Crystalline solid forms of indane compounds

Abstract

Provided herein are crystalline solid forms of Compound 2 and uses thereof.

Description

Attorney Docket No.2017207-0202 CRYSTALLINE SOLID FORMS OF INDANE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of PCT Application No. PCT / CN2024 / 115923, filed August 30, 2024, the entire contents of which are hereby incorporated by reference. BACKGROUND

[0002] Sodium channel blockers are useful in the treatment of dermatological conditions such as inflammation, pruritus and / or pain. Certain indane compounds are useful for the preparation and manufacture of sodium channel blockers for the treatment of inflammation, pruritus and / or pain. SUMMARY

[0003] Previous reports of sodium channel blockers such as lidocaine suffer from the drawback of undesired blockade of motor function. This is because these sodium channel blockers fail to discriminate between sodium channel activity required for normal ongoing sensation and similar activity involved in nociceptor signaling. There remains a need for sodium channel blockers that are useful in treating various conditions such as inflammation, pruritus and / or pain while minimizing impairment of motor function.

[0004] One compound that is being evaluated for use in treating dermatological diseases and conditions, including those that may cause inflammation, pruritus and / or pain is (R)-1,1- dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl] piperidinium bromide (referred to herein as “Compound A”), and having a structure of:Page 1 of 88 12949448v1Attorney Docket No.2017207-0202

[0005] Compound A is described in WO2012 / 112969, wherein Compound A is reported at Example 43, and certain formulations of Compound A are described in WO2020 / 113050, each of which is incorporated herein by reference in its entirety. There remains, however, a need for improved syntheses of Compound A. In particular, Applicant looked to prepare crystalline solid forms of precursors to Compound A, which could have the benefit of avoiding additional purification steps. A precursor to Compound A, (R)-N-(2-(1-methylpiperidin-2-yl)ethyl)-N-(o- tolyl)-2,3-dihydro-1H-inden-2-amine (referred to herein as “Compound 1”), and having a structure of:was initially studied to identify crystal forms that could be used in manufacturing. No stable forms, however, were identified. Tasked with finding solid crystalline forms that could be used in the manufacture of Compound A, Applicant sought to identify solid crystalline salt forms of Compound 1, referred to herein as Compound 2:

[0006] wherein Xthat many solvent systems failed to provide solid crystalline solid forms of Compound 2 through crystallization due to, e.g., Compound 2’s poor solubility in certain solvent systems. Moreover, certain methods of preparing crystalline solid forms of Compound 2 did not yield favorable results due to, e.g., low reproducibility or hygroscopicity. Still further, certain methods of preparing solid crystalline solid form of Compound 2 suffered from low purity due to, e.g., degradation during the process. Page 2 of 88 12949448v1Attorney Docket No.2017207-0202

[0007] The present disclosure provides a solution to the problems identified above and provides crystalline solid forms of Compound 2 that, in some embodiments, exhibit desirable characteristics such as improved stability, hygroscopicity, flow properties, ease of processing, consistency in manufacturing, particle size distribution, and bulk density. In some embodiments, the present disclosure provides, among other things, solid forms, e.g., crystalline, anhydrate, hydrate, and / or solvate forms of a co-former of Compound 1 (referred to herein as “Compound 2”). In some embodiments, the present disclosure provides methods of preparing said solid forms of Compound 2. As described herein, polymorph screening experiments identified certain solid forms that exhibited suitable stability for further development. The present disclosure provides, among other things, processes for preparing Compound A. In some embodiments, a process for preparing Compound A comprises contacting a crystalline solid form of Compound 2 with bromomethane in MTBE to provide Compound A.

[0008] In some embodiments, the present disclosure provides a crystalline solid form of Compound 2:wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid, and n is 1 or 2.

[0009] In some embodiments, a crystalline solid form of Compound 2 is an anhydrate. In some embodiments, a crystalline solid form of Compound 2 is Hydrobromide Form A, as described herein. In some embodiments, a crystalline solid form of Compound 2 is Sulfate Form A, as described herein. In some embodiments, a crystalline solid form of Compound 2 is 1,5- Naphthalenedisulfonate Form A, as described herein. In some embodiments, a crystalline solid form of Compound 2 is Fumarate Form A, as described herein. Page 3 of 88 12949448v1Attorney Docket No.2017207-0202

[0010] In some embodiments, a crystalline solid form of Compound 2 is a hydrate. In some embodiments, a crystalline solid form of Compound 2 is Hydrobromide Form A, as described herein. In some embodiments, a crystalline solid form of Compound 2 is Sulfate Form A, as described herein. In some embodiments, a crystalline solid form of Compound 2 is 1,5- Naphthalenedisulfonate Form D, as described herein. In some embodiments, a crystalline solid form of Compound 2 is L-Tartrate Form A, as described herein.

[0011] In some embodiments, a crystalline solid form of Compound 2 is a solvate. In some embodiments, a crystalline solid form of Compound 2 is 1,5-Naphthalenedisulfonate Form B, as described herein. In some embodiments, a crystalline solid form of Compound 2 is 1,5- Naphthalenedisulfonate Form C, as described herein.

[0012] In some embodiments, a crystalline solid form of Compound 2 is unsolvated. In some embodiments, a crystalline solid form of Compound 2 is Hydrochloride Form A, as described herein.

[0013] In some embodiments, a crystalline solid form of Compound 2 is substantially stable and / or pure (as these terms are defined herein) when stored for extended periods of time under certain conditions, e.g., storage in open containers at 25 ºC / 60% relative humidity (RH) and 40 ºC / 75% RH for about 5 days.

[0014] In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 2. In some embodiments, the present disclosure provides suitable solvent systems for preparing crystalline solid forms of Compound 2. In some embodiments, the present disclosure provides suitable solvent systems that can be utilized in the methods of preparing crystalline solid forms of Compound 2. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 2 with improved yield and / or purity. In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 2 that are suitable for commercial production, e.g., large scale preparation.

[0015] In some embodiments, the present disclosure provides methods of preparing Compound A using a crystalline solid form of Compound 2, as described herein. In some embodiments, the present disclosure provides methods of preparing Compound A comprising Page 4 of 88 12949448v1Attorney Docket No.2017207-0202 contacting a crystalline solid form of Compound 2 with a base and bromomethane in a solvent to provide Compound A. In some embodiments, the present disclosure provides methods of preparing Compound A comprising contacting a crystalline solid form of Compound 2 with a base to provide Compound 1, and contacting Compound 1 with bromomethane in a solvent to provide Compound A. BRIEF DESCRIPTION OF THE DRAWING

[0016] FIG.1A is an X-ray powder diffraction (XRPD) pattern of Compound 2 Hydrobromide Form A.

[0017] FIG.1B is a differential scanning calorimetric (DSC) (bottom trace) and thermal gravimetric analysis (TGA) (top trace) plot of Compound 2 Hydrobromide Form A.

[0018] FIG.1C is an XRPD pattern of Compound 2 Hydrobromide Form A before and after heating.

[0019] FIG.1D is a TGA plot of Compound 2 Hydrobromide Form A before and after heating.

[0020] FIG.2A is an XRPD pattern of Compound 2 Hydrochloride Form A.

[0021] FIG.2B is a DSC (bottom trace) and TGA (top trace) plot of Compound 2 Hydrochloride Form A.

[0022] FIG.3A is an XRPD pattern of Compound 2 Sulfate Form A.

[0023] FIG.3B is a DSC (bottom trace) and TGA (top trace) plot of Compound 2 Sulfate Form A.

[0024] FIG.4A is an XRPD pattern of Compound 21,5-Naphthalenedisulfonate Form A.

[0025] FIG.4B is a DSC (bottom trace) and TGA (top trace) plot of Compound 21,5- Naphthalenedisulfonate Form A.

[0026] FIG.5A is an XRPD pattern of Compound 21,5-Naphthalenedisulfonate Form B. Page 5 of 88 12949448v1Attorney Docket No.2017207-0202

[0027] FIG.5B is a DSC (bottom trace) and TGA (top trace) plot of Compound 21,5- Naphthalenedisulfonate Form B.

[0028] FIG.6A is an XRPD pattern of Compound 21,5-Naphthalenedisulfonate Form C.

[0029] FIG.6B is a DSC (bottom trace) and TGA (top trace) plot of Compound 21,5- Naphthalenedisulfonate Form C.

[0030] FIG.7A is an XRPD pattern of Compound 21,5-Naphthalenedisulfonate Form D.

[0031] FIG.7B is a DSC (bottom trace) and TGA (top trace) plot of Compound 21,5- Naphthalenedisulfonate Form D.

[0032] FIG.8A is an XRPD pattern of Compound 2 Fumarate Form A.

[0033] FIG.8B is a DSC (bottom trace) and TGA (top trace) plot of Compound 2 Fumarate Form A.

[0034] FIG.8C is a high-throughput liquid chromatography (HPLC) overlay graph of Compound 2 Fumarate Form A.

[0035] FIG.9A is an XRPD pattern of Compound 2 L-Tartrate Form A.

[0036] FIG.9B is a DSC (bottom trace) and TGA (top trace) plot of Compound 2 L- Tartrate Form A.

[0037] FIG.10A is an XRPD pattern of Compound 2 Hydrobromide Form A before and after stability testing.

[0038] FIG.10B is an XRPD pattern of Compound 2 Fumarate Form A before and after stability testing.

[0039] FIG.10C is an XRPD pattern of Compound 21,5-Naphthalenedisulfonate Form D before and after stability testing.

[0040] FIG.11A is a dynamic vapor sorption (DVS) isotherm plot of Hydrobromide Form A.

[0041] FIG.11B is an XRPD pattern of Compound 2 Hydrobromide Form A before and after DVS. Page 6 of 88 12949448v1Attorney Docket No.2017207-0202

[0042] FIG.12A is a DVS plot of Compound 2 Fumarate Form A.

[0043] FIG.12B is an XRPD pattern of Compound 2 Fumarate Form A before and after DVS.

[0044] FIG.13 is an XRPD pattern overlay of Compound 2 Fumarate Form A after solvent system testing.

[0045] FIG.14 is a nuclear magnetic resonance (NMR or 1H-NMR) spectrum of Compound 2 Hydrobromide Form A after heating. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0046] (R)-1,1-dimethyl-2-[2-((indan-2-yl)(2-methylphenyl)amino)ethyl] piperidinium bromide (Compound A) is being evaluated in the treatment of dermatological diseases and conditions, including those that may cause inflammation, pruritus and / or pain. The present disclosure provides various crystalline solid forms of Compound 2 that can be used to synthesize Compound A. The present disclosure, among other things, recognizes the surprising discovery that Compound 2 is capable of forming crystalline solid forms, and further, that those forms exhibit improved stability and other beneficial properties relative to a corresponding amorphous form or other crystalline solid forms.

[0047] In some embodiments, the present disclosure provides crystalline solid forms of Compound 2, represented by the structure below:wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. Page 7 of 88 12949448v1Attorney Docket No.2017207-0202

[0048] Moreover, the present disclosure provides methods of preparing crystalline solid forms of Compound 2 that demonstrate improved yield, improved purity (e.g., relative to other crystalline solid forms of Compound 2), improved efficiency, toleration to rapid cooling rate and antisolvent addition rate, and suitability for commercial production.

[0049] In some embodiments, the present disclosure provides methods of preparing crystalline solid forms of Compound 2 through crystallization. In some embodiments, provided methods comprise crystallizing Compound 2 in a solvent system.

[0050] Still further, the present disclosure, among other things, provides methods of preparing Compound A by contacting Compound 2 with a base and bromomethane in a solvent. In some embodiments, a method of preparing Compound A comprises contacting a crystalline solid form of Compound 2 with a base and bromomethane in a solvent. In some embodiments, a method of preparing Compound A comprises contacting a crystalline solid form of Compound 2 with a base to provide Compound 1, and contacting Compound 1 with bromomethane in a solvent to provide Compound A. Definitions

[0051] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0052] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form—e.g., gas, gel, liquid, solid, etc.

[0053] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a Page 8 of 88 12949448v1Attorney Docket No.2017207-0202 desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0054] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0055] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0056] Sample: As used herein, the term “sample” typically refers to an aliquot of material obtained or derived from a source of interest, as described herein. In some embodiments, a source of interest is a chemical material. In some embodiments, a source of interest is or comprises a composition further comprising a chemical material. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. In some embodiments, a sample may be a “crude” sample in that it has been subjected to relatively little processing and / or is complex in that it includes components of relatively varied chemical classes. Page 9 of 88 12949448v1Attorney Docket No.2017207-0202 Crystalline Solid Forms of Compound 2

[0057] (R)-N-(2-(1-methylpiperidin-2-yl)ethyl)-N-(o-tolyl)-2,3-dihydro-1H-inden-2- amine (“Compound 2”) is useful in the manufacture of drug products. Compound 2 is represented by the structure of:wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. As described herein, reference to Compound 2 prepared with a co-former refers to any salt of Compound 2 prepared with the provided acid. For example, Compound 2, where X is hydrobromic acid, refers to a Compound 2 hydrobromide salt form. Compound 2, where X is hydrochloric acid, refers to a Compound 2 hydrochloride salt form. Compound 2, where X is sulfuric acid, refers to a Compound 2 sulfate salt form. Compound 2, where X is 1,5- napthalenedisulfonic acid refers to a Compound 21,5-naphthalenedisulfonate salt form. Compound 2, where X is fumaric acid, refers to a Compound 2 fumarate salt form. Compound 2, where X is L-(+)-tartaric acid, is a Compound 2 tartrate salt form.

[0058] In some embodiments, Compound 2 is a monosalt (i.e., when n is 1). In some embodiments, Compound 2 is a di-salt (i.e., when n is 2).

[0059] As described herein, Compound 2 can each exist in one or more polymorphic solid forms. As used herein, the term “polymorph” refers to the ability of a compound to exist in one or more different crystal structures. For example, one or more polymorphs may vary in pharmaceutically relevant physical properties between one form and another, e.g., solubility, stability, and / or hygroscopicity. In some embodiments, the present disclosure provides a crystalline solid form of Compound 2.

[0060] Applicant has surprisingly discovered that Compound 2 exists in an amorphous form, in a crystalline solid form, or in mixtures of forms. The present disclosure encompasses Page 10 of 88 12949448v1Attorney Docket No.2017207-0202 the surprising discovery that Crystalline solid forms of Compound 2 exist in one or more unique solid forms, which can additionally comprise one or more molecules of water or solvent (i.e., hydrates or solvates, respectively) in the crystal lattice. As described herein, crystalline solid forms of Compound 2 each have distinct characteristic XRPD peaks that are not reported in previous disclosures of Compound 2.

[0061] In some embodiments, a crystalline solid form of Compound 2 is an anhydrate. A crystalline solid form that does not have any water incorporated into the crystalline structure is an “anhydrate.” In some embodiments, a crystalline solid form of Compound 2 is a solvate and / or hydrate. As used herein, the term “solvate” refers to a solid form with a stoichiometric or non-stoichiometric amount of one or more solvents incorporated into the crystal structure. For example, a solvated or heterosolvated polymorph can comprise 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc. equivalents independently of one or more solvents incorporated into the crystal lattice. As used herein, the term “hydrate” refers to a solvate, wherein the solvent incorporated into the crystal structure is water.

[0062] In some embodiments, provided forms (e.g., solid crystalline 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.

[0063] 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 will be 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) Page 11 of 88 12949448v1Attorney Docket No.2017207-0202 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.

[0064] Additionally, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure. Compound 2 Hydrobromide Form A

[0065] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is hydrobromic acid. In some embodiments, a crystalline solid form of Compound 2 is a hydrobromide salt. In some embodiments, a crystalline solid form of Compound 2 is Compound 2 Hydrobromide Form A. In some embodiments, Compound 2 Hydrobromide Form A is an anhydrate. In some embodiments, Compound 2 Hydrobromide Form A is a hydrate. In some embodiments, Compound 2 Hydrobromide Form A is a bromide di-salt. In some embodiments, Compound 2 Hydrobromide Form A is a bromide di-salt anhydrate. In some embodiments, Compound 2 Hydrobromide Form A is a bromide di-salt hydrate.

[0066] In some embodiments, Compound 2 Hydrobromide Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, Page 12 of 88 12949448v1Attorney Docket No.2017207-0202 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrobromide Form A is characterized by the following peaks in its X-ray powder diffraction pattern: 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta.

[0067] In some embodiments, Compound 2 Hydrobromide Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 6412949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 30.1

[0068] In some embodi ide Form A is characterized by adifferential scanning calorimetry (DSC) endotherm having a DSC peak (endotherm) at about 220.2 °C.

[0069] In some embodiments, Compound 2 Hydrobromide Form A is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 2.6% up to 150 °C.

[0070] In some embodiments, Compound 2 Hydrobromide Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.1A. In some embodiments, Compound 2 Hydrobromide Form A is characterized by a DSC pattern substantially similar to FIG.1B. In some embodiments, Compound 2 Hydrobromide Form A is characterized by a TGA pattern substantially similar to FIG.1B. In some embodiments, Compound 2 Hydrobromide Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 1A; (b) a DSC pattern substantially similar to FIG.1B; and (c) a TGA pattern substantially similar to FIG.1B. Compound 2 Hydrochloride Form A

[0071] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is hydrochloric acid. In some embodiments, a crystalline solid form of Compound 2 is a hydrochloride salt. In some embodiments, a crystalline solid form of Compound 2 is Compound 2 Hydrochloride Form A. In some embodiments, Compound 2 Hydrochloride Form A is unsolvated. In some embodiments, Compound 2 Hydrochloride Form A is an unsolvated chloride salt.

[0072] In some embodiments, Compound 2 Hydrochloride Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by two or more peaks in its X-ray powder diffraction Page 14 of 88 12949448v1Attorney Docket No.2017207-0202 pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2- theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2- theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2- theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2- theta. In some embodiments, Compound 2 Hydrochloride Form A is characterized by the following peaks in its X-ray powder diffraction pattern: 12.9, 13.8, 15.2, 17.1, 17.6, 20.0, 22.1, 23.1, and 25.6 ± 0.2 degrees 2-theta.

[0073] In some embodiments, Compound 2 Hydrochloride Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2)12949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 28.1

[0074] In some embodi ride Form A is characterized by a differential scanning calorimetry (DSC) endotherm having two DSC peaks (endotherms) at about 93.2 ºC °C and 173.1 ºC.

[0075] In some embodiments, Compound 2 Hydrochloride Form A is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 4.4% before 150 °C.

[0076] In some embodiments, Compound 2 Hydrochloride Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.2A. In some embodiments, Compound 2 Hydrochloride Form A is characterized by a DSC pattern substantially similar to FIG.2B. In some embodiments, Compound 2 Hydrochloride Form A is characterized by a TGA pattern substantially similar to FIG.2B. In some embodiments, Compound 2 Hydrochloride Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG. 2A; (b) a DSC pattern substantially similar to FIG.2B; and (c) a TGA pattern substantially similar to FIG.2B. Compound 2 Sulfate Form A

[0077] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is sulfuric acid. In some embodiments, a crystalline solid form of Compound 2 is a sulfate salt. In some embodiments, a crystalline solid form of Compound 2 is Compound 2 Sulfate Form A. In some embodiments, Compound 2 Sulfate Form A is an anhydrate. In some embodiments, Compound 2 Sulfate Form A is a hydrate. In some embodiments, Compound 2 Sulfate Form A is a di-salt. In some embodiments, Compound 2 Sulfate Form A is a sulfate di- salt anhydrate. In some embodiments, Compound 2 Sulfate Form A is a sulfate di-salt hydrate.

[0078] In some embodiments, Compound 2 Sulfate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 6.3, Page 16 of 88 12949448v1Attorney Docket No.2017207-0202 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments Compound 2 Sulfate Form A is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Sulfate Form A is characterized by the following peaks in its X-ray powder diffraction pattern: 6.3, 8.0, 12.0, 18.8, 19.8, 21.7, 23.6, 24.5, and 27.9 ± 0.2 degrees 2- theta.

[0079] In some embodiments, Compound 2 Sulfate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 2Page 17 of 88 12949448v1Attorney Docket No.2017207-0202

[0080] In some embodiments, Compound 2 Sulfate Form A is characterized by a differential scanning calorimetry (DSC) endotherm having a DSC peak (endotherm) at about 212.7 ºC.

[0081] In some embodiments, Compound 2 Sulfate Form A is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 1.4% before 190 °C.

[0082] In some embodiments, Compound 2 Sulfate Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.3A. In some embodiments, Compound 2 Sulfate Form A is characterized by a DSC pattern substantially similar to FIG.3B. In some embodiments, Compound 2 Sulfate Form A is characterized by a TGA pattern substantially similar to FIG.3B. In some embodiments, Compound 2 Sulfate Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.3A; (b) a DSC pattern substantially similar to FIG.3B; and (c) a TGA pattern substantially similar to FIG.3B. Compound 21,5-Naphthalenedisulfonate Form A

[0083] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is 1,5-naphthalenedisulfonic acid. In some embodiments, a crystalline solid form of Compound 2 is a 1,5-naphthalenedisulfonate salt. In some embodiments, a crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form A. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is an anhydrate. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is a hydrate. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is a 1,5-naphthalenedisulfonate salt anhydrate. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is a 1,5- naphthalenedisulfonate salt hydrate.

[0084] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by two or more peaks in its X- ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Page 18 of 88 12949448v1Attorney Docket No.2017207-0202 Form A is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by the following peaks in its X-ray powder diffraction pattern: 11.2, 12.4, 14.1, 16.4, 16.6, 17.3, 18.0, 18.7, and 23.9 ± 0.2 degrees 2-theta.

[0085] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2)Page 19 of 88 12949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 14.9

[0086] In some embodi alenedisulfonate Form A ischaracterized by a differential scanning calorimetry (DSC) endotherm having two DSC peaks (endotherms) at about 161.5 °C and 184.9 °C.

[0087] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 2.4% up to 200 °C.

[0088] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by an X-ray powder diffraction pattern substantially similar to FIG.4A. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by a DSC pattern substantially similar to FIG.4B. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form A is characterized by a TGA pattern substantially similar to FIG. 4B. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.4A; (b) a DSC pattern substantially similar to FIG.4B; and (c) a TGA pattern substantially similar to FIG.4B. Page 20 of 88 12949448v1Attorney Docket No.2017207-0202 Compound 21,5-Naphthalenedisulfonate Form B

[0089] In some embodiments, a crystalline solid form of Compound 2 is Compound 2 1,5-Naphthalenedisulfonate Form B. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form B is a solvate. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form B is a 1,5-naphthalenedisulfonate ethyl acetate solvate.

[0090] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by two or more peaks in its X- ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form B is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by the following peaks in its X-ray powder diffraction pattern: 12.9, 14.1, 16.6, 17.0, 17.3, 17.9, 18.5, 18.9, and 22.1 ± 0.2 degrees 2-theta. Page 21 of 88 12949448v1Attorney Docket No.2017207-0202

[0091] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 3.4

[0092] In some embodialenedisulfonate Form B is characterized by a differential scanning calorimetry (DSC) endotherm having three DSC peaks (endotherms) at about 59.5 °C, 126.0 °C, and 192.4 °C.

[0093] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 4.4% up to 200 °C. Page 22 of 88 12949448v1Attorney Docket No.2017207-0202

[0094] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by an X-ray powder diffraction pattern substantially similar to FIG.5A. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by a DSC pattern substantially similar to FIG.5B. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form B is characterized by a TGA pattern substantially similar to FIG. 5B. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form B is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.1A; (b) a DSC pattern substantially similar to FIG.5B; and (c) a TGA pattern substantially similar to FIG.5B. Compound 21,5-Naphthalenedisulfonate Form C

[0095] In some embodiments, a crystalline solid form of Compound 2 is Compound 2 1,5-Naphthalenedisulfonate Form C. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form C is a solvate. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form C is a 1,5-naphthalenedisulfonate THF solvate.

[0096] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by two or more peaks in its X- ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by four or more peaks in its X- ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by six or more peaks in its X- ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C Page 23 of 88 12949448v1Attorney Docket No.2017207-0202 is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by the following peaks in its X-ray powder diffraction pattern: 5.9, 10.0, 12.8, 13.3, 16.5, 17.3, 18.1, 20.1, and 24.1 ± 0.2 degrees 2-theta.

[0097] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 5.912949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 26.3

[0098] In some embodi alenedisulfonate Form C ischaracterized by a differential scanning calorimetry (DSC) endotherm having two DSC peaks (endotherms) at about 135.2 °C and 201.3 °C.

[0099] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 10.7% up to 200 °C.

[0100] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by an X-ray powder diffraction pattern substantially similar to FIG.6A. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by a DSC pattern substantially similar to FIG.6B. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form C is characterized by a TGA pattern substantially similar to FIG. 6B. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form C is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.6A; (b) a DSC pattern substantially similar to FIG.6B; and (c) a TGA pattern substantially similar to FIG.6B. Compound 21,5-Naphthalenedisulfonate Form D

[0101] In some embodiments, a crystalline solid form of Compound 2 is Compound 2 1,5-Naphthalenedisulfonate Form D. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form D is a hydrate. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form D is a 1,5-naphthalenedisulfonate salt hydrate. Page 25 of 88 12949448v1Attorney Docket No.2017207-0202

[0102] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by two or more peaks in its X- ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by three or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form D is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by the following peaks in its X-ray powder diffraction pattern: 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta.

[0103] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2)age 6 o 8812949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 10.9

[0104] In some embodialenedisulfonate Form D is characterized by a differential scanning calorimetry (DSC) endotherm having a DSC peak (endotherm) at about 248 °C.

[0105] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 6.6% up to 200 °C. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by an X-ray powder diffraction pattern substantially similar to FIG.7A. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by a DSC pattern substantially similar to FIG.7B. In some embodiments, Compound 21,5- Naphthalenedisulfonate Form D is characterized by a TGA pattern substantially similar to FIG. 7B. In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is characterized by Page 27 of 88 12949448v1Attorney Docket No.2017207-0202 (a) an X-ray powder diffraction pattern substantially similar to FIG.7A; (b) a DSC pattern substantially similar to FIG.7B; and (c) a TGA pattern substantially similar to FIG.7B. Compound 2 Fumarate Form A

[0107] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is fumaric acid. In some embodiments, a crystalline solid form of Compound 2 is a fumarate salt. In some embodiments, a crystalline solid form of Compound 2 is Compound 2 Fumarate Form A. In some embodiments, Compound 2 Fumarate Form A is an anhydrate. In some embodiments, Compound 2 Fumarate Form A is a fumarate salt anhydrate.

[0108] In some embodiments, Compound 2 Fumarate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by three or more peaks in its X- ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 Fumarate Form A is characterized by the Page 28 of 88 12949448v1Attorney Docket No.2017207-0202 following peaks in its X-ray powder diffraction pattern: 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta.

[0109] In some embodiments, Compound 2 Fumarate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 6.7

[0110] In some embodiorm A is characterized by a differential scanning calorimetry (DSC) endotherm having a DSC peak (endotherm) at about 198.1 °C. Page 29 of 88 12949448v1Attorney Docket No.2017207-0202

[0111] In some embodiments, Compound 2 Fumarate Form A is characterized by a thermogravimetric analysis (TGA) with a negligible weight loss up to 150 °C.

[0112] In some embodiments, Compound 2 Fumarate Form A is characterized by an X- ray powder diffraction pattern substantially similar to FIG.8A. In some embodiments, Compound 2 Fumarate Form A is characterized by a DSC pattern substantially similar to FIG. 8B. In some embodiments, Compound 2 Fumarate Form A is characterized by a TGA pattern substantially similar to FIG.8B. In some embodiments, Compound 2 Fumarate Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.8A; (b) a DSC pattern substantially similar to FIG.8B; and (c) a TGA pattern substantially similar to FIG. 8B. Compound 2 L-Tartrate Form A

[0113] In some embodiments, a crystalline solid form of Compound 2 includes a co- former that is L-(+)-tartaric acid. In some embodiments, a crystalline solid form of Compound 2 is a L-tartrate salt. In some embodiments, a crystalline solid form of Compound 2 is L-Tartrate Form A. In some embodiments, Compound 2 L-Tartrate Form A is a hydrate. In some embodiments, Compound 2 L-Tartrate Form A is a L-tartrate salt hydrate.

[0114] In some embodiments, Compound 2 L-Tartrate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by two or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by three or more peaks in its X- ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by four or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L- Tartrate Form A is characterized by five or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In Page 30 of 88 12949448v1Attorney Docket No.2017207-0202 some embodiments, Compound 2 L-Tartrate Form A is characterized by six or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by seven or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by eight or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta. In some embodiments, Compound 2 L-Tartrate Form A is characterized by the following peaks in its X-ray powder diffraction pattern: 9.7, 14.3, 14.5, 15.5, 15.8, 17.2, 19.5, 19.8, and 20.5 ± 0.2 degrees 2-theta.

[0115] In some embodiments, Compound 2 L-Tartrate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 4.2Page 31 of 88 12949448v1Attorney Docket No.2017207-0202

[0116] In some embodiments, Compound 2 L-Tartrate Form A is characterized by a differential scanning calorimetry (DSC) endotherm having a DSC peak (endotherm) at about 75.4 °C.

[0117] In some embodiments, Compound 2 L-Tartrate Form A is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 3.1% up to 150 °C.

[0118] In some embodiments, Compound 2 L-Tartrate Form A is characterized by an X- ray powder diffraction pattern substantially similar to FIG.9A. In some embodiments, Compound 2 L-Tartrate Form A is characterized by a DSC pattern substantially similar to FIG. 9B. In some embodiments, Compound 2 L-Tartrate Form A is characterized by a TGA pattern substantially similar to FIG.9B. In some embodiments, Compound 2 L-Tartrate Form A is characterized by (a) an X-ray powder diffraction pattern substantially similar to FIG.9A; (b) a DSC pattern substantially similar to FIG.9B; and (c) a TGA pattern substantially similar to FIG. 9B. Methods of Preparing Crystalline Solid Forms

[0119] In some embodiments, the present disclosure provides methods of preparing provided crystalline solid forms of Compound 2. Crystallization with One or More Solvents

[0120] In some embodiments, a provided method comprises crystallizing and / or re- crystallizing Compound 2 in a solvent system comprising one or more solvents. In some embodiments, there are two or more solvents in a solvent system.

[0121] In some embodiments, a solvent system comprises one or more solvents independently selected from water, ethyl acetate (EtOAc), dichloromethane (DCM), chloroform, acetonitrile (MeCN or ACN), methanol (MeOH), ethanol (EtOH), propyl alcohol (n-PrOH), isopropyl alcohol (i-PrOH or IPA), isopropyl acetate (IPAc), 2-butanone (MEK), methyl isobutyl ketone (MIBK), 2-methyl tetrahydrofuran (2-MeTHF), 1,4-dioxane, dimethylsulfoxide (DMSO), acetone, toluene, hexane, cyclohexane, heptane, pentane, cyclopentane, petroleum ether and a compound having a structure of Ra-O-Rb, wherein Ra and Rb are each independently selected Page 32 of 88 12949448v1Attorney Docket No.2017207-0202 from C1-C6 aliphatic and C3-C10 cycloaliphatic, or Ra and Rb are taken together to form a 3-10 membered ring having 0-2 additional heteroatoms independently selected from oxygen and nitrogen. In some embodiments, Ra and Rb are each independently selected from C1-C6 alkyl and C3-C10 cycloalkyl, or Ra and Rb are taken together to form a 3-6 membered ring having 0-1 additional heteroatom selected from oxygen and nitrogen. In some embodiments, Ra-O-Rb is diethyl ether, tetrahydrofuran (THF), or methyl t-butyl ether (MTBE).

[0122] In some embodiments, a solvent system comprises a solvent selected from water, ethyl acetate (EtOAc), dichloromethane (DCM), acetonitrile (MeCN or ACN), methanol (MeOH), ethanol (EtOH), propyl alcohol (n-PrOH), isopropyl alcohol (i-PrOH or IPA), isopropyl acetate (IPAc), 2-butanone (MEK), acetone, toluene, hexane, heptane, pentane, tetrahydrofuran (THF), or methyl t-butyl ether (MTBE). In some embodiments, a solvent system comprises a solvent that is water. In some embodiments, a solvent system comprises a solvent that is EtOAc. In some embodiments, a solvent system comprises a solvent that is DCM. In some embodiments, a solvent system comprises a solvent that MeCN. In some embodiments, a solvent system comprises a solvent that is MeOH. In some embodiments, a solvent system comprises a solvent that is EtOH. In some embodiments, a solvent system comprises a solvent that is n-PrOH. In some embodiments, a solvent system comprises a solvent that is i-PrOH. In some embodiments, a solvent system comprises a solvent that is IPAc. In some embodiments, a solvent system comprises a solvent that is MEK. In some embodiments, a solvent system comprises a solvent that is acetone. In some embodiments, a solvent system comprises a solvent that is toluene. In some embodiments, a solvent system comprises a solvent that is heptane. In some embodiments, a solvent system comprises a solvent that is THF. In some embodiments, a solvent system comprises a solvent that is MTBE. In some embodiments, a solvent system comprises a solvent that is ACN and toluene. In some embodiments, a solvent system comprises a solvent that is water and acetone. In some embodiments, a solvent system comprises a solvent that is water and EtOH. In some embodiments, a solvent system comprises a solvent that is water and THF. In some embodiments, a solvent system comprises a solvent that is water and ACN.

[0123] In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of the first solvent:second solvent is about 1:1 v / v to about 1:1000 v / v. In Page 33 of 88 12949448v1Attorney Docket No.2017207-0202 some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 1000:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 1:500 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 500:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 1:200 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 200:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 1:100 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 100:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 1:50 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v to about 50:1 v / v.

[0124] In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:2 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:3 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:4 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:5 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:6 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:7 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:8 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second Page 34 of 88 12949448v1Attorney Docket No.2017207-0202 solvent is about 1:9 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:10 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:20 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:50 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:100 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:200 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:500 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1:1000 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 2:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 3:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 4:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 5:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 6:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 7:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 8:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 9:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 10:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 20:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 50:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is Page 35 of 88 12949448v1Attorney Docket No.2017207-0202 about 100:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 200:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 500:1 v / v. In some embodiments, a solvent system comprises a first solvent and a second solvent and the ratio of first solvent:second solvent is about 1000:1 v / v.

[0125] In some embodiments, a solvent system comprises a solvent and an antisolvent. As used herein, an “antisolvent” is a solvent in which Compound 2 is insoluble or substantially insoluble at room temperature. In some embodiments, a provided method comprises antisolvent addition to a solution of Compound 2, wherein a crystalline solid form of Compound 2 precipitates from a resulting solvent system comprising a solvent and an antisolvent.

[0126] In some embodiments, a solvent system comprises an antisolvent selected from hexane, cyclohexane, heptane, pentane, cyclopentane, petroleum ether and a compound having a structure of Ra-O-Rb, wherein Ra and Rb are each independently selected from C1-C6 aliphatic and C3-C10 cycloaliphatic, or Ra and Rb are taken together to form a 3-10 membered ring having 0-2 additional heteroatoms independently selected from oxygen and nitrogen. In some embodiments, Ra and Rb are each independently selected from C1-C6 alkyl and C3-C10 cycloalkyl, or Ra and Rb are taken together to form a 3-6 membered ring having 0-1 additional heteroatom selected from oxygen and nitrogen. In some embodiments, Ra-O-Rb is diethyl ether, tetrahydrofuran (THF), or methyl t-butyl ether (MTBE). In some embodiments, a solvent system comprises an antisolvent that is MTBE.

[0127] In some embodiments, a solvent system comprises MeOH and MTBE. In some embodiments, a solvent system comprises EtOH and MTBE. In some embodiments, a solvent system comprises n-PrOH and MTBE.

[0128] In some embodiments, a first solvent is a solvent in which Compound 2 is soluble or substantially soluble and is as described herein. In some embodiments, a second solvent is an antisolvent in which Compound 2 is insoluble or substantially insoluble and is as described herein. In some embodiments, a first solvent is MeOH and a second solvent is MTBE. In some embodiments, the ratio of MeOH:MTBE is about 1:9 v / v. In some embodiments, the ratio of MeOH:MTBE is 1:1 v / v. Page 36 of 88 12949448v1Attorney Docket No.2017207-0202

[0129] In some embodiments, a crystalline solid form of Compound 2 is prepared through antisolvent addition using a solvent system as described herein. In some embodiments, a crystalline solid form of Compound 2 is prepared through antisolvent addition in a solvent system comprising toluene, MTBE, n-heptane, or combinations thereof. In some embodiments, an antisolvent comprises toluene. In some embodiments, an antisolvent comprises MTBE. In some embodiments, an antisolvent comprises n-heptane. In some embodiments, an antisolvent comprises MTBE and n-heptane. In some embodiments, an antisolvent comprises MTBE and toluene.

[0130] In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:1000 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:500 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:200 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:100 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:50 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:10 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1000:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 500:1 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 200:1 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 100:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 50:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 10:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 1:9 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v to about 9:1 v / v.

[0131] In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:2 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:3 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:4 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 1:5 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:6 v / v. In some embodiments, a ratio of Page 37 of 88 12949448v1Attorney Docket No.2017207-0202 solvent:antisolvent in a sample is about 1:7 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:8 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:9 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:10 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:20 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:50 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:100 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:200 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:500 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1:1000 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 2:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 3:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 4:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 5:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 6:1 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 7:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 8:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 9:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 10:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 20:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 50:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 100:1 v / v. In some embodiments a ratio of solvent:antisolvent in a sample is about 200:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 200:1 v / v. In some embodiments, a ratio of solvent:antisolvent in a sample is about 1000:1 v / v.

[0132] In some embodiments, Compound 2 Hydrobromide Form A is prepared by contacting Compound 1 with a solution comprising HBr and MEK. In some embodiments, a solution comprising HBr and MEK is prepared by adding 2-butanone to hydrobromic acid.

[0133] In some embodiments, a provided method comprises: (a) adding MEK to HBr to get stock solution; Page 38 of 88 12949448v1Attorney Docket No.2017207-0202 (b) contacting HBr-MEK stock solution with Compound 1; (c) optionally diluting the resulting mixture from step (b) with MEK; (d) optionally treating the resulting mixture from step (b) or step (c) to a temperature cycle of 50 ºC to 5 ºC at the rate of 0.1 ºC / min for cooling and 0.75 ºC / min for heating with three cycles.

[0134] In some embodiments, a method of preparing Compound 2 Hydrobromide Form A comprises: (a) adding MEK to HBr to get a stock solution; (b) contacting HBr-MEK stock solution with Compound 1; (c) optionally diluting the resulting mixture from step (b) with MEK; (d) optionally treating the resulting mixture from step (b) or step (c) to a temperature cycle of 50 ºC to 5 ºC at the rate of 0.1 ºC / min for cooling and 0.75 ºC / min for heating with three cycles.

[0135] In some embodiments, Compound 2 Fumarate Form A is prepared by contacting Compound 1 with fumaric acid in the presence of a solvent. In some embodiments, the solvent comprises ethanol, acetone, acetonitrile, tetrahydrofuran, water, or combinations thereof. In some embodiments, the solvent comprises ethanol. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises tetrahydrofuran. In some embodiments, the solvent comprises water. In some embodiments, the first solvent is water. In some embodiments, the first solvent is water and the second solvent is THF. In some embodiments, the first solvent is water and the second solvent is ethanol. In some embodiments, the first solvent is water and the second solvent is acetone. In some embodiments, the first solvent is water and the second solvent is acetonitrile.

[0136] In some embodiments, a provided method comprises: (a) dissolving Compound 1 in a solvent to get a solution; (b) adding fumaric acid to the solution; (c) optionally diluting the solution with an additional amount of the solvent.

[0137] In some embodiments, a provided method comprises: Page 39 of 88 12949448v1Attorney Docket No.2017207-0202 (a) dissolving Compound 1 in THF to get a solution; (b) adding fumaric acid to the solution; (c) optionally diluting the solution with an additional amount of THF.

[0138] In some embodiments, a provided method comprises: (a) dissolving Compound 1 in a solvent comprising acetone and water to get a solution; (b) adding fumaric acid to the solution; (c) optionally diluting the solution with an additional amount of acetone and water.

[0139] In some embodiments, a method of preparing Compound 2 Fumarate Form A comprises: (a) dissolving Compound 1 in a solvent to get a solution; (b) adding fumaric acid to the solution; (c) optionally diluting the solution with an additional amount of the solvent.

[0140] In some embodiments, Compound 21,5-Naphthalenedisulfonate Form D is prepared by contacting Compound 1 with 1,5-naphthalenedisulfonic acid in the presence of a solvent. In some embodiments, the solvent comprises a first solvent and a second solvent. In some embodiments, the solvent comprises acetonitrile, toluene, or combinations thereof. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises acetonitrile and toluene.

[0141] In some embodiments, a provided method comprises: (a) dissolving Compound 1 in a solvent to get a solution; (b) adding 1,5-naphthalenedisulfonic acid to the solution; (c) optionally diluting the solution with an additional amount of the solvent.

[0142] In some embodiments, a provided method comprises: (a) dissolving Compound 1 in acetonitrile and toluene to get a solution; (b) adding 1,5-naphthalenedisulfonic acid to the solution; (c) optionally diluting the solution with an additional amount of acetonitrile and toluene.

[0143] In some embodiments, a method of preparing Compound 21,5- Naphthalenedisulfonate Form D comprises: Page 40 of 88 12949448v1Attorney Docket No.2017207-0202 (a) dissolving Compound 1 in a solvent to get a solution; (b) adding 1,5-naphthalenedisulfonic acid to the solution; (c) optionally diluting the solution with an additional amount of the solvent. Purity

[0144] In some embodiments, the present disclosure provides compositions comprising a crystalline solid form of Compound 2. In some embodiments, a provided composition comprises a crystalline solid form of Compound 2 that is substantially free of impurities or substantially pure. As used herein, the terms “substantially free of impurities” and “substantially pure” mean that the composition contains no significant amount of extraneous matter. Such extraneous matter may include starting materials, alternative crystalline solid forms, 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 solid crystalline form of Compound 2.

[0145] In some embodiments, a provided composition comprising a crystalline solid form of Compound 2 (e.g., Hydrobromide Form A, Hydrochloride Form A, Sulfate Form A, Fumarate Form A, 1,5-Naphthalenedisulfonate Form A, 1,5-Naphthalenedisulfonate Form B, 1,5-Naphthalenedisulfonate Form C, 1,5-Naphthalenedisulfonate Form D, L-Tartrate Form A) 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 provided crystalline solid form based on the total weight of the composition). In some embodiments, a composition comprising 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 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 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 of Compound 2 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a composition comprising 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. Page 41 of 88 12949448v1Attorney Docket No.2017207-0202

[0146] In some embodiments, a sample comprises a crystalline solid form of Compound 2, wherein the sample comprises about 90% by weight of the crystalline solid form. In some embodiments, a sample comprises a crystalline solid form of Compound 2, wherein the sample comprises about 95% by weight of the crystalline solid form. In some embodiments, a sample comprises a crystalline solid form of Compound 2, wherein the sample comprises about 98% by weight of the crystalline solid form. In some embodiments, a sample comprises a crystalline solid form of Compound 2, wherein the sample comprises about 99% by weight of the crystalline solid form. In some embodiments, a sample comprises a crystalline solid form of Compound 2, wherein the sample is substantially free of impurities. Stability

[0147] In some embodiments, a crystalline solid form of the present disclosure is stable or substantially stable when subject to predetermined conditions for predetermined times. As used herein, the term “stable” or “substantially stable” means a crystalline solid form remains substantially free of impurities when subject to predetermined conditions for predetermined times. In some embodiments, a crystalline solid form of the present disclosure remains stable when subject to predetermined conditions for predetermined times. In some embodiments, a crystalline solid form of the present disclosure can be stored and remain stable or substantially stable at various predetermined temperatures and relative humidities for defined or predetermined time periods, for example in an open or closed container. In some embodiments, a crystalline solid form of the present disclosure is stable or substantially stable upon storage at about 5, 25, 30, 37 or 40 °C and about 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% relative humidity for a period of at least about 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5,9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 20, 25, 30, 35, 40, 45, 48, 50, 51, 52, 53, 55 or 60 h, 1 week, 2 weeks, 3 weeks or 4 week; 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months. In some embodiments, a crystalline solid form of Compound 2 remains substantially stable after drying under atmospheric pressure at 25 °C for about 3 days. In some embodiments, a crystalline solid form of Compound 2 remains substantially stable after drying under atmospheric pressure at 25 °C for about 5 days. Page 42 of 88 12949448v1Attorney Docket No.2017207-0202 In some embodiments, a crystalline solid form of Compound 2 remains substantially stable after drying under atmospheric pressure at 40 °C for about 5 days. In some embodiments, Compound 2 Hydrobromide Form A remains substantially stable after drying under atmospheric pressure at 40 °C for about 5 days. In some embodiments, Compound 2 Fumarate Form A remains substantially stable after drying under atmospheric pressure at 40 °C for about 5 days. In some embodiments, a crystalline solid form of Compound 2 remains substantially stable after drying at 25 °C and 60% relative humidity (RH) for about 5 days. In some embodiments, a crystalline solid form of Compound 2 remains substantially stable after drying at 40 °C and 75% relative humidity RH for about 5 days. Uses

[0148] Provided crystalline solid forms and compositions are useful in the synthesis and manufacture of various drug products. For example, in some embodiments, a provided crystalline solid form is useful for preparing Compound A.

[0149] In some embodiments, the present disclosure provides a method of preparing Compound A , the method comprising:contacting a crystalline solid form of Compound 212949448v1Attorney Docket No.2017207-0202 with a base and bromomethane in a solvent to provide Compound A, wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5- naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. In some embodiments, X is selected from the group consisting of hydrobromic acid, 1,5- naphthalenedisulfonic acid, and fumaric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is hydrochloric acid. In some embodiments, X is sulfuric acid. In some embodiments, X is 1,5-naphthalenedisulfonic acid. In some embodiments, X is fumaric acid. In some embodiments, X is L-(+)-tartaric acid. In some embodiments, n is 1. In some embodiments, n is 2.

[0150] In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 2 Hydrobromide Form A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 2 Hydrochloride Form A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 2 Sulfate Form A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form B. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 21,5- Naphthalenedisulfonate Form C. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form D. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and Page 44 of 88 12949448v1Attorney Docket No.2017207-0202 bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 2 Fumarate Form A. In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the crystalline solid form of Compound 2 is Compound 2 L-Tartrate Form A.

[0151] In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the base is selected from a tertiary amine and an inorganic base. In some embodiments, the base is selected from triethylamine, di-isopropylethylamine (DIPEA), pyridine, 4-dimethylamine pyridine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, and cesium carbonate. In some embodiments, the base is triethylamine. In some embodiments, the base is DIPEA. In some embodiments, the base is pyridine. In some embodiments, the base is 4-dimethylamine pyridine. In some embodiments, the base is DABCO. In some embodiments, the base is DBU. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is cesium carbonate.

[0152] In some embodiments, a crystalline solid form of Compound 2 is contacted with a base and bromomethane in a solvent to provide Compound A, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises MBTE. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises DMSO. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises nitromethane.

[0153] In some embodiments, the present disclosure provides a method of preparing Compound A Page 45 of 88 12949448v1Attorney Docket No.2017207-0202 ,the method comprising contacting a crystalline solid form of Compound 2with a base to provide Compound 1 contacting Compound 1 withCompound A; wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. In some embodiments, X is selected from the group consisting of hydrobromic acid, 1,5- naphthalenedisulfonic acid, and fumaric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is hydrochloric acid. In some embodiments, X is sulfuric acid. In some embodiments, X is 1,5-naphthalenedisulfonic acid. In some embodiments, X is fumaric acid. In some embodiments, X is L-(+)-tartaric acid. In some embodiments, n is 1. In some embodiments, n is 2.

[0154] In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 2 Hydrobromide Form A. In some embodiments, a crystalline solid form of Compound 2 is Page 46 of 88 12949448v1Attorney Docket No.2017207-0202 reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 2 Hydrochloride Form A. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 2 Sulfate Form A. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form A. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form B. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 21,5- Naphthalenedisulfonate Form C. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 21,5-Naphthalenedisulfonate Form D. In some embodiments, a crystalline solid form Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 2 Fumarate Form A. In some embodiments, a crystalline solid form of Compound 2 is reacted with a base to provide Compound 1, wherein the crystalline solid form of Compound 2 is Compound 2 L-Tartrate Form A.

[0155] A person of ordinary skill in the art will understand suitable bases useful for reacting with Compound 2 to provide Compound 1. In some embodiments, the base is an organic base or an inorganic base. In some embodiments, the base is an aqueous base.

[0156] In some embodiments, Compound 1 is contacted with bromomethane in a solvent to provide Compound A, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises MBTE. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises 2- MeTHF. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises DMSO. In some embodiments, the solvent comprises acetone. In some embodiments, the solvent comprises nitromethane. Page 47 of 88 12949448v1Attorney Docket No.2017207-0202

[0157] In some embodiments, a method of preparing Compound A further comprises the step of extracting Compound 1 from the base with an organic solvent. In some embodiments, a method of preparing Compound A comprises contacting a crystalline solid form of Compound 2with a base to provide Compound 1isolating Compound 1; and contacting Compound 1 with bromomethane in a solvent to provide Compound A; wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. In some embodiments, the step of isolating Compound 1 comprises extracting Compound 1 with an organic solvent. Exemplary organic solvents for extracting Compound 1 include, but are not limited to, methanol, ethanol, dichloromethane, diethyl ether, hexane, heptane, ethyl acetate and mixtures thereof. EXEMPLARY EMBODIMENTS 1. Compound 2:12949448v1Attorney Docket No.2017207-0202 wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. 2. A crystalline solid form of Compound 2:wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. 3. The crystalline solid form of embodiment 2, wherein X is fumaric acid. 4. The crystalline solid form of embodiment 3, wherein the crystalline solid form is Compound 2 Fumarate Form A. 5. The crystalline solid form of embodiment 4, wherein Compound 2 Fumarate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta. 6. The crystalline solid form of embodiment 4, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2)Page 49 of 88 12949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 11.67. The crystalline solid form of embodiment 4, wherein Compound 2 Fumarate Form A is characterized by an XRPD pattern substantially similar to that depicted in FIG.8A. 8. The crystalline solid form of embodiment 7, wherein Compound 2 Fumarate Form A is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG.8B; or (ii) a DSC pattern substantially similar to that depicted in FIG.8B. 9. The crystalline solid form of embodiment 2, wherein X is hydrobromic acid. Page 50 of 88 12949448v1Attorney Docket No.2017207-0202 10. The crystalline solid form of embodiment 9, wherein the crystalline solid form is Compound 2 Hydrobromide Form A. 11. The crystalline solid form of embodiment 10, wherein Compound 2 Hydrobromide Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta. 12. The crystalline solid form of embodiment 10, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 6.4 13. The crystalline solid form of em wherein Compound 2 Hydrobromide FormA is characterized by an XRPD pattern substantially similar to that depicted in FIG.1A. 14. The crystalline solid form of embodiment 13, wherein Compound 2 Hydrobromide Form A is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG 1B; or Page 51 of 88 12949448v1Attorney Docket No.2017207-0202 (ii) a DSC pattern substantially similar to that depicted in FIG.1B. 15. The crystalline solid form of embodiment 2, wherein X is 1,5-naphthalenedisulfonic acid. 16. The crystalline solid form of embodiment 15, wherein the crystalline solid form is Compound 21,5-Naphthalenedisulfonate Form D. 17. The crystalline solid form of embodiment 16, wherein Compound 21,5- Naphthalenedisulfonate Form D is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta. 18. The crystalline solid form of embodiment 16, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 718 12949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 25.7 19. The crystalline solid form of emb, wherein Compound 21,5- Naphthalenedisulfonate Form D is characterized by an XRPD pattern substantially similar to that depicted in FIG.7A. 20. The crystalline solid form of embodiment 19, wherein Compound 21,5- Naphthalenedisulfonate Form D is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG.7B; or (ii) a DSC pattern substantially similar to that depicted in FIG.7B. 21. A crystalline solid form obtainable by a process described herein (e.g., in Example 1, Example 2, or Example 3). 22. A sample comprising the crystalline solid form of any one of embodiments 2-21, wherein the sample comprises about 90% by weight of the crystalline solid form. 23. A sample comprising the crystalline solid form of any one of embodiments 2-21, wherein the sample comprises about 95% by weight of the crystalline solid form. 24. A sample comprising the crystalline solid form of any one of embodiments 2-21, wherein the sample comprises about 98% by weight of the crystalline solid form. 25. A sample comprising the crystalline solid form of any one of embodiments 2-21, wherein the sample comprises about 99% by weight of the crystalline solid form. 26. A sample comprising the crystalline solid form of any one of embodiments 2-21, wherein the sample is substantially free of impurities. Page 53 of 88 12949448v1Attorney Docket No.2017207-0202 27. A composition comprising Compound A and the crystalline solid form of any one of embodiments 2-21. 28. A method of preparing the crystalline solid form of any one of embodiments 2-21 according to a method described herein. 29. A method of preparing Compound 2 Fumarate Form A comprising: reacting Compound 1 with fumaric acid in the presence of a solvent comprising ethanol, acetone, acetonitrile, tetrahydrofuran, water, or combinations thereof. 30. The method of embodiment 29, wherein the solvent is tetrahydrofuran. 31. The method of embodiment 29, wherein the solvent comprises ethanol and water in a ratio that is 9:1 v / v of ethanol to water. 32. The method of embodiment 29, wherein the solvent comprises acetone and water in a ratio that is 9:1 v / v of acetone to water. 33. The method of embodiment 29, wherein the solvent comprises tetrahydrofuran and water in a ratio that is 9:1 v / v of tetrahydrofuran to water. 34. The method of embodiment 29, wherein the solvent comprises acetonitrile and water in a ratio that is 9:1 v / v of acetonitrile to water. 35. A method of preparing Compound 2 Hydrobromide Form A comprising: reacting amorphous Compound 1 with a HBr-MEK solution. 36. The method of embodiment 35, further comprising adding 2-butanone to hydrobromic acid to create the HBr-MEK solution. Page 54 of 88 12949448v1Attorney Docket No.2017207-0202 37. A method of preparing Compound 21,5-Naphthalenedisulfonate Form D comprising: reacting Compound 1 with 1,5-naphthalenedisulfonic acid in the presence of acetonitrile and toluene. 38. The method of embodiment 37, wherein the acetonitrile and toluene are present in a 1:1 ratio. 39. A method of preparing Compound A , the method comprising:contacting a crystalline solid form of Compound 2with a base and bromomethane in a solvent to provide Compound A, and wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. 40. The method of embodiment 39, wherein Compound 2 is prepared according to the method of any one of embodiments 29-38. Page 55 of 88 12949448v1Attorney Docket No.2017207-0202 41. The method of embodiment 39 or 40, wherein the base is selected from triethylamine, di- isopropylethylamine (DIPEA), pyridine, 4-dimethylamine pyridine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, and cesium carbonate. 42. The method of any one of embodiments 39-41, wherein the base is triethylamine. 43. The method of any one of embodiments 39-41, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof. 44. The method of any one of embodiments 39-43, wherein the solvent comprises MBTE. 45. A method of preparing Compound A ,the method comprising: contacting a crystalline solid form of Compound 2with a base to provide Compound 1 Page 56 of 88 12949448v1Attorney Docket No.2017207-0202contacting Compound 1 a to provide Compound A; wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2. 46. The method of embodiment 45, wherein Compound 2 is prepared according to the method of any one of claims 29-38. 47. The method of embodiment 45 or 46, wherein the base is an organic base. 48. The method of embodiment 45 or 46, wherein the base is an aqueous base. 49. The method of any one of embodiments 45-48, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof. 50. The method of any one of embodiments 45-48, wherein the solvent comprises MBTE. EXAMPLES

[0158] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in Page 57 of 88 12949448v1Attorney Docket No.2017207-0202 the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0159] The following abbreviations may be used in the Examples below: Abbreviation Name ACN or MeCN acetonitrileage 58 o 88 12949448v1Attorney Docket No.2017207-0202 Abbreviation Name RH relative humidity Materials and Methods X-Ray Powder Diffraction (XRPD)

[0160] X-ray powder diffraction data was collected under ambient conditions on a Bruker D2 PHASER diffractometer. A ~2 mg sample was flattened on a silicon sample holder and compacted with a glass slide with protection of a piece of weighting paper. An X-ray generator of 300 W was employed at 30 kV and 10 mA and was equipped with an X-ray tube of Cu (Kα), with the Kα2 / Kα1 intensity ratio of 0.50 (1.54439 Å / 1.5406 Å). The divergence slit was 0.6 mm and soller slit was 4°. Data was collected at a speed of 0.15 s / step with step size of 0.02º (2θ) and a total step of 1837.

[0161] X-ray powder diffraction data was also collected under ambient conditions on a Malvern Panalytical Aeris diffractometer. A few milligrams of sample was flattened on a silicon sample holder and compacted by a glass slide with protection of a piece of weighting paper. An X-ray generator of 300 W was employed at 40 kV and 7.5 mA and was equipped with an X-ray tube of Cu (Kα), with the Kα2 / Kα1 intensity ratio of 0.50 (1.54439 Å / 1.5406 Å). Data was collected from 3º to 40º (2θ) at a scan speed of 0.14 º / s with step size of 0.02º (2θ). Page 59 of 88 12949448v1Attorney Docket No.2017207-0202 Thermal Gravimetric Analysis (TGA)

[0162] Thermogravimetric analysis data were collected with a TA Discovery 550 / 5500 series TGA. A few milligrams of material were weighed into a Tzero aluminum pan and the sample were heated from room temperature to target temperature with a heating rate of 10 ºC per minute under nitrogen protection (flow rate: 60 mL / min for TGA550 and 25 mL / min for TGA5500). Differential Scanning Calorimetric Analysis (DSC)

[0163] Differential scanning calorimetry was performed with a TA Discovery 2500 series DSC. A few milligrams of material were weighed into a Tzero aluminum pan and seal it with a Tzero hermetic lid. Samples were analyzed from room temperature to target temperature with a heating rate of 10 ºC per minute under 50 mL per minute of nitrogen flow.

[0164] Differential scanning calorimetry was performed with a TA Discovery series DSC2500. A few milligrams of material were weighed into a Tzero aluminum pan and covered with a Tzero hermetic lid. Samples were heated from room temperature to target temperature and then cooled to room temperature, with heating rate of 10 ºC per minute under 50 mL per minute of nitrogen flow. Dynamic Vapor Sorption (DVS)

[0165] Dynamic vapor sorption was performed with an ADVENTURE or Intrinsic series DVS at 25 ºC under nitrogen blow. Approximately 30 milligrams of material were used. Samples were analyzed using (1) 0% RH to 95% RH at 10% RH (5% from 90 to 95%RH); and / or (2) 95% RH to 0% RH at 10% RH (5% from 95 to 90%RH). Proton Nuclear Magnetic Resonance (1H NMR)

[0166] NMR data was taken using Bruker AVANCE NEO 400 MHz in DMSO-d6 solvent. And 1,3,5-trimethoxybenzene was used as internal standard substance for quantitative nuclear magnetic resonance (QNMR). Page 60 of 88 12949448v1Attorney Docket No.2017207-0202 High Performance Liquid Chromatography (HPLC)

[0167] HPLC of Waters Arc with UV detector and Shimadzu NEXERA XR with UV detector were employed to detect the purity / assay and chiral purity, respectively, with the methods shown in the tables below.

[0168] HPLC method for purity test: Instrument Waters Arc with UV detector Column Waters symmetry C18 (4.6*100 mm, 3.5 μm) PN: WAT066220 Mobile phase A: 0.05% TFA in H2O, B: 0.05% TFA in ACN Time (min) %A %B 0.00 95 5 5.00 70 30 Gradient 20.00 30 70 26.00 5 95 26.10 95 5 30.00 95 5 Detector UV, 220 nm Column temperature 30 ºC Flow rate 1.0 mL / min Injection volume5 µLDiluent ACN: H2O=1:1 (v / v) HPLC method for chiral purity: Instrument SHIMADZU NEXERA XR Column Daicel CHIRALPAK AD-3 (4.6*150 mm, 3 μm) PN: 19524 Mobile phase n-Hexane: EtOH: DEA: TFA = 950: 50 :1 :1 (v / v / v / v) Detector UV, 220 nm Column temperature 30 ºC Flow rate 0.6 mL / min Injection volume 5 µL Run time 40 min Page 61 of 88 12949448v1Attorney Docket No.2017207-0202 Instrument SHIMADZU NEXERA XR Diluent EtOH Ion Chromatography (IC)

[0169] The data of ion content was collected with ion chromatography system of DIONEX ICS-6000+DP (Chromeleon 7.2 system) and the method was shown in the table below.

[0170] Summary of IC method: Items Parameters H2O (Milli-Q water) Reagents Eluent Generator: Dionex EGC 500 KOH RFICTM & HPLCTM P / N: 075778 Column Dionex IonPac AS11-HC, 4×250mm, Part No.052960 Guard column: Dionex IonPac AG11-HC, 4×50mm, Part No.052962 temperature 30 ºC Flow rate 1.0 mL / min Detector Electrical conductivity detector Suppressor Dionex ADRS 6004mm; P / N: 088666 Mobile phase A: H2O; B: Dionex EGC 500 KOH RFICTM & HPLCTM P / N: 075778 Injection volume 25 µL Concentration (mM) 12 mM KOH Br- Run time 20 min Concentration (mM) 20 mM KOH Fumarate Run time 20 min Time (min) Concentration (mM) 0.0 20 11.0 20 SO42-11.1 40 20.0 40 20.1 20 25.0 20 Page 62 of 88 12949448v1Attorney Docket No.2017207-0202 Example 1: Salt and Polymorph Screening

[0171] In the present Example, a total of 75 salt screening experiments were performed using 15 acids and five solvent systems. Specifically, stock solutions of starting material (Compound 1) were prepared (~20 mg per experiment). Stock solution and corresponding acid were added to a HPLC vial, with equivalent molar charge ratio. After magnetically stirring at RT overnight, for group A~D, 1) turbid systems were centrifuged to isolate the solids, 2) clear solutions were stirred at RT for another day followed by cooling at 5 ºC / -5 ºC / -20 ºC. If no precipitate was obtained, anti-solvent (MTBE, toluene or n-heptane) was added. The final clear solutions of salt trial systems with no precipitation occurred were subjected to evaporation. Any solid residues were vacuum dried at 30 ºC for ~15 h before characterization. For group E, 1) turbid systems were centrifuged to isolate the solids for XRPD analysis, 2) clear solutions were transferred to stir at 5 ºC. If no precipitate was obtained, it was subjected to evaporation at RT.

[0172] As summarized in Table 2. Page 63 of 88 12949448v1Attorney Docket No.2017207-0202

[0173] Table 1, most systems generated oils / gels, and a total of 9 crystalline salt forms were obtained, namely Hydrobromide Form A, Hydrochloride Form A, Sulfate Form A, 1,5- Naphthalenedisulfonate Form A~D, Fumarate Form A and L-Tartrate Form A. Hydrochloride Form A was visually hygroscopic at ambient conditions, whereas the other eight salt forms were good white powders and further fully characterized. The results indicated that Hydrobromide Form A and Sulfate Form A were likely anhydrates / hydrates of di-salts, while other six salt forms were mono-salts, including one anhydrate (Fumarate Form A), one anhydrate or hydrate (1,5-Naphthalenedisulfonate Form A), two hydrates (1,5-Naphthalenedisulfonate Form D and L- Tartrate Form A), and two solvates (1,5-Naphthalenedisulfonate Form B / C). The results are shown in Table 2. Page 64 of 88 12949448v1Attorney Docket No.2017207-0202

[0174] Table 1. Summary of salt screening ACN / Toluene Solvent MEK EtOAc THF IPAc (1:1, v / v) Acid A B C E D mi A m tyo o . -so e s e e a - ep a e o sa p e a a o o e sa p es. %: stirring at RT (clear) → cooling at 5 / -5 ºC (clear) → cooling at -20 ºC (solid). @: stirring at RT (clear) → cooling at 5 / -5 / -20 ºC (clear) → anti-solvent (MTBE) addition (clear) → evaporation at RT or vacuum evaporation at 30 ºC overnight (gel). Anti-solvents were MTBE and toluene for samples at D8 / D9 and MTBE for other samples. And samples at A15 / B15 / C15 / D15 were vacuum evaporation at 30 ºC overnight, others were evaporation at RT. &: stirring at RT (clear) → cooling at 5 / -5 / -20 ºC (clear). *: oil was obtained after reactive crystallization and no improvement was observed after temp. cycling (50~5 ºC with 2 cycles at the rate of 0.1 ºC / min for cooling and 0.75 ºC for heating). !: stirring at RT (clear) → cooling at 5 ºC (clear) → evaporation at RT (gel). Underlined forms were selected for further evaluation. Page 65 of 88 12949448v1Attorney Docket No.2017207-0202 ro F detalucep fitSo.aroap NerP moihciotS stnetno Ctne1vlo S ytir2u d Pn n) ]0]0]0]0] ]bi ]nitnastoecuo.tissACº 5 5 9 000,1[1[1[2[2[7. ]000gi05 r ,s02[ lel1[at)y oltnp WoG m T o L%( 4.1 4..4 4.1 4.2 4012[ 6ge 1s,shanerpwef..4.6N.3erarW-1hecrru,0 8 0 4 9n4 tCi3 6 go2 1 2 2 1i7 27(.o.fk( h)a / / 2 / / / fCr. 4.8 9 3 8 13 5 2 4 4t1 1o / 2 / [a1 aoS. . . . .e9. . . . . s / eC 5 w8 4 1 6 8dº a18 1 5 4 52 1 5p 7. . ,sD2 ]t np / (ml5 6 3 7 603 9ok) w1 1 1 1 1m E9 5 nda rseitathicalcepnagoC)a bd(n aie c e e e e e e erndt t t t t t t t nislyehwtieli i i i i i i i)e il ah c h h h h h h hoo da Ie rr hontgt (pMw w w w w w w ws / sg w(eypd)y :ndCdr ] Ihe (Ai [ a ccypll.pf em mnas(oabh h h h h h hyalu ui it oiast yiyg g g g g g g di i i i i i i baretd der yae enia rsH H H H H H Hesnivzi oM MeCrmr Am[efkfrmtec =a h oyteuttds ieaes ires 3 1 1 2 2 2 2 1 1pf cnwd saaaalAhyto sdiSab iC / crt ea pwr diuozpi epyB C D Ae m f caArmrd r ade ia lmrismim ordfm m m oitr rrmrr F lrc Fs emeoooA Al aoo ovooeoaeo lF Fr F sFFFr h tbnt y oc am mb rA Al r r aa seiiethd shr ttsaoroio teorortaaa- d ather sF Ftes nr5 a oCiddeflm wm. y,yp ny oa 1tTfe -pru unoki2 mH HilSlFN La ueCl u ahnel eo: ci ob c pDo :a: :tPage 66 of 88* s #@ T N 12949448v1Attorney Docket No.2017207-0202 Example 2: Evaluation of Salt Leads Reproducibility of Salt Leads

[0175] Based on the characterization data, four salt forms of Compound 2, Hydrobromide Form A, Fumarate Form A, L-Tartrate Form A, and 1,5-Naphthalenedisulfonate Form D were selected for further evaluation. Hydrobromide Form A, Fumarate Form A and 1,5- Naphthalenedisulfonate Form D were prepared in 150-mg scale successfully, with the characterization results summarized in Table 3 and procedures according to embodiments of the present disclosure. However, two preparation trials of L-Tartrate Form A with seeding generated gel and no more attempts were conducted (Table 4). Table 3. Solid State Characterization summary of Compound 2 salt leads 1,5- Salt Form Hydrobromide Form Fumarate Naphthalenedisulfonate12949448v1Attorney Docket No.2017207-0202 Form Change post No No NT DVS d al 0 H. y p p p Scale Acid Molar Charge Conc. R Solvent Resultsatio (acid / base) (mg / mL)#: Seeds ent was observed ºC forheating.

[0176] Compound 2 Hydrobromide Form A was prepared successfully as evidenced by the XRPD comparison in FIG.1AError! Reference source not found.. The isolated solids were 1 further characterized by HPLC, TGA, DSC, H NMR and IC. And details are shown in Table 5 and FIG.1B. After heating to 150 ºC followed by cooling to RT under N2blow, no form change 1 (FIG.1C) and similar weight loss (FIG.1D) were observed. H NMR results showed no solvent signals after heating (FIG.14). Based on the results, Form A wasspeculated to be an anhydrate or channel hydrate of di-salt. Table 5. Summary of characterization result of Compound 2 Hydrobromide Form A Salt Form Hydrobromide Form APage 68 of 88 12949448v1Attorney Docket No.2017207-0202 Acid Assay by IC (wt%) 30.7 Stoichiometry (acid / base) 20

[0177] Compound 2 Fumarate Form A was re-prepared successfully as evidenced by the XRPD comparison in FIG.8A. It was further characterized by HPLC, TGA, DSC,1H NMR and IC. Details were summarized in Table 6. Based on the results, Compound 2 Fumarate Form A was speculated to be an anhydrate of the mono-salt. Table 6. Summary of characterization result of Compound 2 Fumarate Form A Salt Form Fumarate Form Ag y p , g p .

[0178] Compound 21,5-Naphthalenedisulfonate Form D was re-prepared successfully as evidenced by the XRPD comparison in Error! Reference source not found.. It was further characterized by HPLC, TGA, DSC, and1H NMR. Details were summarized in Table 7. Based Page 69 of 88 12949448v1Attorney Docket No.2017207-0202 on the results, Compound 21,5-Naphthalenedisulfonate Form D was speculated to be a hydrate of the mono-salt. Table 7. Summary of characterization result of Compound 21,5-Naphthalenedisulfonate Form D Salt Form 1,5-Naphthalenedisulfonate Form D A Whit lidSolid-state Stability

[0179] The solid-state stability was evaluated for Compound 2 Hydrobromide Form A, Fumarate Form A, and 1,5-Naphthalenedisulfonate Form D at 25 ºC / 60% RH and 40 ºC / 75% RH in open containers. After storage for 3~5 days, samples were tested by XRPD and HPLC.

[0180] As the results summarized in Table 8 show, Hydrobromide Form A and Fumarate Form A showed no appearance / form change and no substantial purity change after storage (FIG. 10A and FIG.10B), indicating good physicochemical stability.1,5-Naphthalenedisulfonate Form D showed no substantial change at 25 ºC / 60% RH while color change and new diffraction peaks were observed at 40 ºC / 75% RH (FIG.10C). Table 8. Solid-state stability results of three salt leads Initial After Storage Salt Form Conditions Appearance Purity Appearance Purity Form (area%) (area%) change 25 Hydrobromide Form A White solid 99.1 ºC / 60%RH, 5 White solid 99.2 No days Page 70 of 88 12949448v1Attorney Docket No.2017207-0202 40 ºC / 75%RH, 5 White solid 99.2 No days 25 ºC / 60%RH, 5 White solid 99.6 No Fumarate Form A White solid 99.4 days 401,5- ºC / 60%RH, 3 White solid 99.4 No Naphthalenedisulfonate White solid 98.9 days D 40Hygroscopicity

[0181] To understand the hygroscopicity of Compound 2 Hydrobromide Form A and Fumarate Form A, DVS was employed to measure the mass change as a function of relative humidity at 25 ºC. All samples were pre-dried at 0% RH to remove the adsorbed moisture or solvent.

[0182] As shown in FIGs.11A-11B, Compound 2 Hydrobromide Form A showed a water uptake of 3.3% at 25 ºC / 80% RH, indicating that it was moderately hygroscopic. XRPD showed no form change after DVS evaluation. As shown in FIGs.12A-12B, Compound 2 Fumarate Form A showed a water uptake of 0.13% at 25 ºC / 80%RH, indicating that it was non- hygroscopic. XRPD showed no form change after DVS evaluation. Salt Formation and Salt Break Processes

[0183] Salt formation and salt break processes were carried out (500 mg scale) for both Compound 2 Fumarate Form A and Hydrobromide Form A to compare the impurity rejection effect and other issues with starting material of Compound 1. For Compound 2 Fumarate Form A, results indicated that: 1) In the salt formation process, purity was significantly increased from ~94.9 A% to 99.6 A%. 2) In the salt break process, purity was slightly decreased from ~99.6 A% to 99.2 A%. The Page 71 of 88 12949448v1Attorney Docket No.2017207-0202 chiral purity of the freebase after salt break was 99.7%. The residual Na+was 626ppm in the freebase after salt break. Salt formation and salt break procedure for Compound 2 Fumarate Form A:

[0184] Salt formation: A flask was charged with 500 mg of Compound 1 and to the flask was added 3.0 equivalents of fumaric acid and 7.4 v THF. The resulting mixture was stirred at 25℃ overnight and then filtered and washed with THF. The product was then dried under vacuum at 35℃ for about 24 hours.

[0185] Salt break: A flask was charged with 6.4 v of 1 M NaOH and Compound 2 Fumarate Form A. The resulting mixture was stirred at 25℃ overnight and then extracted with 16 v DCM four times. The organic phase was washed with 12 v aqueous 5% NaCl three times and then concentrated under reduced pressure at about 35℃. Table 9. Results summary of salt formation process, Compound 2 Fumarate Form A Mother liquor Purity, A% SM Acid Solvent rTable 10. Results summary of salt break process, Compound 2 Fumarate Form A Results of free base after salt break Alkaline

[0186] For Compound 2 Hydrobromide Form A, results indicated that: 1) In the salt formation process, purity was significantly increased from ~94.9 A% to ~99.7 A%. 2) In the salt break process, purity was slightly decreased from ~99.7 A% to 99.5 A%. The chiral purity of freebase after salt break was ~99.4%. The residual Na+was 734ppm in the freebase after salt break. Page 72 of 88 12949448v1Attorney Docket No.2017207-0202

[0187] Salt formation and salt break procedure for Compound 2 Hydrobromide Form A:Salt formation: A flask was charged with 500 mg of Compound 1. To the flask was added 8.62 equivalents of hydrobromic acid and 15.4 v MEK. The resulting mixture was stirred overnight at 25℃ and then filtered and washed with MEK. The product was then dried under vacuum at 35℃ for about 24 hours.

[0188] Salt break: A flask was charged with 3 v of 1 M NaOH and Compound 2 Hydrobromide Form A. The resulting mixture was stirred at 25℃ overnight and then extracted with 6 v DCM four times. The organic phase was washed with 6 v aqueous 5% NaCl three times and then concentrated under reduced pressure at about 35℃ until distillation was complete. Table 11. Results summary of salt formation process, Compound 2 Hydrobromide Form A Mother Purity, A% SM Acid Solvent liquorTable 12. Results summary of salt break process, Compound 2 Hydrobromide Form A Alkaline Results of free base after salt break

[0189] The salt formation process was firstly investigated with material of lower purity, and the purity was significantly increased instead of column purification. Compound 2 Fumarate Form A was selected for further evaluation due to relatively lower mother liquor loss. The process was heterogeneous due to the low solubility of fumaric acid in THF, and solvent screening should be performed to enable a homogeneous process. However, formation of hydrochloride was applied in the manufacture to avoid a solid-liquid separation process. Moreover, the purity could also be significantly increased. Page 73 of 88 12949448v1Attorney Docket No.2017207-0202 Example 3: Salt Formation Process Development of Compound 2 Fumarate Form A Solvent Screening

[0190] In order to screen for a suitable solvent system, the solubility of different samples was estimated in common-used Class II / III solvents at RT (~25 ºC). Specially, approximately ~20 mg typical material was added into a HPLC glass vial. Solvents were then added stepwise into the vials until the solids were dissolved or a total volume of 2 mL was reached. Results indicated that: 1) Compound 1 was soluble in most solvents at ~25 ºC except for H2O. 2) Fumaric acid was insoluble in most solvents at ~25 ºC except for MeOH, EtOH and DMSO. Moreover, solubility of Fumaric acid was significantly increased in mixed solvents such as EtOH: H2O=9:1 (v:v), Acetone: H2O=9:1 (v:v), THF: H2O=9:1 (v:v) and ACN: H2O=9:1 (v:v). 3) Compound 2 Fumarate Form A was insoluble in all single solvents at ~25 ºC.

[0191] Therefore, EtOH: H2O=9:1 (v:v), Acetone: H2O=9:1 (v:v) could be selected as candidate solvent systems to enable a homogeneous salt formation process. Table 13. Approximate solubility of different samples at room temperature (~25°C) Solubility / (mg / mL) S l tPage 74 of 88 12949448v1Attorney Docket No.2017207-0202 THF >500 S<11.1* S<9.7 2-MeTHF >500 S<100* S<101Preliminary Trials

[0192] To confirm impurity rejection effect and yield, preliminary trials (100mg) were carried out in EtOH: H2O=9:1 (v:v) and Acetone: H2O=9:1 (v:v) solvent system, respectively. FIG.13 shows an overlay of XRPD patterns for Compound 2 Fumarate Form A samples obtained in the trials. Results indicated that: 1) In EtOH: H2O=9:1 (v:v) system, the purity of product was significantly increased from 90.9 A% to 99.7 A% with mother liquor loss as 10.0%. 2) In Acetone: H2O=9:1 (v:v) system, the purity of product was significantly increased from 90.9 A% to 99.6 A% with mother liquor loss as 5.5%.

[0193] Therefore, the Acetone: H2O=9:1 (v:v) solvent system was suitable for further verification. Table 14. Results summary of salt formation process for Compound 2 Fumarate Form A SM Acid Solvent Purity, A%Page 75 of 88 12949448v1Attorney Docket No.2017207-0202 Mother liquor Wet Cake Dry Mother loss % product liquorExample 4: Synthesis of Compound Aare charged to a reactor and the mixture is cooled to 0–5 °C. Acetic acid (0.56 kg) is added followed by 4.1 (1.0 kg) and 4Å molecular sieves. A solution of 4.2 (1.2 kg) in dichloromethane is added slowly while maintaining the temperature of the mixture at 0–5 °C and stirring continued. The mixture is quenched with 0.1M aqueous HCl and the layers are allowed to separate. The aqueous layer is extracted twice more with dichloromethane and the combined organic extracts are washed with 0.1M aqueous NaOH solution and water. The organic layers are concentrated and swapped with THF to give a solution of 4.3 in THF which is used directly in the next step. Page 76 of 88 12949448v1Attorney Docket No.2017207-0202

[0195] Step 2: A 2.5M solution of lithium aluminum hydride in THF (3.22 kg) and additional THF are charged to a reactor and the resulting mixture is heated to about 65–70 °C. A solution of 4.3 (1.0 kg based on assay) in THF is added to the reactor at the same temperature and the mixture is stirred. Acetic acid and THF are added to the reactor and stirring is continued; the reaction mixture is cooled to 20–30 °C, THF is added and the reaction mixture further cooled to 0-5 °C. Water is added slowly followed by aqueous sodium hydroxide solution. The mixture is filtered and washed with THF. The combined filtrates are concentrated and swapped to MTBE. Dilute aqueous hydrochloric acid is added until the pH is 3–4 and the layers are separated. The aqueous layer is washed with MTBE and the pH is adjusted to pH 9–10 with aqueous NaOH solution. The basic aqueous phase is extracted multiple times with MTBE and the combined MTBE layers are washed with 5% aqueous NaCl solution. The organic layer is concentrated to give a solution of Compound 1 which is used directly in the next step.

[0196] Step 3: A solution of Compound 1 (1 kg) and MTBE are charged to a reactor autoclave and cooled to -10–0 °C. Methyl bromide (1.63 kg) is added while maintaining the same temperature. The autoclave reactor is sealed and warmed to 20–30 °C and stirred. The reaction mixture is filtered, and the solids are washed with MTBE and then dried to afford crude Compound A. The crude Compound A (1 kg) is charged to a reactor followed by a mixture of methanol and MTBE 1:1 and the mixture is stirred at approximately 30 °C to give a clear solution, which is polish-filtered into a second reactor. The filtered solution is then heated to 40– 50 °C, then additional MTBE is added followed by Compound A seed crystals. The mixture is stirred at 40–50 °C, then MTBE is added slowly followed by cooling to 0–5 °C. The product is filtered, washed, and dried at 30–40 °C to afford Compound A drug substance.

[0197] The embodiments of the disclosure described above are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims. Page 77 of 88 12949448v1

Claims

Attorney Docket No.2017207-0202 CLAIMS 1. Compound 2:wherein X is a co- group of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2.

2. A crystalline solid form of Compound 2:wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2.

3. The crystalline solid form of claim 2, wherein X is fumaric acid.

4. The crystalline solid form of claim 3, wherein the crystalline solid form is Compound 2 Fumarate Form A. Page 78 of 88 12949448v1Attorney Docket No.2017207-0202 5. The crystalline solid form of claim 4, wherein Compound 2 Fumarate Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.2, 11.6, 14.1, 16.7, 17.6, 18.6, 18.8, 24.8, and 25.7 ± 0.2 degrees 2-theta.

6. The crystalline solid form of claim 4, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 6.7 or7. The crystalline solid form of claim 4, wherein Compound 2 Fumarate Form A is characterized by an XRPD pattern substantially similar to that depicted in FIG.8A. Page 79 of 88 12949448v1Attorney Docket No.2017207-0202 8. The crystalline solid form of claim 7, wherein Compound 2 Fumarate Form A is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG.8B; or (ii) a DSC pattern substantially similar to that depicted in FIG.8B.

9. The crystalline solid form of claim 2, wherein X is hydrobromic acid.

10. The crystalline solid form of claim 9, wherein the crystalline solid form is Compound 2 Hydrobromide Form A.

11. The crystalline solid form of claim 10, wherein Compound 2 Hydrobromide Form A is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.4, 16.6, 17.1, 19.8, 20.1, 23.2, 24.3, 25.6, and 26.4 ± 0.2 degrees 2-theta.

12. The crystalline solid form of claim 10, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: Page 80 of 88 12949448v1Attorney Docket No.2017207-0202 °2θ (± 0.2) 6.4 or .

13. The crystalline solid form of claim 10, wherein Compound 2 Hydrobromide Form A is characterized by an XRPD pattern substantially similar to that depicted in FIG.1A.

14. The crystalline solid form of claim 13, wherein Compound 2 Hydrobromide Form A is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG 1B; or (ii) a DSC pattern substantially similar to that depicted in FIG.1B.

15. The crystalline solid form of claim 2, wherein X is 1,5-naphthalenedisulfonic acid.

16. The crystalline solid form of claim 15, wherein the crystalline solid form is Compound 2 1,5-Naphthalenedisulfonate Form D. Page 81 of 88 12949448v1Attorney Docket No.2017207-0202 17. The crystalline solid form of claim 16, wherein Compound 21,5-Naphthalenedisulfonate Form D is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.9, 9.5, 12.9, 13.1, 14.1, 18.0, 18.6, 19.3, and 22.2 ± 0.2 degrees 2-theta.

18. The crystalline solid form of claim 16, wherein the crystalline solid form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from: °2θ (± 0.2) 7.1 or19. The crystalline solid form of claim 16, wherein Compound 21,5-Naphthalenedisulfonate Form D is characterized by an XRPD pattern substantially similar to that depicted in FIG.7A. Page 82 of 88 12949448v1Attorney Docket No.2017207-0202 20. The crystalline solid form of claim 19, wherein Compound 21,5-Naphthalenedisulfonate Form D is further characterized by one or more of the following: (i) a TGA pattern substantially similar to that depicted in FIG.7B; or (ii) a DSC pattern substantially similar to that depicted in FIG.7B.

21. A crystalline solid form obtainable by a process described herein (e.g., in Example 1, Example 2, or Example 3).

22. A sample comprising the crystalline solid form of any one of claims 2-21, wherein the sample comprises about 90% by weight of the crystalline solid form.

23. A sample comprising the crystalline solid form of any one of claims 2-21, wherein the sample comprises about 95% by weight of the crystalline solid form.

24. A sample comprising the crystalline solid form of any one of claims 2-21, wherein the sample comprises about 98% by weight of the crystalline solid form.

25. A sample comprising the crystalline solid form of any one of claims 2-21, wherein the sample comprises about 99% by weight of the crystalline solid form.

26. A sample comprising the crystalline solid form of any one of claims 2-21, wherein the sample is substantially free of impurities.

27. A composition comprising Compound A and the crystalline solid form of any one of claims 2-21.

28. A method of preparing the crystalline solid form of any one of claims 2-21 according to a method described herein.

29. A method of preparing Compound 2 Fumarate Form A comprising: Page 83 of 88 12949448v1Attorney Docket No.2017207-0202 reacting Compound 1 with fumaric acid in the presence of a solvent comprising ethanol, acetone, acetonitrile, tetrahydrofuran, water, or combinations thereof.

30. The method of claim 29, wherein the solvent is tetrahydrofuran.

31. The method of claim 29, wherein the solvent comprises ethanol and water in a ratio that is 9:1 v / v of ethanol to water.

32. The method of claim 29, wherein the solvent comprises acetone and water in a ratio that is 9:1 v / v of acetone to water.

33. The method of claim 29, wherein the solvent comprises tetrahydrofuran and water in a ratio that is 9:1 v / v of tetrahydrofuran to water.

34. The method of claim 29, wherein the solvent comprises acetonitrile and water in a ratio that is 9:1 v / v of acetonitrile to water.

35. A method of preparing Compound 2 Hydrobromide Form A comprising: reacting amorphous Compound 1 with a HBr-MEK solution.

36. The method of claim 35, further comprising adding 2-butanone to hydrobromic acid to create the HBr-MEK solution.

37. A method of preparing Compound 21,5-Naphthalenedisulfonate Form D comprising: reacting Compound 1 with 1,5-naphthalenedisulfonic acid in the presence of acetonitrile and toluene.

38. The method of claim 37, wherein the acetonitrile and toluene are present in a 1:1 ratio.

39. A method of preparing Compound A Page 84 of 88 12949448v1Attorney Docket No.2017207-0202 the method comprising:contacting a crystallinewith a base and bromomethane in a solvent to provide Compound A, and wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and n is 1 or 2.

40. The method of claim 39, wherein Compound 2 is prepared according to the method of any one of claims 29-38.

41. The method of claim 39 or 40, wherein the base is selected from triethylamine, di- isopropylethylamine (DIPEA), pyridine, 4-dimethylamine pyridine, triethylenediamine (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, and cesium carbonate.

42. The method of any one of claims 39-41, wherein the base is triethylamine. Page 85 of 88 12949448v1Attorney Docket No.2017207-0202 43. The method of any one of claims 39-41, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof.

44. The method of any one of claims 39-43, wherein the solvent comprises MBTE.

45. A method of preparing Compound A , the method comprising:contacting a crystalline solid form of Compound 2with a base to provide Compound 1contacting Compound 1 with bromomethane in a solvent to provide Compound A; wherein X is a co-former selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid, 1,5-naphthalenedisulfonic acid, fumaric acid, and L-(+)-tartaric acid; and Page 86 of 88 12949448v1Attorney Docket No.2017207-0202 n is 1 or 2.

46. The method of claim 45, wherein Compound 2 is prepared according to the method of any one of claims 29-38.

47. The method of claim 45 or 46, wherein the base is an organic base.

48. The method of claim 45 or 46, wherein the base is an aqueous base.

49. The method of any one of claims 45-48, wherein the solvent is selected from acetonitrile, dichloromethane, MTBE, THF, 2-MeTHF, DMF, DMSO, acetone, nitromethane, and combinations thereof.

50. The method of any one of claims 45-48, wherein the solvent comprises MBTE. Page 87 of 88 12949448v1

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