 150 mg, about 210 mg, or about 300 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 30 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about60 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 90 mg QD. In some embodiments, Compound 1 is administered to the subject in an amount that is about 120 mg QD.

[0116] In some embodiments, Compound 1 is administered to the subject in a unit dosage form. In some embodiments, unit dosage form is a capsule or tablet. In some embodiments, a unit dosage form comprises about 15 mg to about 120 mg of Compound 1. In some embodiments, a unit dosage form comprises about 15 mg to about 100 mg of Compound 1. In some embodiments, a unit dosage form comprises about 60 mg to about 120 mg of Compound 1. In some embodiments, a 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, a unit dosage form comprises about 15 mg of Compound 1. In some embodiments, a unit dosage form comprises about 30 mg of Compound 1. In some embodiments, a unit dosage form comprises about 60 mg of Compound 1. In some embodiments, a unit dosage form comprises about 90 mg of Compound 1. In some embodiments, a unit dosage form comprises about 120 mg of Compound 1. In some embodiments, a unit dosage form is a capsule. In some embodiments, a unit dosage form is a tablet.

[0117] In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is about 15 mg to about 360 mg per day (QD). In some embodiments, a total daily dose of Compound 1 administered to the subject is about 30 mg to about 360 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 30 mg to about 300 mg. In some embodiments, atotal daily dose of Compound 1 administered to the subject is about 60 mg to about 120 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is from about 15 mg to about 100 mg QD. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is 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, a total daily dose of Compound 1 administered to the subject is about 120 mg, about 150 mg, about 210 mg, or about 300 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is in an amount that is about 30 mg QD. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 60 mg. In some embodiments, a total daily dose of Compound1 administered to the subject is about 90 mg. In some embodiments, a total daily dose of Compound 1 administered to the subject is about 120 mg.Combination Therapy

[0118] The present disclosure encompasses the recognition that a combination of certain agents can beneficially be used to completely antagonize the estrogen receptor. Accordingly, in some embodiments, the present disclosure provides a method of treating a subject suffering from an ER-associated disorder (e.g., a cancer, e.g., a breast cancer) comprising administering a complete estrogen receptor antagonist and an anti-cancer agent. For example, in some embodiments, a complete estrogen receptor antagonist is Compound 1 in any suitable form (e.g., a crystalline form or complex form thereof). In some embodiments, an anti-cancer agent is a CDK 4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

[0119] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1 in any suitable form) and a CDK4 / 6 inhibitor (i.e., an agent that inhibits one or both of CDK4 and CDK6). In some embodiments, an anti -cancer agent is a CDK4 / 6 inhibitor selected from palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, and SHR6390. In some embodiments, a CDK4 / 6 inhibitor is palbocociclib. In some embodiments, a CDK4 / 6 inhibitor is ribociclib. In some embodiments, a CDK4 / 6 inhibitor is abemaciclib. In some embodiments, a CDK4 / 6 inhibitor is lerociclib. In some embodiments, a CDK4 / 6 inhibitor is trilaciclib. In some embodiments, a CDK 4 / 6 inhibitor is SHR6390.

[0120] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1 in any suitable form) and a PIK3CA inhibitor. In some embodiments, a PIK3CA inhibitor is selected from alpelisib, taselisib, and LY3023414. In some embodiments, a PIK3CA inhibitor is alpelisib. In some embodiments, a PIK3CA inhibitor is taselisib. In some embodiments, a PIK3CA inhibitor is LY3023414.

[0121] In some embodiments, the present disclosure provides a method of treating a patient or subject suffering from a cancer, the method comprising administering a complete estrogen receptor antagonist (e.g., Compound 1 in any suitable form) and an mTOR inhibitor. In some embodiments, an mTOR inhibitor is selected from sirolimus, temsirolimus, everolimus, and LY3023414. Insome embodiments, an mTOR inhibitor is sirolimus. In some embodiments, an mTOR inhibitor is temsirolimus. In some embodiments, an mTOR inhibitor is everolimus. In some embodiments, an mTOR inhibitor is LY3023414.

[0122] In some embodiments, the present disclosure provides methods of treating a subject with ER+ and HER+ disease with a complete estrogen receptor antagonist (e.g., Compound 1 in any suitable form) and a HER2 inhibitor. In some embodiments, a HER2 inhibitor is selected from tucatinib, pertuzumab, lapatinib, trastuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, and neratinib.

[0123] It is understood that combination therapy comprising a complete estrogen receptor antagonist and an anti-cancer agent described herein can comprise administration of the agents simultaneously or separately. For example, in some embodiments, a complete estrogen receptor antagonist and an anti-cancer agent are administered simultaneously. In some embodiments, an anti-cancer agent is administered prior to administration of a complete estrogen receptor antagonist. In some embodiments, an anti-cancer agent is administered after administration of a complete estrogen receptor antagonist.EXAMPLES

[0124] The Examples provided herein document and support certain aspects of the present disclosure but are not intended to limit the scope of any claim. The following non-limiting examples are provided to further illustrate certain teachings provided by the present disclosure. Those of skill in the art, in light of the present application, will appreciate that various changes can be made in the specific embodiments that are illustrated in the present Examples without departing from the spirit and scope of the present teachings.

[0125] The following abbreviations may be used in the Examples below: 2-MeTHF (2- methyltetrahydrofuran); aq. (aqueous); ACN (acetonitrile); br (broad); CPME (cyclopentyl methyl ether); DCM (dichloromethane); DMF (N,N-dimethylformamide); EA (elemental analysis); EtOAc (ethyl acetate); ee (enantiomeric excess); equiv. (equivalent); ethanol (EtOH); h (hour or hours); Hex (hexanes); HPLC (high-performance liquid chromatography); HPW (highly purified water); IPA (isopropyl alcohol); IP Ac (isopropyl acetate); LC (liquid chromatography); LCMS (liquid chromatography-mass spectrometry); MEK (methyl ethyl ketone); MeOH (methanol); min(minute or minutes); NMR (nuclear magnetic resonance); Rf (retention factor); rt or RT (room temperature); sat. (saturated); SM (starting material); TGA (thermogravimetric analysis); THF (tetrahydrofuran); TLC (thin layer chromatography); wt% (weight percent); and XRPD (X-Ray Powder Diffraction).Example 1: Synthesis of Compound 1

[0126] A complete synthesis of Compound 1 is provided in PCT Pub. No. WO 2017 / 059139, which is incorporated herein by reference and repeated below.Preparation of 4-((l-propylazetidin-3-yl)oxy)benzaldehyde:

[0127] The compound 3-azetidinone hydrochloride (10.000 g, 93.0 mmol, 1.0 equiv.), anhydrous 1,2-di chloroethane (200 mL) and diisopropylethylamine (38.9 mL, 223 mmol, 2.4 equiv.) were added to a round bottom flask (500 mL) to provide a light yellow suspension. The suspension was sonicated for 1 h and then cooled to -10 °C (dry-ice / MeOH) for 10 min. Propionyl chloride (9.8 mL, 112 mmol, 1.2 equiv.) was added dropwise to the cooled suspension to provide an orange solution. The reaction was removed from the bath and stirred at room temperature for 16 h. The solvent was removed to provide a semi-solid. The semi-solid was suspended into EA (300 mL) and the suspension was filtered. The solid was rinsed with EA (2 x 100 mL). TLC analysis (10% MeOH / DCM, KMnO? stain / Heat) indicated there were three spots: Rf: 0.2, 0.5, 0.7. TLC (50% EA / Hex, KMnO? stain / Heat) indicated there were two spots: Rf: 1, 0.3. The filtrate was concentrated, adsorbed onto silica gel (25 g) and chromatographed through silica gel (100 g cartridge) with DCM (5 min) then 0-10 % MeOH over 15 min. The product came off early from the column in DCM and continued to elute from the column with up to 10 % MeOH. TLC in both solvent systems was carried out to determine if any propionyl chloride was present in earlyfractions. Fractions containing product were pooled and concentrated to afford the title compound as a yellow liquid (11.610 g, 98.2%).

[0128] ^NMR (300 MHz, CDCI3) 5: 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).Step 2. Preparation of 1-propylazeti din-3 -ol

[0129] Lithium aluminum hydride (10.397 g, 273.9 mmol, 3.0 equiv.) was suspended into THF (200 mL) and cooled in an ice bath. A solution of l-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 min. The addition funnel was removed. The flask was then fitted with a condenser and the reaction was heated at reflux in an oil bath at 75 °C for 16 h. The reaction was cooled in an ice bath for 20 min and sodium sulfate decahydrate (Glauber's salt, 25 g) was added in small portions over 20 min. After complete addition, the mixture was stirred at room temperature for 2 h. The mixture was filtered through a bed of Celite® (2 cm) and the solids 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 without further purification in the preparation of the compounds of the examples below.

[0130] ^NMR (300 MHz, CDC13) 6: 4.39 (pent, 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 (hextet, J= 7.2 Hz, 2H), 0.87 (t, J = 7.8 Hz, 3H).Step 3. Preparation of 4-((l-propylazetidin-3-yl)oxy)benzaldehyde

[0131] 4-Fluorobenzaldehyde (15.00 g, 120.9 mmol, 0.9 equiv.), 1-propylazeti din-3 -ol (15.00g, 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 with a Teflon™ stir bar in a 500 mL round bottomed flask. The flask was sealed and heated in a heat block at 95 °C for 6 h. The reaction was analyzed by LCMS to indicate the aldehyde was consumed. The suspension was filteredthrough 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 x 200 mL), brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an orange liquid (21.74 g, 76,1 %). The material was used without further purification.

[0132] 1HNMR (300 MHz, CDCI3), 6 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).

[0133] Indole-3-acetone (25.0 g, 144 mmol, 1.0 equiv.) was added to a solution of (7?)-(+)-l- phenylethylamine (23.0 mL, 181 mmol, 1.3 equiv.) in dichloromethane (600 mL) under N2 at 25 °C and the mixture was allowed to stir for 1 hr. The reaction was cooled to 0-5 °C and sodium triacetoxyborohydride (100 g, 472 mmol, 3.3 equiv.) was added over 30 minutes via powder addition funnel to the ice cooled solution. The orange solution was stirred for 1 h at 0 °C and then was allowed to warm to RT. The reaction was stirred at RT for 19 h. At this time, ESI+ indicated that no indole starting material was present. Saturated NaHCCL solution (lOOmL) was added in 5 mL portions over 15 min at 10 °C with vigorous stirring. The solution was stirred for 15 min and sat. Na2CC>3 solution (200 mL) was added over 15 minutes. Solid K2CO3 (9 g) was added in 3 g portions at which 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 sat. aq. NaHCCf (2 x 100 mL). The aqueous layers were combined and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product (49 g). TLC (90: 10 DCM:MeOH) showed four spots (Rf = 0.63, 0.50, 0.16, 0.26), two of which were the separated diastereomeric major products (Rf = 0.16 and 0.26). The crude was adsorbed onto silica gel and purified via flash chromatography (330 g cartridge, 0-100% EA:Hex). Fractions containing the R,R diastereomer were pooled and purified a second time with the same flash chromatography conditions to afford 24 g of product (-82% ee). Previous successful separationwas achieved by a silica gekcrude ratio of 40: 1, so the mixture was divided into 3 portions and separated on 3 x 330 g silica gel cartridges (0-40% EA / Hex for 20 min, isocratic 40% EA / Hex 40 min). All fractions containing the desired product were > 99 % diastereomerically pure. Pure fractions were concentrated and pooled to yield (A)-l-(lH-indol-3-yl)-N-((7?)-l-phenylethyl)- propan-2-amine as an orange semi-solid (11.91 g, 29.6 %).

[0134] 'H NMR (CDCh, 300 MHz) R, R diastereomer: 6 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: 5 1.11 (d, J = 5.7 Hz, 3H), 1.30 (d, J = 5.4 Hz, 3H) 2.80 (m, 3H), 3.92 (q, J= 6.9 Hz, 1H), 6.93-7.40 (m, 10H), 8.13 (br s, 1H); the aromatic region was difficult to distinguish from the R, R diastereomer due to lack of purity.

[0135] LCMS: ES+ [M+H]+ 279.0.

[0136] The compound ( )-l-(lH-indol-3-yl)-A-(( )-l-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 and the solution was sparged with N2 for 10 min. 20% Pd(OH)2 on carbon wet with water (10.71 g, 76.3 mmol, 1.8 equiv.) was added and the bottle was pressurized with 50 psi of hydrogen and shaken in a Parr apparatus for 22 h, LCMS analysis indicated that the reaction was completed. The suspension was filtered through Celite® and concentrated to remove MeOH. The crude was dissolved into DCM and washed with saturated ISfeCCh solution (50 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The organic layers were combined, dried, and concentrated to yield (27?)-l-(lH-indol-3-yl)propan-2-amine as a light brown solid that did not require further purification (6.68 g, 89.6 %).

[0137] 1H NMR (CDC13, 300 MHZ) 8 1.17 (d, J= 6.6 Hz, 3H), 2.66 (dd, 7= 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).

[0138] LCMS: ES+ [M+H]+ 174.9.Preparation of 2-fluoro-2-methylpropanol:

[0139] 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 hours, 2.0 mL water, 2.0 mL 15% w / v NaOH, and 5.0 mL water were added sequentially dropwise. After 15 min, the white suspension was diluted with DCM, gravity fdtered through Celite®, and the solids were washed with DCM. The filtrate was concentrated (200 mbar, 25 °C) to afford 2-fluoro-2- methylpropanol as a colorless oil (2.09 g, 56.1 %).

[0140] 1H NMR (300 MHz, CDC13) 8 1.34 (d, J = 21.3 Hz, 6H), 1.95 (br t, 1H), 3.56 (dd, J = 6.6, 20.7 Hz, 2H).

[0141] Trifluoromethanesulfonic anhydride (5.0 mL, 29.7 mmol, 1.3 equiv.) was added dropwise to a 0 °C 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) over 30 minutes. After 2 hours, the red solution had turned light brown. TLC (20:80 EA:Hex, KMnCU stain) indicated that the starting material was not present. The reaction mixture was washed with IM HC1 solution (2 x 20 mL) and sat. NaHCCL solution (2 x 20 mL). The aqueous layers were each back extracted with DCM (20 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure (150 mbar, 25 °C) to afford 2-fluoro-2-m ethylpropyl trifluoromethanesulfonate as a red oil (4.39 g, 86.3%).

[0142] ^NMR (300 MHz, CDCI3) 8 1.46 (d, J = 20.4 Hz, 6H), 4.41 (d, J = 18.6 Hz, 2H).19F NMR (282 MHz, CDCI3) 8 -147.1, -74.5.Preparation of (R)-N-( I -( lH-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-l -amine:

[0143] The compound 2-fluoro-2-methylpropyl trifluoromethanesulfonate (9.587 g, 42.8 mmol, 1.1 equiv.) (solution in DCM, 16% DCM by wt%, 11.4384 g) was added to a solution of (2R)-l-(lH-indol-3-yl)propan-2-amine (6.680 g, 38.3 mmol, 1.0 equiv.), anhydrous 1,4-dioxanes (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 hours. After 3h, LCMS indicated that a small amount of indolamine starting material was still present. TLC (10% MeOH / DCM) indicated triflate (Rf = 0.54) had been used up. NMR of unused triflate SM (286- 30) indicated the triflate had not decomposed overnight, so another 0.1 equiv (0.9883 g, 13% DCM wt%, 0.8563 g triflate SM) was added and the reaction was heated for 2 h at 90 °C. LCMS indicated the reaction had completed and TLC (10% MeOH / DCM) showed one spot (Rf = 0.24) (TLC with 50% EA / Hex, 1 streaked spot Rf <= 0.12, another spot at Rf = 0). EtOAc (50 mL) was added and the solution was washed with NaHCOs (2 x 50 mL) and the combined aqueous layer was washed with EtOAc (50 mL). The combined organic extracts were dried over Na SO4 and concentrated under reduced pressure. The crude (brown oil, 14.8 g) was purified via flash silica chromatography (240 g cartridge, 0-100% EA / Hex). The desired product eluted as a long tailing peak. Pure fractions were concentrated to yield (R)-N-(l-(lH-indol-3-yl)propan-2-yl)-2-fluoro-2- methylpropan-1 -amine (4.211 g, 17.0 mmol) as a dark yellow oil.

[0144] 'H NMR (300 MHz, CDC13) 6 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).19F NMR (282 MHz, CDCI3) 8 -144.2. m / z: ES+ [M+H]+ 249.0.Preparation of Compound 1

[0145] 4-((l-propylazeti din-3 -yl)oxy)benzaldehy de (0.096 g, 0.4 mmol, 1.3 equiv.) was added to a solution of (A)-N-(l-(lH-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-l-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 under N2 in the dark at 80 °C for 8 hours. The reaction solution was diluted in DCM, filtered, and washed with saturatedNa2COs solution. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4. The solution was fdtered and concentrated. The residue was dissolved into acetonitrile (2 mL) and filtered through a syringe filter before purification via prep LC (40 to 90% ACN:H2O over 18 min, followed by isocratic 90% ACN for 7 min). Pure fractions were concentrated and dried to afford (lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-l-(4-((l- propylazetidin-3-yl)oxy)phenyl)-2,3,4,9,-tetrahydro-lH-pyrido[3,4-b]indole as a white powder.

[0146] ^NMR (300 MHz, CDC13) 8 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 (quin, 7= 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.Example 2: Instruments and MethodsXRPD

[0147] XRPD was performed with a Panalytical Aeris Powder XRPD (CPNJ-E51) on a Si zero-background holder. The 20 position was calibrated against a Panalytical Si reference standard disc. The parameters used are listed in Table 1.Table 1 Parameters for XRPD testParameters Reflection ModeCu, kaKai (A): 1.540598, X-Ray wavelengthKa2 (A): 1.544426,Ka2 / Kal intensity ratio: 0.50X-Ray tube setting 40 kV, 15 mADivergence slit Fixed 1 / 8°Scan mode ContinuousScan range3-40(° 2TH)Scan step time [s] 17.595Step size (° 2TH) 0.0109Test Time 4.5 minTGA and DSC

[0148] TGA data was collected using a TA Discovery 550 TGA from TA Instrument (CPNJ- E4). TGA was calibrated using a nickel reference standard. DSC was performed using a TA D2500 DSC from TA Instrument (CPNJ-E27). DSC was calibrated with an Indium reference standard. Detailed parameters used are listed in Table 2.Table 2 Parameters for TGA and DSC testParameters TGA DSCMethod Ramp RampSample pan Platinum, open Aluminum, crimpedTemperature RT - desired temperature 25 °C - desired temperatureHeating rate 10 °C / min 10 °C / minPurge gas N2 N2DVS

[0149] DVS was measured via a SMS (Surface Measurement Systems) DVS Resolution (CPNJ-E54). The relative humidity at 25 °C was calibrated against the deliquescence point of LiCl, Mg(NC>3)2 and KC1. Actual parameters for DVS test were listed in Table 3.Table 3 Parameters for DVS testItem ValueTemperature 25 °CSample size 10 - 20 mgGas and flow rate N2, 200 mL / min dm / dt 0.002% / minMin. dm / dt stability duration 10 minMax. equilibrium time 180 minRH range Ambient % RH - 95% RH - 0% RH - 95% RHRH step size 10%HPLC

[0150] For High-performance Liquid Chromatography (HPLC) analysis, a Thermo Scientific system (CPNJ-E42) was used to determine the Compound l:salt stoichiometry. The method parameters used are listed in Table 4.Table 4 HPLC ParametersHPLC Method ParametersInstrument Thermo Scientific HP CColumn Waters XSelect CSH Cl 8, 4.6 x 150 mm, 3.5 pm (PN: 186005270) A: 100 mM Formic Acid in HPWB: 100% AcetonitrileTime (min) % A % B0.0 50 50Gradient 10.0 35 6525.0 35 6530.0 20 8035.0 50 50Run Time 35.0 minFlow Rate 1.0 mL / minInj ection V olume 10 pLColumn temperature 40 °CWavelength 254 nmDiluent 90: 10 ACN:HPWExample 3: Solubility Screening of Compound 1

[0151] The solubility of Compound 1 was estimated at RT. Approximately 2 mg Compound 1 were added into a glass vials. Solvents in Table 5 were then added stepwise to the vials until the solids were dissolved or a total volume of 1 mL was reached.Table 5 Approximate solubility of Compound 1 at RTSolvent Solubility (mg / mL) Solvent Solubility (mg / mL)H2O <3.3 CHC13>66.0MeOH >86.0 DMF >54.0EtOH >78.0 Toluene >68.0IPA >66.0 n-Heptane >46.0ACN >52.0 1-Butanol >66.0Acetone >62.0 n-Propanol >58.0EtOAc >58.0 MEK >66.0IPAc >72.0 2-MeTHF >68.0THF >56.0 CPME >56.0MTBE >56.0Example 4: Screening far Compound 2 Solid Forms

[0152] Salt screening of Compound 1 was performed with 19 co-formers and 5 solvents. 25 mg of amorphous Compound 1 (see, for example, FIG. 1 (top trace) for XRPD spectrum) and a corresponding molar ratio of co-former (1: 1 or 1 :2) were dissolved separately in the selected solvents (EtOH / FFO (3: 1), MeOH, 2-MeTHF, CPME, IP Ac). Then, the dissolved solutions were combined and allowed to stir at RT. After stirring overnight, solids were isolated for XRPD analysis. If no precipitation was observed, the clear solutions were transferred to 5 °C or evaporated at RT to induce precipitation. The solids were then analyzed, e.g., with XRPD. The results of salt screening are summarized in Table 6.Table 6 Summary of salt screening experiments* Moved to 5 °C; ** Set to slow evaporation; $ Moved to temperature cyclingNote: Temperature cycling between 50 °C and 5 °C at a rate of 0.1 °C / mm was applied to gels, or samples yielding amorphous solids to facilitate crystallization through periodic dissolution and precipitation.APurple solids formedNote: Pure EtOH was used to dissolve Compound 1 for column “a”Example 5: Preparation and Characterization of Compound 2 Solid FormsCompound 1 Cyclamate Form A

[0153] Compound 1 Cyclamate Form A was observed from reactive crystallization of Compound 1 with cyclamic acid (1 : 1 mole ratio) in 2-MeTHF as described in Example 4. The salt was also obtained from 2-MeTHF where the Compound 1 :acid mole ratio was 1 :2, and from CPME and IP Ac with a 1 : 1 Compound 1 :acid mole ratio.An initial XRPD pattern of Compound 1 Cyclamate Form A obtained using 2-MeTHF as the solvent is shown in FIG. 1 (third from top).

[0154] The XRPD pattern in FIG. 1 (bottom) showed that the Compound 1 Cyclamate Form A exhibited a different XRPD pattern after air-drying, suggesting that it may be a labile solvate. The corresponding data are summarized below:

[0155] PLM imaging showed irregularly shaped, birefringent particles.

[0156] TGA showed a weight loss of 4.11% up to 198.5 °C and the DSC thermogram exhibited a melting endotherm with an onset of 151.0 °C (FIG. 2A). A low enthalpy of melting (6.50 J / g)was observed. The solvate stoichiometry based on the TGA weight loss was 1 :0.31 (Compound 1 :2- MeTHF). Based on these data, the sample was assigned as a hemi 2-MeTHF solvate.

[0157] Compound 1 Cyclamate Form A samples obtained by reactive crystallization from IP Ac and CPME also showed low enthalpies of melting of 31.9 and 21.9 J / g respectively, suggesting that they may be isostructural solvates (FIG. 2B).Compound 1 l-Hydroxy-2-naphthoate Form A

[0158] Compound 1 l-Hydroxy-2-naphthoate Form A was observed from reactive crystallization of Compound 1 with l-hydroxy-2-naphthoic acid (1: 1) in EtOH / FEO (3:1) as described in Example 4.

[0159] The XRPD pattern in FIG. 3 A indicated that Compound 1 l-Hydroxy-2-naphthoate Form A has a different pattern from the starting materials. The corresponding data are summarized below:

[0160] PLM imaging showed irregularly shaped, birefringent particles.

[0161] TGA showed a negligible weight loss of 0.36% up to 164.8 °C and the DSC thermogram exhibited a melting endotherm with an onset of 184.2 °C (FIG. 4A). Based on the thermal data, the salt was considered anhydrous.

[0162] Compound 1 l-Hydroxy-2-naphthoate Form A was also prepared by dissolving 120 mg of Compound 1 in 0.96 mL of EtOH. Separately, 50.2 mg of 1 -hydroxy -2-naphthoic acid was dissolved in 2.88 mL of EtOH / H2O (3: 1) and then the solutions were combined. The salt was quickly formed after stirring at room temperature, and stirring the suspension overnight resultedin additional generation of solids. As displayed in FIG. 3B, the sample showed substantially the same pattern by XRPD as the salt prepared previously.

[0163] PLM imaging showed irregularly shaped, birefringent particles.

[0164] The TGA of the sample indicated a weight loss of 0.36% up to 165.0 °C, and the DSC thermogram exhibited a melting endotherm with an onset of 185.2 °C (FIG. 4B).

[0165] Analysis of the sample by HPLC in duplicate indicated a 1 :0.95 (Compound Ecounterion) salt stoichiometry (FIG. 5).

[0166] DVS showed a 0.4% weight gain at 25 °C / 80% RH, indicating that the sample is slightly hygroscopic in nature (FIG. 6). No form change was observed by XRPD post-DVS test (FIG. 3C).Compound 1 Napthalene-2-sulfonate Form A

[0167] Compound 1 Naphthalene-2-sulfonate Form A was observed from reactive crystallization with naphthalene-2-sulfonic acid (1 : 1) in CPME as described in Example 4. The XRPD pattern shown in FIG. 7A indicated that Compound 1 Naphthal ene-2-sulfonate Form A has a different pattern from the starting materials. The corresponding data are summarized below:

[0168] PLM imaging showed irregularly shaped, birefringent particles.

[0169] TGA showed a weight loss of 0.23% up to 153.9 °C and the DSC thermogram exhibited a melting endotherm with an onset of 167.2 °C (FIG. 8A). Based on the thermal data, the salt was considered anhydrous.

[0170] Compound 1 Naphthalene-2-sulfonate Form A was also prepared by dissolving 120 mg of Compound 1 in 0.96 mL of IP Ac. Separately, 55.6 mg of naphthalene-2-sulfonic acid was dissolved in 2.88 mL of IPAc and then the solutions were combined. The salt was quickly formed after stirring at room temperature, and stirring the suspension overnight yielded additional generation of solids. As displayed in FIG. 7B, the sample showed substantially the same pattern by XRPD as the salt prepared previously.

[0171] PLM imaging showed irregularly shaped, birefringent particles.

[0172] The TGA of the sample indicated a weight loss of 0.08% up to 154.0 °C by TGA, and the DSC thermogram exhibited a melting endotherm with an onset of 171.6 °C.

[0173] Analysis of the sample in duplicate by HPLC indicated a 1 : 1.26 (Compound 1 counterion) salt stoichiometry (FIG. 9).

[0174] DVS showed a 0.2% weight gain at 25 °C / 80% RH, indicating that the sample is slightly hygroscopic in nature (FIG. 10). No form change was observed post-DVS test by XRPD (FIG. 7C).Compound 1 Formate Form A

[0175] Compound 1 Formate Form A was observed from reactive crystallization with formic acid (1 : 1) in IP Ac as described in Example 4. The XRPD pattern in FIG. 11 showed that Compound 1 Formate Form A has a different pattern from the starting material. The corresponding data are summarized below:

[0176] PLM imaging showed plate-like, birefringent particles.

[0177] TGA showed a weight loss of 4.96% up to 109.3 °C and the DSC thermogram exhibited a melting endotherm with an onset of 76.7 °C (FIG. 12). Based on the TGA weight loss, the calculated stoichiometry was 1 :0.25 (Compound l :IPAc) for a solvate and 1: 1.43 (Compound 1 :H2O) for a hydrate.Compound 1 Sodium Bisulfate Form A

[0178] Compound 1 Sodium Bisulfate Form A was observed from reactive crystallization with NaHSCE (1:1) in EtOH / FEO (3:1) as described in Example 4. The XRPD pattern shown in FIG. 13 indicated that Compound 1 Formate Form A has a different pattern from the starting materials. The corresponding data are summarized below:

[0179] PLM imaging showed irregularly shaped, birefringent particles.

[0180] TGA showed a weight loss of 1.38% up to 185.0 °C and the DSC thermogram exhibited two broad endotherms with onsets of 35.6 and 122.3 °C (FIG. 14A). Based on the TGA weight loss, the calculated stoichiometry is 1:0.17 (Compound l :EtOH) for a solvate and 1:0.44 (Compound 1 :H2O) for a hydrate.Compound 1 Sodium Bisulfate Form B

[0181] Compound 1 Sodium Bisulfate Form B was observed from reactive crystallization with NaHSCL (1 :1) in 2-MeTHF as described in Example 4. The XRPD pattern shown in FIG. 13 indicated Compound 1 Sodium Bisulfate Form B had a different pattern from the starting materials, as well as Compound 1 Sodium Bisulfate Form A. The corresponding data are summarized below:

[0182] PLM imaging showed irregularly shaped, birefringent particles.

[0183] TGA showed a two-step weight loss of 10.57% up to 160.0 °C and the DSC thermogram exhibited three endotherms with onsets of 74.5, 196.0, and 243.6 °C (FIG. 14B). Based on the TGA weight loss, the calculated stoichiometry is 1 :0.78 (Compound l :2-MeTHF) for a solvate and 1 :3.75 (Compound EH2O) for a hydrate.Compound 1 Potassium Bisulfate Form A

[0184] Compound 1 Potassium Bisulfate Form A was observed from reactive crystallization with KHSO4 (1 :1) in 2-MeTHF as described in Example 4. The XRPD pattern shown in FIG. 15A indicated that Compound 1 Potassium Bisulfate Form A had a different pattern from the starting materials. The corresponding data are summarized below:

[0185] PLM imaging showed irregularly shaped, birefringent particles.

[0186] TGA showed a weight loss of 9.59% up to 185.8 °C and the DSC thermogram exhibited a melting endotherm with an onset of 200.6 °C (FIG. 16). Based on the thermal profile, the sample was concluded to be a 2-MeTHF solvate, with a calculated stoichiometry of 1:0.72 (Compound l:2-MeTHF).

[0187] A sample of Compound 1 Potassium Bisulfate Form A was heated to 175 °C, after the TGA weight loss measurement. XRPD of the heated sample showed a less crystalline pattern than the Compound 1 Potassium Bisulfate Form A reference, but no form change was observed (FIG. 15B).

Claims

CLAIMS1. A crystalline solid form of Compound 2Compound 2, wherein X is a co-former selected from the group consisting of cyclamic acid, l-hydroxy-2- naphthoic acid, naphthalene-2-sulfonic acid, formic acid, sodium bisulfate, and potassium bi sulfate.

2. The solid form of claim 1, wherein X is cyclamic acid.

3. The solid form of claim 2, wherein the solid form is Compound 1 Cyclamate Form A.

4. The solid form of claim 3, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 6.4, about 7.1, about 18.5, about 19.4, about 21.5 degrees 2-theta.

5. The solid form of claim 3, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

6. The solid form of claim 3, wherein Compound 1 Cyclamate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 1 (third from top trace) and / or FIG. 1 (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 2A (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 2A (bottom trace), FIG 2B (top trace), FIG 2B (middle trace), and / or FIG. 2B (bottom trace).

7. The solid form of claim 1, wherein X is l-hydroxy-2-naphthoic acid.

8. The solid form of claim 7, wherein the solid form is Compound 1 l-Hydroxy-2- naphthoate Form A.

9. The solid form of claim 8, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2-theta.

10. The solid form of claim 8, wherein the solid form is characterized by peaks in its XRPD pattern at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2-theta.

11. The solid form of claim 8, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

12. The solid form of claim 8, wherein Compound 1 l-Hydroxy-2-naphthoate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 3 A (bottom trace), FIG. 3B (top trace), FIG. 3B (bottom trace), FIG. 3C (top trace), and / or FIG. 3C (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 4A (top trace) and / or FIG. 4B (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 4A (bottom trace) and / or FIG. 4B (bottom trace).

13. The solid form of claim 1, wherein X is naphthal ene-2-sulfonic acid.

14. The solid form of claim 13, wherein the solid form is Compound 1 Naphthalene-2- sulfonate Form A.

15. The solid form of claim 14, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2-theta.

16. The solid form of claim 14, wherein the solid form is characterized by peaks in its XRPD pattern at about 6.5, about 7.6, about 10.7, about 11.2, about 11.9, about 13.0, about 16.0, about 18.4, about 18.9, and about 22.1 degrees 2-theta.

17. The solid form of claim 14, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

18. The solid form of claim 14, wherein Compound 1 Naphthal ene-2-sulfonate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 7A (bottom trace), FIG. 7B (top trace), FIG. 7B (bottom trace), FIG. 7C (top trace) and / or FIG. 7C (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 8A (top trace) and / or FIG. 8B; and(iii) a DSC pattern substantially similar to that depicted in FIG. 8 (bottom trace) and / or FIG. 8B.

19. The solid form of claim 1, wherein X is formic acid.

20. The solid form of claim 19, wherein the solid form is Compound 1 Formate Form A.

21. The solid form of claim 20, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta.

22. The solid form of claim 20, wherein the solid form is characterized by peaks in its XRPD pattern at about 3.8, about 4.8, about 5.7, about 5.9, about 6.4, about 9.2, about 10.1, about 11.3, about 11.5, and about 15.7 degrees 2-theta.

23. The solid form of claim 20, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

24. The solid form of claim 20, wherein Compound 1 Formate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 11 (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 12 (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 12 (bottom trace).

25. The solid form of claim 1, wherein X is sodium bisulfate.

26. The solid form of claim 25, wherein the solid form is Compound 1 Sodium BisulfateForm A.

27. The solid form of claim 26, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta.

28. The solid form of claim 26, wherein the solid form is characterized by peaks in its XRPD pattern at about 19.0, about 23.2, about 28.0, about 29.0, about 32.1, about 33.8, and about 38.6 degrees 2-theta.

29. The solid form of claim 26, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

30. The solid form of claim 26, wherein Compound 1 Sodium Bisulfate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 13 (third from top trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 14A (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 14A (bottom trace).

31. The solid form of claim 25, wherein the solid form is Compound 1 Sodium Bisulfate Form B.

32. The solid form of claim 31, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta.

33. The solid form of claim 31, wherein the solid form is characterized by peaks in its XRPD pattern at about 5.4, about 19.1, about 22.7, about 23.7, about 25.6, about 28.1, about 29.0, about 31.9, about 32.2, and about 33.9 degrees 2-theta.

34. The solid form of claim 31, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

35. The solid form of claim 31, wherein Compound 1 Sodium Bisulfate Form B is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 13 (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 14B (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 14B (bottom trace).

36. The solid form of claim 1, wherein X is potassium bisulfate.

37. The solid form of claim 36, wherein the solid form is Compound 1 Potassium Bisulfate Form A.

38. The solid form of claim 37, wherein the solid form is characterized by one or more peaks in its XRPD pattern selected from those at about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2-theta.

39. The solid form of claim 37, wherein the solid form is characterized by peaks in its XRPD pattern at about 5.5, about 21.4, about 23.8, about 29.8, about 30.9, and about 37.1 degrees 2- theta.

40. The solid form of claim 37, wherein the solid form is characterized by peaks in its XRPD pattern at substantially all of:

41. The solid form of claim 37, wherein Compound 1 Potassium Bisulfate Form A is characterized by one or more of the following:(i) an XRPD pattern substantially similar to that depicted in FIG. 15 A (bottom trace), FIG. 15B (top trace), and / or FIG. 15B (bottom trace);(ii) a TGA pattern substantially similar to that depicted in FIG. 16 (top trace); and(iii) a DSC pattern substantially similar to that depicted in FIG. 16 (bottom trace).

42. Compound 2:Compound 2, wherein X is a co-former selected from the group consisting of cyclamic acid, l-hydroxy-2- naphthoic acid, naphthalene-2-sulfonic acid, formic acid, sodium bisulfate, and potassium bi sulfate.

43. A solid form obtainable by a process described herein (e.g., in Example 4 or Example 5).

44. The solid form of claim 43, wherein the solid form is the solid form of any one of claims 1-41.

45. A pharmaceutical composition comprising the compound of claim 42 or the solid form of any one of claims 1-41, 43, and 44 and a pharmaceutically acceptable carrier.

46. The pharmaceutical composition of claim 45, wherein the pharmaceutical composition is solid.

47. The pharmaceutical composition of claim 45 or 46, wherein the pharmaceutical composition is formulated for oral administration.

48. A method of inhibiting an estrogen receptor or mutant thereof in a biological sample comprising contacting the biological sample with the compound of claim 42 or the solid form of any one of claims 1-41, 43, and 44.

49. A method of inhibiting an estrogen receptor or mutant thereof in a patient comprising contacting the patient with the compound of claim 42 or the solid form of any one of claims 1- 41, 43, and 44.

50. A method of treating a disease, disorder, or condition associated with the estrogen receptor in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 42 or the solid form of any one of claims 1-41, 43, and 44.

51. The method of claim 50, 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.

52. The method of claim 50, wherein the disease, disorder, or condition is breast cancer.

53. The method of any one of claims 50-52, further comprising administering another anticancer agent.

54. The method of claim 53, wherein the anti-cancer agent is a CDK4 / 6 inhibitor, a PI3KCA inhibitor, or an mTOR inhibitor.

55. A method of preparing the compound of claim 42 or the solid form of any one of claims 1-41, 43, and 44 according to a method described herein.

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