Crystal Forms of Neuroactive Steroids

Abstract

The present disclosure relates to Compound 1, as well as its crystalline solid forms and solid dosage forms. The present disclosure also provides methods for preparing the crystalline solid forms and solid dosage forms of Compound 1 and methods of using them. In a second aspect, the present disclosure provides a solid dosage form comprising a crystalline form of Compound 1 disclosed herein and at least one pharmaceutically acceptable carrier. In a third aspect, the present disclosure provides a method of treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1 disclosed herein or a solid dosage form comprising a crystalline form of Compound 1. JPEG2025523505000029.jpg2977

Description

Technical Field

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 355,238, filed Jun. 24, 2022, the disclosure of which is incorporated herein by reference in its entirety.

Background Art

[0002] The NMDA receptor is a heteromeric complex composed of NR1, NR2, and / or NR3 subunits and has distinct recognition sites for exogenous and endogenous ligands. These recognition sites include a binding site for glycine and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some situations and to excitotoxicity in other situations. These receptors are ligand-gated ion channels that accept Ca 2+ upon binding of glutamate and glycine and are essential for excitatory neurotransmission and normal CNS function. Positive modulators may be useful as therapeutic agents with potential clinical use as nootropics and may be useful in the treatment of mental disorders in which glutamatergic transmission is reduced or deficient (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0003] Compound 1 disclosed herein is a positive allosteric modulator (PAM) of the NMDA receptor. For a positive allosteric NMDA modulator to be a useful therapeutic agent, it must have an appropriate balance of various characteristics including affinity for the NMDA receptor, positive allosteric regulatory activity, duration of activity, oral bioavailability, tissue distribution, and stability (e.g., shelf life, formulatability, and crystallizability). An appropriate balance of such a combination of characteristics can lead to an NMDA receptor PAM with improved efficacy, safety, tolerability, patient compliance, manufacturing, etc. Thus, large-scale commercial preparations of the solid forms of Compound 1 and their corresponding solid dosage forms having appropriate properties (including chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying characteristics, milling characteristics, and stability during tableting) present many challenges. Accordingly, there is a current need for one or more solid forms of an NMDA receptor PAM (e.g., Compound 1) that have an appropriate balance of these characteristics and may be useful in the preparation of its pharmaceutically acceptable solid dosage forms.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] Various polymorphic forms of Compound 1

Chemical Formula

[0006] In a first aspect, the present disclosure provides Compound 1: [Chemical Formula] in a crystalline form.

[0007] In some embodiments, the crystalline form of Compound 1 is a) Crystalline Form A, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ, Crystalline Form A, b) Crystalline Form B, wherein Form B is characterized by an XRPD pattern comprising peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ, Crystalline Form B, c) Crystalline Form D, wherein Form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ, Crystalline Form D, d) Crystalline Form E, wherein Form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, and 17.0 ± 0.2 degrees 2θ, Crystalline Form E, e) Crystalline Form F, wherein Form F is characterized by an XRPD pattern comprising peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ, Crystalline Form F, and f) Crystalline Form G, wherein Form G is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, and 17.2 ± 0.5 degrees 2θ, and is selected from the group consisting of Crystalline Form G.

[0008] In some embodiments, the crystalline form of Compound 1 is a) Crystalline Form A, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ, Crystalline Form A, b) Crystal form B, wherein form B is characterized by an XRPD pattern comprising peaks at 10.9 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2 and 19.0 ± 0.2 degrees 2θ, crystal form B, c) Crystal form D, wherein form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ, crystal form D, d) Crystal form E, wherein form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, 17.0 ± 0.2, and 21.4 ± 0.2 degrees 2θ, crystal form E, e) Crystal form F, wherein form F is characterized by an XRPD pattern comprising peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ, crystal form F, and f) Crystal form G, wherein form G is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 12.0 ± 0.5, 13.5 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, 17.2 ± 0.5, and 17.7 ± 0.5 degrees 2θ, crystal form G, selected from the group consisting of crystal form G.

[0009] In some embodiments, the crystal form of Compound 1 is a) Crystal form A, wherein form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.3 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ, crystal form A, b) Crystal form B, wherein form B is characterized by an XRPD pattern comprising peaks at 10.9 ± 0.2, 14.4 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2 and 19.0 ± 0.2 degrees 2θ, crystal form B, c) Crystal form D, wherein form D is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.2, 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ, crystal form D, d) Crystal form E, wherein form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 8.5 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, 14.9 ± 0.2, 15.8 ± 0.2, 17.0 ± 0.2, 18.2 ± 0.2 and 21.4 ± 0.2 degrees 2θ, crystal form E, e) Crystal form F, wherein form F is characterized by an XRPD pattern comprising peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ, crystal form F, and f) Crystal form G, which is selected from the group consisting of crystal form G, characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 12.0 ± 0.5, 13.5 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, 17.2 ± 0.5, and 17.7 ± 0.5 degrees 2θ.

[0010] In some embodiments, the crystal form is an anhydrate.

[0011] In some embodiments, the crystalline form is crystalline form A characterized by an XRPD pattern comprising peaks at 15.3±0.2, 16.6±0.2, and 17.9±0.2 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form A further comprises at least one additional peak at a position selected from the group consisting of 11.3±0.2, 14.5±0.2, 17.7±0.2, and 20.1±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form A characterized by an XRPD pattern comprising peaks at 14.5±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, and 20.1±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form A characterized substantially by the XRPD pattern shown in FIG. 1A.

[0012] In some embodiments, crystalline form A has a thermogravimetric analysis (TGA) thermogram substantially as shown in FIG. 1B. In some embodiments, crystalline form A has a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 1B. In some embodiments, the DSC thermogram comprises an endothermic peak at about 203°C.

[0013] In some embodiments, the crystalline form is crystalline form B characterized by an XRPD pattern comprising peaks at 14.4±0.2, 16.8±0.2, and 18.5±0.2 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form B further comprises at least one additional peak at a position selected from the group consisting of 10.9±0.2, 15.4±0.2, and 19.0±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form B characterized by an XRPD pattern comprising peaks at 10.9±0.2, 14.4±0.2, 16.8±0.2, 18.5±0.2 and 19.0±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form B characterized substantially by the XRPD pattern shown in FIG. 2A.

[0014] In some embodiments, crystalline form B has a TGA thermogram substantially as shown in FIG. 2B. In some embodiments, crystalline form B has a DSC thermogram substantially as shown in FIG. 2B. In some embodiments, the DSC thermogram includes an endothermic peak at about 204 °C.

[0015] In some embodiments, the crystalline form is a solvate. In some embodiments, the crystalline form is a hydrate. In some embodiments, the crystalline form is a monohydrate.

[0016] In some embodiments, the crystalline form is crystalline form D characterized by an XRPD pattern including peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form D further includes at least one additional peak at a position selected from the group consisting of 9.1 ± 0.2, 16.4 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form D characterized by an XRPD pattern having characteristic peaks at 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form D characterized by an XRPD pattern substantially as shown in FIG. 3A.

[0017] In some embodiments, crystalline form D has a TGA thermogram substantially as shown in FIG. 3B. In some embodiments, crystalline form D has a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 3B. In some embodiments, the DSC thermogram includes an endothermic peak at about 204 °C. In some embodiments, the DSC thermogram includes an endothermic peak at about 127 °C.

[0018] In some embodiments, the crystalline form is the n-BuOH solvate. In some embodiments, the crystalline form is crystalline form E characterized by an XRPD pattern comprising peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form E further comprises at least one additional peak at a position selected from the group consisting of 8.5±0.2, 14.9±0.2, 15.8±0.2, 18.2±0.2, and 21.4±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form E characterized by having an XRPD pattern with characteristic peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, 17.0±0.2, and 21.4±0.2 degrees 2θ. In some embodiments, the crystalline form is crystalline form E characterized substantially by the XRPD pattern shown in FIG. 4A.

[0019] In some embodiments, crystalline form E has a TGA thermogram substantially as shown in FIG. 4B. In some embodiments, crystalline form E has a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 4B. In some embodiments, the thermogram comprises an endothermic peak at about 203 °C. In some embodiments, the DSC thermogram comprises an endothermic peak at about 87 °C.

[0020] In some embodiments, the crystalline form is crystalline form F characterized by an XRPD pattern comprising peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form F further comprises at least one additional peak at a position selected from the group consisting of 7.6 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, and 22.8 ± 0.5 degrees 2θ. In some embodiments, the crystalline form is crystalline form F characterized by an XRPD pattern comprising peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ. In some embodiments, the crystalline form is crystalline form F characterized by an XRPD pattern substantially as shown in FIG. 5A.

[0021] In some embodiments, the crystalline form is crystalline form G characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5 and 17.2 ± 0.5 degrees 2θ. In some embodiments, the XRPD pattern of crystalline form G further comprises at least one additional peak at a position selected from the group consisting of 12.0 ± 0.5, 13.5 ± 0.5, and 17.7 ± 0.5 degrees 2θ. In some embodiments, the crystalline form is crystalline form G characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 12.0 ± 0.5, 13.5 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, 17.2 ± 0.5, and 17.7 ± 0.5 degrees 2θ. In some embodiments, the crystalline form is crystalline form G characterized by an XRPD pattern substantially as shown in FIG. 5A.

[0022] In some embodiments, the crystalline form is a) crystalline form A characterized by an XRPD pattern substantially as shown in FIG. 1A, b) crystalline form B characterized by an XRPD pattern substantially as shown in FIG. 2A, c) Crystalline Form D, substantially characterized by the XRPD pattern shown in Figure 3A, d) Crystalline Form E, substantially characterized by the XRPD pattern shown in Figure 4A, e) Crystalline Form F, substantially characterized by the XRPD pattern shown in Figure 5A, and f) selected from the group consisting of Crystalline Form G, substantially characterized by the XRPD pattern shown in Figure 5A.

[0023] In a second aspect, the disclosure provides a solid dosage form comprising a crystalline form of Compound 1 disclosed herein and at least one pharmaceutically acceptable carrier.

[0024] In a third aspect, the disclosure provides a method of treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1 disclosed herein or a solid dosage form comprising a crystalline form of Compound 1. In some embodiments, the CNS-related condition is selected from the group consisting of adjustment disorder, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depressive states, bipolar disorder, and mood-cycling disorders), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorder (including those with mutations in the Shank protein group), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis), pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic epilepsy, such as Dravet syndrome, etc.), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

[0025] In a fourth aspect, the present disclosure provides a method of inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 1 disclosed herein, or a solid dosage form comprising a crystalline form of Compound 1 disclosed herein.

[0026] In a fifth aspect, the present disclosure provides a method of preparing a crystalline form of Compound 1. In some embodiments, the method of preparing a crystalline form of Compound 1 comprises: a) dissolving Compound 1 in at least one solvent to form a solution; b) adding an antisolvent until a precipitate is formed; and c) isolating the precipitate. In some embodiments, the solvent is selected from the group consisting of THF, 1,4-dioxane, and MEK. In some embodiments, the antisolvent is selected from the group consisting of H2O and ACN.

[0027] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of DME, acetone, nBuOH, EtOAc, IPAc, BuOAc, diethyl ether, and ACN.

[0028] In some embodiments, the method of preparing a crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at about 40 °C to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of IPAc, BuOAc, ACN, and n-heptane.

[0029] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a volatile solvent to form a mixture; b) aging the mixture at room temperature to allow the volatile solvent vapor to interact with Compound 1 and precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of DME, MEK, diethyl ether, and t-BuOH.

[0030] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a solution; b) adding the solution to a poor solvent; c) aging the mixture at room temperature to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is BuOH. In some embodiments, the poor solvent is n-heptane.

[0031] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) filtering the mixture to provide a filtrate; c) aging the filtrate at room temperature; d) precipitating a solid; and e) isolating the solid. In some embodiments, the solvent is selected from the group consisting of IPAc and t-BuOH.

[0032] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) heating the mixture to about 50 °C; c) filtering the mixture to provide a filtrate; d) cooling the filtrate to about -20 °C; e) precipitating a solid; and f) isolating the solid. In some embodiments, the solvent is acetone.

[0033] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) heating Compound 1 to about 205 °C; b) cooling the heated Compound 1 to about 25 °C to provide a solid; and c) isolating the solid. In some embodiments, the cooling in step b) is at a rate selected from the group consisting of about 2 °C / min, about 10 °C / min, and about 50 °C / min.

[0034] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at about 90 °C to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is n-heptane.

[0035] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Compound 1 to a solvent to form a mixture; b) grinding the mixture to provide a solid; and d) isolating the solid. In some embodiments, the solvent is acetone / MIBK.

[0036] In some embodiments, the method for preparing the crystalline form of Compound 1 comprises: a) adding Form E of Compound 1 to a first solvent to form a mixture; b) concentrating the mixture by distillation at atmospheric pressure; c) cooling the mixture to about 80 - 85 °C; d) adding a second solvent to the mixture and maintaining the temperature of the mixture at about 80 - 85 °C for at least 1 hour; e) concentrating the mixture by distillation at atmospheric pressure; f) cooling the mixture to about 20 °C to precipitate a solid; and g) isolating the solid. In some embodiments, the first solvent is heptane. In some embodiments, the second solvent is n-BuOH.

[0037] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Form E of Compound 1 to a solvent to form a mixture; b) heating the mixture to about 50 °C; c) adding an anti-solvent; d) adding seeds of Form X of Compound 1 and aging the mixture at about 50 °C; e) cooling the mixture to about 20 °C over at least 3 hours and holding the mixture at 20 °C (with optional wet milling) to precipitate a solid; and f) isolating the solid. In some embodiments, the solvent is acetone. In some embodiments, the anti-solvent is acetone / water. In some embodiments, the anti-solvent is acetone / water (1:1 v / v).

[0038] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding crude Compound 1 to a solvent to form a mixture and heating the mixture to about 80 °C; b) concentrating the mixture via distillation; c) adding a solvent to the mixture; d) adjusting the temperature of the mixture to about 80 °C; e) adding seeds of Form E of Compound 1; f) cooling the mixture to about 15 - 25 °C; g) aging the mixture at about 15 - 25 °C for about 4 - 18 hours to precipitate a solid; and h) isolating the solid. In some embodiments, the solvent is n-BuOH.

Brief Description of the Drawings

[0039]

Figure 1A

Figure 1B

Figure 1C

Figure 1D

Figure 1E

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 4C

Figure 4D

Figure 5A

Figure 5B

Figure 5C

Mode for Carrying Out the Invention

[0040] General Definitions The term "this specification" means the entire present application.

[0041] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art to which this disclosure pertains. In general, the terms used in connection with the compounds, compositions, and methods described herein are well known and commonly used in the art.

[0042] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of this specification (including embodiments described only in the examples), can be combined with one or more other embodiments of the disclosure, unless explicitly denied or inappropriate. Combinations of embodiments are not limited to those specific combinations claimed through the scope of multiple dependent claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same basic claim. When elements are presented as a list, for example, in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0043] Throughout this specification, the phrase "comprise", or variations such as "comprises" or "comprising", is understood to mean including the stated integer (or component) or group of integers (or components), but not meaning the exclusion of any other integer (or component) or group of integers (or components).

[0044] Throughout this specification, when a composition is described as having, including, or comprising (or a variation thereof) a particular component, it is contemplated that the composition may also consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process may also consist essentially of or consist of the recited process steps. Further, it should be understood that the order of steps or the order of performing certain actions is not critical as long as the compositions and methods described herein remain operable. Additionally, two or more steps or actions can be performed simultaneously.

[0045] As used herein, the term "including" means "including but not limited to". "Including" and "including but not limited to" are used interchangeably. Thus, these terms are understood to mean including the recited integer (or component) or group of integers (or components), but not meaning the exclusion of any other integer (or component) or group of integers (or components).

[0046] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0047] The use of the terms "a", "an", "the", and similar referents in the context of describing an element (especially in the context of the following claims) are to be construed to cover both the singular and the plural forms unless otherwise indicated herein or clearly contradicted by the context.

[0048] As used herein, the term "or" is to be understood as meaning "and / or" unless the context clearly dictates otherwise.

[0049] References to ranges of values herein are intended to serve simply as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0050] All publications, patents, and patent applications cited in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control. Additionally, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Such embodiments are considered to be known to those of ordinary skill in the art and may be excluded even if not explicitly recited herein. Any particular embodiment of the present disclosure may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0051] The terms "active ingredient", "active agent", and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient", "active agent", and "active substance" may be optical isomers of the compounds described herein.

[0052] The terms "drug" and "therapeutic agent" refer to a compound, or a pharmaceutical composition thereof, that is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.

[0053] As used herein, the term "polymorph" refers to a crystalline form of a compound or a salt, hydrate, or solvate thereof in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "polymorph" typically includes pseudopolymorphs, which are different solvates of a material, and thus, their properties differ from one another. Accordingly, each distinct polymorph and pseudopolymorph disclosed herein is considered to be a distinct single crystalline form disclosed herein.

[0054] As used herein, the term "crystalline" refers to a solid form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, result from different packings of the molecules in the solid state, which gives rise to different crystal symmetries and / or unit cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, for example, Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa., 173 (1990), The United States Pharmacopeia, 23.sup.rd ed., 1843-1844 (1995), which are incorporated herein by reference. As used herein, the terms "crystalline form", "single crystalline form", "crystalline solid form", and "polymorph" are used interchangeably, and these terms distinguish crystals having different properties (e.g., different XRPD patterns and / or different DSC scan results).

[0055] The term "substantially pure" relates to a composition of a particular crystalline solid form of Compound 1 that can be free of at least a specific weight percentage of impurities and / or other solid forms of Compound 1. The specific weight percentage is 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound 1 can be a substantially pure sample of any of the crystalline solid forms described herein. In some embodiments, Compound 1 can be substantially pure Form A. In some embodiments, Compound 1 can be substantially pure Form B. In some embodiments, Compound 1 can be substantially pure Form D. In some embodiments, Compound 1 can be substantially pure Form E. In some embodiments, Compound 1 can be substantially pure Form F. In some embodiments, Compound 1 can be substantially pure Form G.

[0056] Crystal forms are generally characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks, typically expressed in degrees 2-theta) is generally regarded as a distinct characteristic of a particular crystal form. The relative intensity of XRPD peaks can vary depending, inter alia, on sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the particular instrument used. In some examples, depending on the type or setting of the instrument, more (i.e., new peaks) or fewer (i.e., peaks can disappear) peaks can be present in the XRPD pattern. In some examples, any particular peak in the XRPD pattern can appear as a singlet, doublet, triplet, quartet, or multiplet depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal form. In some examples, any particular peak in XRPD can appear with a symmetric or asymmetric shape, e.g., a shape with a shoulder. Further, instrument variations and other factors can affect the 2-theta values. Those skilled in the art to understand these variations can use not only XRPD but also other known physicochemical techniques to identify or confirm the definitive characteristics or features of a particular crystal form.

[0057] The term "characteristic peak" when referring to peaks in the XRPD pattern of a crystalline form of Compound 1 refers to a specific set of peaks to which 2θ values in the range of 0° to 40° are uniquely assigned to one of the crystalline forms of Compound 1 as a whole.

[0058] The term "amorphous" as applied to a compound refers to a state in which the material lacks long-range order at the molecular level and can exhibit physical properties of a solid or a liquid depending on temperature. Typically, such materials give no distinct X-ray diffraction pattern and exhibit solid properties but are more formally described as liquids. Upon heating, a change in state occurs, typically a solid-to-liquid change characterized by a secondary change ("glass transition").

[0059] The terms "anhydrate" or "anhydrous" are used interchangeably and, when applied to a compound, refer to the solid state in which the compound does not contain water of crystallization or other solvent molecules within the crystal lattice.

[0060] The term "solvate" refers to a compound or a salt thereof provided herein that further contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces (e.g., hydrogen bonding). When the solvent is water, the solvate is a hydrate. When the solvent contains ethanol, the compound can be an ethanol solvate.

[0061] The term "stable" in the context of the polymorphic forms disclosed herein refers to the stability of the polymorphic form with respect to heat and / or humidity.

[0062] The crystalline form of Compound 1 described herein, for example, Form A, can melt over a specific temperature or temperature range. Such a specific temperature or temperature range is the onset temperature (T 開始) can be represented by. In some embodiments, at such an onset temperature, a sample of the crystalline form of Compound 1 melts and gives rise to concurrent secondary processes, such as recrystallization or chemical decomposition. In some embodiments, at such an onset temperature, the crystalline form of Compound 1 melts in the absence of other concurrent processes.

[0063] The present disclosure provides forms of Compound 1 having suitable properties for preparing solid dosage forms. Such properties include chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, milling properties, and stability during tableting.

[0064] The present disclosure relates to solid forms of Compound 1. [Chemical formula] In some embodiments, the solid form is a crystalline form of Compound 1. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is a hydrate. In some embodiments, the crystalline form is a solvate. Exemplary individual crystalline forms of the present disclosure are Forms A, B, D, E, F, and G.

[0065] Compound 1 and its chemical synthesis are disclosed in U.S. Patent No. 10,227,375 / PCT Application Publication No. WO2014160480.

[0066] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic peaks in the XRPD spectrum, as disclosed herein.

[0067] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in the differential scanning calorimetry (DSC) thermogram, as disclosed herein.

[0068] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in a thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0069] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic endothermic peaks in a differential scanning calorimetry (DSC) thermogram or a thermogravimetric analysis (TGA) thermogram, as disclosed herein.

[0070] In some embodiments, the crystal structure of the present disclosure can be identified by having one or more characteristic peaks in an XRPD spectrum in combination with having one or more characteristic endothermic peaks in a differential scanning calorimetry thermogram and / or a thermogravimetric analysis (TGA) thermogram.

[0071] In some embodiments, the crystalline form of Compound 1 is a) Crystalline Form A, wherein Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ, b) Crystalline Form B, wherein Form B is characterized by an XRPD pattern comprising peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ, c) Crystalline Form D, wherein Form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ, d) Crystalline Form E, wherein Form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, and 17.0 ± 0.2 degrees 2θ, e) Crystalline Form F, wherein Form F is characterized by an XRPD pattern comprising peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ, and f) Crystal form G, wherein form G is selected from the group consisting of crystal form G, characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5 and 17.2 ± 0.5 degrees 2θ.

[0072] In some embodiments, the crystal form of Compound 1 is a) Crystal form A, wherein form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ, crystal form A b) Crystal form B, wherein form B is characterized by an XRPD pattern comprising peaks at 10.9 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2, and 19.0 ± 0.2 degrees 2θ, crystal form B c) Crystal form D, wherein form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ, crystal form D d) Crystal form E, wherein form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, 17.0 ± 0.2, and 21.4 ± 0.2 degrees 2θ, crystal form E e) Crystal form F, wherein form F is characterized by an XRPD pattern comprising peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ, crystal form F, and f) Crystal form G, wherein form G is selected from the group consisting of crystal form G, characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 12.0 ± 0.5, 13.5 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, 17.2 ± 0.5, and 17.7 ± 0.5 degrees 2θ.

[0073] In some embodiments, the crystal form of Compound 1 is a) Crystal form A, wherein form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.3 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ, Crystal form A, b) Crystal form B, wherein form B is characterized by an XRPD pattern comprising peaks at 10.9 ± 0.2, 14.4 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2 and 19.0 ± 0.2 degrees 2θ, Crystal form B, c) Crystal form D, wherein form D is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.2, 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ, Crystal form D, d) Crystal form E, wherein form E is characterized by an XRPD pattern comprising peaks at 4.9 ± 0.2, 8.5 ± 0.2, 12.0 ± 0.2, 12.2 ± 0.2, 14.9 ± 0.2, 15.8 ± 0.2, 17.0 ± 0.2, 18.2 ± 0.2 and 21.4 ± 0.2 degrees 2θ, Crystal form E, e) Crystal form F, wherein form F is characterized by an XRPD pattern comprising peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ, Crystal form F, and f) Crystal form G, wherein form G is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.5, 12.0 ± 0.5, 13.5 ± 0.5, 14.7 ± 0.5, 16.0 ± 0.5, 17.2 ± 0.5, and 17.7 ± 0.5 degrees 2θ, is selected from the group consisting of Crystal form G.

[0074] In some embodiments, the crystal form of Compound 1 is a) Crystal form A, wherein form A is characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1A, Crystal form A, b) Crystal Form B, wherein Form B is characterized substantially by the XRPD pattern shown in Figure 2A, Crystal Form B, c) Crystal Form D, wherein Form D is characterized by XRPD pattern 3A, Crystal Form D, d) Crystal Form E, wherein Form E is characterized substantially by the XRPD pattern shown in Figure 4A, Crystal Form E, e) Crystal Form F, wherein Form F is characterized substantially by the XRPD pattern shown in Figure 5A, Crystal Form F, and f) Crystal Form G, wherein Form G is characterized substantially by the XRPD pattern shown in Figure 5A, selected from the group consisting of Crystal Form G.

[0075] In some embodiments, the crystalline form of Compound 1 is an anhydrate. In some embodiments, the crystalline form of Compound 1 is a solvate. In some embodiments, the crystalline form of Compound 1 is a hydrate. In some embodiments, the crystalline form of Compound 1 is a monohydrate. In some embodiments, the crystalline form of Compound 1 is an n-butanol solvate.

[0076] A. Crystal Form A In some embodiments, the present disclosure relates to Crystal Form A of Compound 1. In some embodiments, the anhydrous crystalline form of Compound 1 is Form A. In some embodiments, Form A is a) an XRPD pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ, b) an XRPD pattern substantially shown in Figure 1A, c) a DSC thermogram profile comprising an endothermic peak at about 203°C, d) a DSC thermogram profile substantially shown in Figure 1B, e) a TGA profile showing a loss of at least about 0.04 wt% between about 25°C and about 190°C, and f) having one or more characteristics selected from the group consisting of a TGA profile substantially shown in Figure 1B.

[0077] In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ. In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at 15.3 ± 0.2, 16.6 ± 0.2, and 17.9 ± 0.2 degrees 2θ and further comprising at least one additional peak at a position selected from the group consisting of 11.3 ± 0.2, 14.5 ± 0.2, 17.7 ± 0.2, and 20.1 ± 0.2 degrees 2θ. In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ. In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at 11.3 ± 0.2, 14.5 ± 0.2, 15.3 ± 0.2, 16.6 ± 0.2, 17.7 ± 0.2, 17.9 ± 0.2, and 20.1 ± 0.2 degrees 2θ. In some embodiments, crystalline Form A is characterized by an XRPD pattern substantially as shown in Figure 1A.

[0078] In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form A loses at least about 0.04 wt% between about 25°C and about 190°C. In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form A loses about 0.04 wt% between about 25°C and about 190°C. In some embodiments, Form A is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 1B.

[0079] In some embodiments, Form A is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 1B. In some embodiments, Form A is characterized by a DSC thermogram comprising an endothermic peak at about 203°C. In some embodiments, Form A is characterized by a DSC thermogram comprising a melting endothermic peak at about 203°C.

[0080] In some embodiments, Polymorph A substantially does not contain other polymorphic forms. In some embodiments, Polymorph A has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Polymorph A has a polymorph purity of at least 90%. In some embodiments, Polymorph A has a polymorph purity of at least 92%. In some embodiments, Polymorph A has a polymorph purity of at least 94%. In some embodiments, Polymorph A has a polymorph purity of at least 96%. In some embodiments, Polymorph A has a polymorph purity of at least 98%. In some embodiments, Polymorph A has a polymorph purity of at least 99%.

[0081] B. Crystal Form B In some embodiments, the present disclosure relates to Crystal Form B of Compound 1. In some embodiments, the anhydrous crystal form of Compound 1 is Form B. In some embodiments, Form B a) an XRPD pattern comprising peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ, b) an XRPD pattern substantially as shown in Figure 2A, c) a DSC thermogram profile comprising an endothermic peak at about 204 °C, d) a DSC thermogram profile substantially as shown in Figure 2B, e) a TGA profile showing a loss of at least about 0.2 wt% between about 70 °C and about 150 °C, and f) has one or more characteristics selected from the group consisting of a TGA profile substantially as shown in Figure 2B.

[0082] In some embodiments, Form B is characterized by an XRPD pattern that includes peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ. In some embodiments, Form B is characterized by an XRPD pattern that includes peaks at 14.4 ± 0.2, 16.8 ± 0.2, and 18.5 ± 0.2 degrees 2θ and further includes at least one additional peak at a position selected from the group consisting of 10.9 ± 0.2, 15.4 ± 0.2, and 19.0 ± 0.2 degrees 2θ. In some embodiments, Form B is characterized by an XRPD pattern that includes peaks at 10.9 ± 0.2, 14.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2, and 19.0 ± 0.2 degrees 2θ. In some embodiments, Form B is characterized by an XRPD pattern that includes peaks at 10.9 ± 0.2, 14.4 ± 0.2, 15.4 ± 0.2, 16.8 ± 0.2, 18.5 ± 0.2, and 19.0 ± 0.2 degrees 2θ. In some embodiments, crystalline Form B is characterized by an XRPD pattern substantially as shown in Figure 2A.

[0083] In some embodiments, Form B is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form B loses at least about 0.2 weight % between about 70 °C and about 150 °C. In some embodiments, Form B is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 2B.

[0084] In some embodiments, Form B is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2B. In some embodiments, Form B is characterized by a DSC thermogram that includes an endothermic peak at about 204 °C. In some embodiments, Form B is characterized by a DSC thermogram that includes a melting endothermic peak at about 204 °C.

[0085] In some embodiments, Polymorph Form B substantially does not contain other polymorphic forms. In some embodiments, Polymorph Form B has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Polymorph Form B has a polymorph purity of at least 90%. In some embodiments, Polymorph Form B has a polymorph purity of at least 92%. In some embodiments, Polymorph Form B has a polymorph purity of at least 94%. In some embodiments, Polymorph Form B has a polymorph purity of at least 96%. In some embodiments, Polymorph Form B has a polymorph purity of at least 98%. In some embodiments, Polymorph Form B has a polymorph purity of at least 99%.

[0086] C. Crystal Form F In some embodiments, the present disclosure relates to Crystal Form F of Compound 1. In some embodiments, the anhydrous crystal form of Compound 1 is Form F. In some embodiments, Form F a) an XRPD pattern comprising peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ, b) an XRPD pattern substantially as shown in FIG. 5A, c) a DSC thermogram profile comprising an endothermic peak at about 203 °C, d) a DSC thermogram profile substantially as shown in FIG. 5B, and e) has one or more characteristics selected from the group consisting of a TGA profile substantially as shown in FIG. 5C.

[0087] In some embodiments, Form F is characterized by an XRPD pattern that includes peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ. In some embodiments, Form F includes peaks at 10.8 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, and 22.9 ± 0.5 degrees 2θ and is further characterized by an XRPD pattern that includes at least one additional peak at a position selected from the group consisting of 7.6 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, and 22.8 ± 0.5 degrees 2θ. In some embodiments, Form F is characterized by an XRPD pattern that includes peaks at 7.6 ± 0.5, 10.8 ± 0.5, 13.6 ± 0.5, 14.9 ± 0.5, 15.4 ± 0.5, 15.9 ± 0.5, 17.1 ± 0.5, 20.5 ± 0.5, 22.8 ± 0.5, and 22.9 ± 0.5 degrees 2θ. In some embodiments, crystalline Form F is characterized by an XRPD pattern substantially as shown in FIG. 5A.

[0088] In some embodiments, Form F is substantially free of other polymorphic forms. In some embodiments, Form F has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Form F has a polymorphic purity of at least 90%. In some embodiments, Form F has a polymorphic purity of at least 92%. In some embodiments, Form F has a polymorphic purity of at least 94%. In some embodiments, Form F has a polymorphic purity of at least 96%. In some embodiments, Form F has a polymorphic purity of at least 98%. In some embodiments, Form F has a polymorphic purity of at least 99%.

[0089] D. Crystalline Form G In some embodiments, the present disclosure relates to crystalline Form G of Compound 1. In some embodiments, the anhydrous crystalline form of Compound 1 is Form G. In some embodiments, Form G is a) an XRPD pattern comprising peaks at 9.1±0.5, 14.7±0.5, 16.0±0.5 and 17.2±0.5 degrees 2θ, and b) having one or more characteristics selected from the group consisting of XRPD patterns substantially shown in Figure 5A.

[0090] In some embodiments, Form G is characterized by an XRPD pattern comprising peaks at 9.1±0.5, 14.7±0.5, 16.0±0.5 and 17.2±0.5 degrees 2θ. In some embodiments, Form G comprises peaks at 9.1±0.5, 14.7±0.5, 16.0±0.5 and 17.2±0.5 degrees 2θ and is further characterized by an XRPD pattern further comprising at least one additional peak at a position selected from the group consisting of 12.0±0.5, 13.5±0.5 and 17.7±0.5 degrees 2θ. In some embodiments, Form G is characterized by an XRPD pattern comprising peaks at 9.1±0.5, 12.0±0.5, 13.5±0.5, 14.7±0.5, 16.0±0.5, 17.2±0.5, and 17.7±0.5 degrees 2θ. In some embodiments, crystalline Form G is characterized by an XRPD pattern substantially shown in Figure 5A.

[0091] In some embodiments, polymorphic form G substantially does not contain other polymorphic forms. In some embodiments, polymorphic form G has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, polymorphic form G has a polymorph purity of at least 90%. In some embodiments, polymorphic form G has a polymorph purity of at least 92%. In some embodiments, polymorphic form G has a polymorph purity of at least 94%. In some embodiments, polymorphic form G has a polymorph purity of at least 96%. In some embodiments, polymorphic form G has a polymorph purity of at least 98%. In some embodiments, polymorphic form G has a polymorph purity of at least 99%.

[0092] E. Crystalline Form D In some embodiments, the present disclosure relates to crystalline form D of Compound 1. In some embodiments, the monohydrate crystalline form of Compound 1 is Form D. In some embodiments, Form D is a) an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ, b) an XRPD pattern substantially shown in FIG. 3A, c) a DSC thermogram profile comprising an endothermic peak at about 204°C, d) a DSC thermogram profile comprising an endothermic peak at about 127°C, e) a DSC thermogram profile substantially shown in FIG. 3B, f) a TGA profile showing a loss of at least about 14% by weight between about 60°C and about 150°C, and g) has one or more characteristics selected from the group consisting of a TGA profile substantially shown in FIG. 3B.

[0093] In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ. In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 17.4 ± 0.2, and 17.7 ± 0.2 degrees 2θ and further comprising at least one additional peak at a position selected from the group consisting of 9.1 ± 0.2, 16.4 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ. In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ. In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at 9.1 ± 0.2, 15.2 ± 0.2, 16.4 ± 0.2, 17.4 ± 0.2, 17.7 ± 0.2, 18.3 ± 0.2, and 18.9 ± 0.2 degrees 2θ. In some embodiments, crystalline Form D is characterized by an XRPD pattern substantially as shown in Figure 3A.

[0094] In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form D loses at least about 14 wt% between about 60°C and about 150°C. In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form D loses about 14 - 15 wt% between about 60°C and about 150°C. In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form D loses about 14 wt% between about 60°C and about 150°C. In some embodiments, Form D is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3B.

[0095] In some embodiments, Form D is characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 3B. In some embodiments, Form D is characterized by a DSC thermogram that includes an endothermic peak at about 204°C. In some embodiments, Form D is characterized by a DSC thermogram that includes an endothermic peak at about 127°C. In some embodiments, Form D is characterized by a DSC thermogram that includes endothermic peaks at about 127°C and about 204°C. In some embodiments, Form D is characterized by a DSC thermogram that includes a desolvation endothermic peak at about 127°C. In some embodiments, Form D is characterized by a DSC thermogram that includes a melting endothermic peak at about 204°C.

[0096] In some embodiments, Form D is substantially free of other polymorphic forms. In some embodiments, Form D has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Form D has a polymorphic purity of at least 90%. In some embodiments, Form D has a polymorphic purity of at least 92%. In some embodiments, Form D has a polymorphic purity of at least 94%. In some embodiments, Form D has a polymorphic purity of at least 96%. In some embodiments, Form D has a polymorphic purity of at least 98%. In some embodiments, Form D has a polymorphic purity of at least 99%.

[0097] F. Crystal Form E In some embodiments, the crystalline form of Compound 1 is a solvate. In some embodiments, the solvate is an nBuOH solvate.

[0098] In some embodiments, the present disclosure relates to crystalline Form E of Compound 1. In some embodiments, the solvate crystalline form of Compound 1 is Form E. In some embodiments, the nBuOH solvate crystalline form of Compound 1 is Form E. In some embodiments, Form E has one or more characteristics selected from the group consisting of: a) an XRPD pattern comprising peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ, b) an XRPD pattern substantially as shown in FIG. 4A, c) a DSC thermogram profile comprising an endothermic peak at about 203 °C, d) a DSC thermogram profile comprising an endothermic peak at about 87 °C, e) a DSC thermogram profile substantially as shown in FIG. 4B, f) a TGA profile showing a loss of at least about 7 wt% between about 22 °C and about 100 °C, and f) a TGA profile substantially as shown in FIG. 4B.

[0099] In some embodiments, Form E is characterized by an XRPD pattern that includes peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ. In some embodiments, Form E is characterized by an XRPD pattern that includes peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ and further includes at least one additional peak at a position selected from the group consisting of 8.5±0.2, 14.9±0.2, 15.8±0.2, 18.2±0.2, and 21.4±0.2 degrees 2θ. In some embodiments, Form E is characterized by an XRPD pattern that includes peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, 17.0±0.2, and 21.4±0.2 degrees 2θ. In some embodiments, Form E is characterized by an XRPD pattern that includes peaks at 4.9±0.2, 8.5±0.2, 12.0±0.2, 12.2±0.2, 14.9±0.2, 15.8±0.2, 17.0±0.2, 18.2±0.2, and 21.4±0.2 degrees 2θ. In some embodiments, crystalline Form E is characterized by an XRPD pattern substantially as shown in Figure 4A.

[0100] In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA) thermogram showing that Form E loses at least about 7 wt% between about 22°C and about 100°C. In some embodiments, Form E is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 4B.

[0101] In some embodiments, Form E is characterized substantially by the differential scanning calorimetry (DSC) thermogram shown in FIG. 4B. In some embodiments, Form E is characterized by a DSC thermogram that includes an endothermic peak at about 203°C. In some embodiments, Form E is characterized by a DSC thermogram that includes an endothermic peak at about 87°C. In some embodiments, Form E is characterized by a DSC thermogram that includes endothermic peaks at about 87°C and about 203°C. In some embodiments, Form E is characterized by a DSC thermogram that includes a desolvation endothermic peak at about 87°C. In some embodiments, Form E is characterized by a DSC thermogram that includes a melting endothermic peak at about 203°C.

[0102] In some embodiments, Form E is substantially free of other polymorphic forms. In some embodiments, Form E has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In some embodiments, Form E has a polymorphic purity of at least 90%. In some embodiments, Form E has a polymorphic purity of at least 92%. In some embodiments, Form E has a polymorphic purity of at least 94%. In some embodiments, Form E has a polymorphic purity of at least 96%. In some embodiments, Form E has a polymorphic purity of at least 98%. In some embodiments, Form E has a polymorphic purity of at least 99%.

[0103] Pharmaceutical composition In one aspect, the present invention provides a pharmaceutical composition which is a solid dosage form comprising a solid form of Compound 1 disclosed herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of Compound 1. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound 1. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of Compound 1.

[0104] Solid dosage forms suitable for oral administration include solid preparations such as tablets, caplets, capsules, powders, lozenges (including liquid-filled), sachets, and the like.

[0105] The solid dosage forms disclosed herein include a carrier, which may include one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, binders, surfactants, diluents or fillers, buffers, anti-adhesion agents, flow promoters, hydrophilic or hydrophobic polymers, retardants, stabilizers or stabilizers, disintegrants or super disintegrants, dispersants, antioxidants, defoamers, fillers, fragrances, colorants, lubricants, adsorbents, preservatives, plasticizers, coating agents, or sweeteners, or mixtures thereof, as well as other excipients known in the art. For example, the excipient(s) may be binders such as microcrystalline cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, low-viscosity hydroxypropylmethyl cellulose, tragacanth gum or gelatin; diluents such as mannitol, microcrystalline cellulose, maltodextrin, starch or lactose; disintegrants such as alginic acid, PRIMOGEL®, sodium starch glycolate, croscarmellose sodium, crospovidone or corn starch; lubricants such as magnesium stearate, sodium stearyl fumarate or glyceryl behenate; glidants such as colloidal silicon dioxide; preservatives such as potassium sorbate or methyl paraben; surfactants such as sodium lauryl sulfate, sodium docusate, polysorbate 20, polysorbate 80, cetyltriethylammonium bromide, polyethylene oxide - polypropylene oxide copolymer, or CREMOPHOR® EL; antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, ascorbic acid, tocopherol or tocopherol acetate, sodium sulfite, or sodium metabisulfite; coatings including one or more of hydroxypropylmethyl cellulose, polyvinyl alcohol, methacrylate copolymer, cellulose acetate, hydroxypropylmethyl cellulose acetate succinate, shellac, etc.; sweeteners such as sucrose, sucralose, acesulfame K, sodium aspartame or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavor.Any of the well-known pharmaceutical excipients can be incorporated into the dosage form and can be found in the FDA’s Inactive Ingredients Guide, Remington: The Science and Practice of Pharmacy, Twenty-first Ed., (Pharmaceutical Press, 2005), Handbook of Pharmaceutical Excipients, Sixth Ed. (Pharmaceutical Press, 2009), all of which are incorporated by reference. In some embodiments, the solid dosage forms disclosed herein include any one or more of the following excipients: microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and opadry AMB II 88A180040 white. In some embodiments, the disclosed solid dosage forms include microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, colloidal silicon dioxide, sodium stearyl fumarate, and opadry AMB II 88A180040 white. In some embodiments, the disclosed solid dosage forms include microcrystalline cellulose low humidity, silicified microcrystalline cellulose low humidity type 90, mannitol, sodium starch glycolate, and sodium stearyl fumarate.

[0106] Method of Use As described herein, Compound 1 is generally designed to be a positive allosteric modulator of NMDA function and is thus useful, for example, in the treatment and prevention of CNS-related conditions in a subject.

[0107] In some embodiments, as described herein, Compound 1 is generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). In certain embodiments of the present disclosure, Compound 1 acts as a positive allosteric modulator (PAM) of NMDA and enhances NMDA receptor function.

[0108] In one aspect, the present disclosure provides a method for treating a disease, disorder, or condition in a subject that requires positive allosteric NMDA modulation, the method comprising administering to the subject an effective amount of a crystalline form or solid dosage form of Compound 1 disclosed herein.

[0109] In one aspect, the present disclosure provides a method for treating a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of a crystalline form or solid dosage form of Compound 1 disclosed herein.

[0110] In one aspect, the present disclosure provides a method for preventing a disease, disorder, or condition in a subject that requires positive allosteric NMDA modulation, the method comprising administering to the subject an effective amount of a crystalline form or solid dosage form of Compound 1 disclosed herein.

[0111] In one aspect, the present disclosure provides a method for preventing a CNS-related condition in a subject, the method comprising administering to the subject an effective amount of a crystalline form or solid dosage form of Compound 1 disclosed herein.

[0112] In one aspect, the present disclosure provides a method for inducing sedation or anesthesia in a subject, the method comprising administering to the subject an effective amount of a crystalline form or solid formulation of Compound 1 disclosed herein.

[0113] In one aspect, the present disclosure provides a crystalline form or solid formulation of Compound 1 disclosed herein for use in the treatment of a disease, disorder, or condition in a subject that requires positive allosteric NMDA modulation.

[0114] In one aspect, the present disclosure provides a crystalline form or solid formulation of Compound 1 disclosed herein for use in the treatment of CNS-related conditions in a subject.

[0115] In one aspect, the present disclosure provides a crystalline form or solid formulation of Compound 1 disclosed herein for use in the prevention of a disease, disorder, or condition that requires positive NMDA modulation in a subject.

[0116] In one aspect, the present disclosure provides a crystalline form or solid formulation of Compound 1 disclosed herein for use in the prevention of CNS-related conditions in a subject.

[0117] In one aspect, the present disclosure provides a crystalline form or solid formulation of Compound 1 disclosed herein for use in inducing sedation or anesthesia in a subject.

[0118] In one aspect, the present disclosure provides the use of a crystalline form or solid formulation of Compound 1 disclosed herein for the manufacture of a medicament for preventing a disease, disorder, or condition that requires positive allosteric NMDA modulation in a subject.

[0119] In one aspect, the present disclosure provides the use of a crystalline form or solid formulation of Compound 1 disclosed herein for the manufacture of a medicament for treating CNS-related conditions in a subject.

[0120] In one aspect, the present disclosure provides the use of a crystalline form or solid formulation of Compound 1 disclosed herein for the manufacture of a medicament for treating a disease, disorder, or condition that requires positive allosteric NMDA modulation in a subject.

[0121] In one aspect, the present disclosure provides the use of a crystalline form or solid formulation of Compound 1 disclosed herein for the manufacture of a medicament for preventing CNS-related conditions in a subject.

[0122] In one aspect, the present disclosure provides the use of a crystalline form of Compound 1 or a solid formulation disclosed herein for the manufacture of a medicament for inducing sedation or anesthesia in a subject.

[0123] In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), an organic disorder affecting the GI, an anal disorder (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissure, perianal abscess, fistula-in-ano), a colorectal polyp, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0124] In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is a SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is related to phenylketonuria.

[0125] Exemplary conditions related to positive NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), an organic disorder affecting the GI, an anal disorder (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissure, perianal abscess, fistula-in-ano), a colorectal polyp, cancer, colitis, and CNS conditions such as those described herein.

[0126] Exemplary CNS conditions associated with positive NMDA modulation include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other types of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, mood-cycling disorder, suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance use-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorder (including those related to mutations in the Shank protein family (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, steroid synthesis disorders, pain (acute and chronic pain; headache, e.g., migraine), seizure disorders (including status epilepticus and single-gene epilepsy, e.g., Dravet syndrome, and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus, but are not limited thereto.

[0127] In certain embodiments, the crystalline form or solid formulation of Compound 1 disclosed herein can be used to induce sedation or anesthesia. In certain embodiments, the crystalline form or solid formulation of Compound 1 disclosed herein is useful in the treatment or prevention of adjustment disorders, anxiety, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorder, neurodevelopmental disorders, steroid synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders, and visual function disorders, hearing loss, and tinnitus. In certain embodiments, the disorder is Huntington's disease. In certain embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is an inflammatory disease (e.g., lupus).

[0128] In another aspect, provided is a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, the method comprising administering to the subject an effective amount of the crystalline form or solid formulation of Compound 1 disclosed herein.

[0129] In yet another aspect, the present disclosure provides a combination of a crystalline form of a compound of the present disclosure, such as Compound 1, and another pharmaceutically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. The combined administration can be effected by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

[0130] Diseases and Disorders Movement Disorders Methods of treating movement disorders are also described herein. As used herein, "movement disorder" refers to a variety of diseases and disorders associated with hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly as defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremors (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0131] Tremors are involuntary and sometimes rhythmic contractions and relaxations of muscles, which may be accompanied by vibrations or contractions in one or more body parts (e.g., hands, arms, eyes, face, head, vocal cord folds, trunk, legs). Tremors include, respectively, hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor; metabolic diseases (e.g., thyroid and parathyroid diseases, liver diseases, and hypoglycemia); peripheral neuropathies (related to Charcot-Marie-Tooth, Roussy-Lévy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and mental disorders. Clinical tremors can be classified into physiological tremors, enhanced physiological tremors, essential tremor syndromes (including classical essential tremor, orthostatic tremor, and task- and position-specific tremors), dystonic tremors, parkinsonian tremors, cerebellar tremors, Holmes tremors (i.e., rubral tremors), palatal tremors, neuropathic tremors, toxic or drug-induced tremors, and psychogenic tremors. Other forms of tremors include cerebellar tremors or intention tremors, dystonic tremors, essential tremors, orthostatic tremors, parkinsonian tremors, physiological tremors, psychogenic tremors, or rubral tremors.

[0132] Cerebellar tremors or intention tremors are slow, wide-ranging tremors of the limbs that occur after intentional movements. Cerebellar tremors are caused by, for example, lesions or injuries to the cerebellum due to tumors, strokes, diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0133] Dystonic tremors occur in individuals affected by dystonia, a movement disorder in which persistent involuntary muscle contractions cause twisting, repetitive movements, and / or pain and abnormal postures or positions. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and can often be alleviated by complete rest.

[0134] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and non - progressive, or it may progress slowly. It usually starts on one side of the body but affects both sides within three years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk may also be involved. The tremor frequency may decrease with aging, but the severity may increase. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia may trigger and / or increase the severity of the tremor. The symptoms generally progress over time and include both visible and persistent ones after onset.

[0135] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing up. The thighs and legs may feel like they are shaking, and the patient may sway uncontrollably when asked to stand still in one place. Orthostatic tremor can occur in patients with essential tremor.

[0136] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill - rolling" movement of the hand, and may also affect the jaw, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after the age of 60. The movement starts in one limb or one side of the body and may progress to include the opposite side.

[0137] Physiological tremor can occur in normal individuals and has no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

[0138] Psychogenic tremor or hysterical tremor can occur at rest or during body sway or movement. Patients with psychogenic tremor may have a conversion disorder or another mental illness.

[0139] Palatal myoclonus is characterized by a coarse, slow tremor that may be present at rest, in a posture, and intentionally. The tremor is associated with a condition that affects the red nucleus of the midbrain, a classical abnormal stroke.

[0140] Parkinson's disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and walking. Parkinsonism is characterized by tremors, bradycardia, rigidity, and postural instability. Parkinsonism shares the symptoms found in Parkinson's disease but is a syndrome, not a progressive neurodegenerative disease.

[0141] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive, movements or postures. Dystonic movements are patterned and can be torsional or tremulous. Dystonia often begins or worsens with voluntary actions and is associated with overflow muscle activation.

[0142] Chorea is a neurological disorder typically characterized by involuntary, jerky movements that typically affect the shoulders, hips, and face.

[0143] Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, talking, and swallowing.

[0144] Ataxia refers to the inability to fully control body movements and can affect the movements of the fingers, hands, arms, legs, body, speech, and eyes.

[0145] Myoclonus and startle are responses to sudden, unexpected stimuli, which can be auditory, tactile, visual, or vestibular.

[0146] Tics are typically involuntary movements that occur suddenly, are repetitive over a short period of time, are not rhythmic, typically mimic normal behavior, and often arise against a background of normal activity. Tics can be classified as motor or vocal; motor tics are associated with movements, and vocal tics are associated with sounds. Tics are characterized as simple or complex. For example, simple motor tics involve only some muscles restricted to a particular body part.

[0147] Tourette syndrome is a hereditary neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0148] Restless legs syndrome is a sensorimotor disorder characterized by an overwhelming urge to move the legs at rest.

[0149] Generalized dystonia is a progressive movement disorder characterized by involuntary painful contractions and muscle rigidity (usually involving the trunk and legs). A typical result is a walking pattern with an exaggerated lumbar lordosis and stiff legs. Characteristic abnormalities in EMG recordings with continuous motor unit activity of the paraspinal muscles are typically observed. Variant forms include "focal dystonia of the limbs syndrome" which typically produces focal dystonia affecting the distal legs and feet.

[0150] Gait disorders refer to abnormalities in the pattern or style of walking due to neuromuscular, arthritic, or other physical changes. Gait is classified according to the system causing the abnormal movement and includes hemiparetic gait, diparetic gait, neuropathic gait, myopathic gait, parkinsonian gait, chorea-like gait, ataxic gait, and sensory gait.

[0151] Mood disorders Also provided herein is a method for treating mood disorders, which can be, for example, clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, bipolar disorder, double depression, dysthymic personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendency, suicidal ideation, or suicidal behavior.

[0152] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by a wide range and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Among people with clinical depression, there are those with sleep disorders, weight loss, and those who are generally excited and irritable. Clinical depression can affect an individual's emotions, thoughts, and behaviors, and can lead to various emotional and physical problems. Individuals with clinical depression may have problems performing daily activities and may feel that life is not worth living.

[0153] Postnatal depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is refractory depression (e.g., refractory depression as described herein).

[0154] In some embodiments, a subject with PND has also experienced depression, or symptoms of depression, during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, subjects who experience perinatal depression have an increased risk of experiencing PND.

[0155] Atypical depression (AD) is characterized by mood reactivity (e.g., anhedonia), and positive affect, significant weight gain or increased appetite. Patients with AD may also have significant social impairment as a result of hypersensitivity to excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the limbs, and a perceived sense of interpersonal rejection.

[0156] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failure to respond to pleasurable stimuli, a depressive mood more prominent than sadness or loss, excessive weight loss, or excessive guilt.

[0157] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, especially of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0158] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become mute and immobile, or may exhibit purposeless or strange movements.

[0159] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0160] Mood swings refer to a condition related to unipolar depression in which the same physical and cognitive problems manifest. These are less severe and tend to be more persistent (e.g., at least two years).

[0161] Double depression refers to a fairly depressive mood (mood swings) that lasts for at least two years and is interrupted by periods of major depression.

[0162] Depressive personality disorder (DPD) refers to a personality disorder with depressive characteristics.

[0163] Recurrent brief depression (RBD) refers to a condition where an individual has depressive episodes about once a month, and each episode lasts for two weeks or less, or typically less than two to three days.

[0164] Mild depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0165] Bipolar disorder or manic-depressive disorder causes extreme mood swings that include elevated mood (mania or hypomania) and depression. During a manic episode, an individual may feel or act abnormally happy, energetic, or irritable. Often, the individual makes decisions without much consideration and without adequate deliberation, usually with little regard for the consequences. Typically, the need for sleep is reduced. During a depressive episode, there may be crying, little eye contact with others, and a negative outlook on life. The risk of suicide in people with the disorder is as high as over 6% over 20 years, and self-harm occurs in 30 - 40%. Other mental health problems such as anxiety disorders and substance use disorders are commonly associated with bipolar disorder.

[0166] Depression caused by a chronic medical condition refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0167] Treatment-resistant depression refers to a condition where an individual has received treatment for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not relieve the depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression may experience symptom improvement but then relapse. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0168] Suicidal tendency, suicidal thoughts, and suicidal acts refer to the tendency of an individual to attempt suicide. Suicidal thoughts are related to thoughts about suicide or abnormal preoccupation. The scope of suicidal thoughts varies, for example, from momentary thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, obtaining means to attempt suicide, withdrawing from social contact, becoming obsessed with death, feeling trapped or hopeless in a certain situation, increasing the use of alcohol or drugs, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if they will never see them again.

[0169] Symptoms of depression include persistent anxiety or feelings of sadness, weakness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, movement problems, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm behavior, suicidal thoughts, and suicidal attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Symptoms of depression and their alleviation can be confirmed by a doctor or psychologist (e.g., through a mental state examination).

[0170] Anxiety disorder Methods for treating anxiety disorders are provided herein. Anxiety disorder is an umbrella term covering several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0171] Generalized anxiety disorder is a common chronic disorder characterized by chronic anxiety that does not focus on any one object or situation. People troubled by generalized anxiety experience non-specific, persistent fears and worries and become overly concerned about everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting the elderly.

[0172] In panic disorder, people are troubled by sudden episodes of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as sudden onsets of fear or discomfort that peak in less than 10 minutes, but they can last for hours and may also be triggered by stress, fear, or exercise. However, the specific causes are not always clear. In addition to the recurrence of unexpected panic attacks, a diagnosis of panic disorder also requires the chronic consequence of either worrying about the potential impact of the attacks, persistent fear of future attacks, or significant changes in behavior related to the attacks. Thus, people with panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heart rate are noticed by panic patients, leading them to think there is something wrong with their heart or that another panic attack is about to occur. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, and the perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., extreme hypochondriasis).

[0173] Obsessive-compulsive disorder is a type of anxiety disorder characterized mainly by repetitive obsessions (distressing, persistent, intrusive thoughts or images) and compulsive impulses (urges to perform specific actions or ritualistic behaviors). OCD thought patterns can be likened to superstitions insofar as they involve beliefs in causal relationships that do not actually exist. Often, this process is not entirely logical; for example, the compulsive impulse to walk in a certain pattern can be used to relieve the obsessive thought of an impending harm. Also often, compulsive impulses are simply inexplicable urges to stop a habitual behavior caused by anxiety. In a minority of cases, OCD patients may experience only obsessions without obvious compulsive impulses, and an even smaller number of patients experience only compulsive impulses.

[0174] The single largest category of anxiety disorders is the phobia category, which includes all cases in which fear and anxiety are triggered by specific stimuli or situations. Patients typically encounter the object of their fear, which can be anything from animals to places to body fluids, and anticipate terrifying consequences.

[0175] Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations, or even major accidents. It can also result from being exposed to intense stressors over a long period of time (chronically), such as soldiers who can withstand individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0176] Epilepsy Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy include general epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, childhood benign focal epilepsy, but are not limited to these.

[0177] Epileptogenesis Epileptogenesis is the stepwise process by which a normal brain develops epilepsy (the chronic state in which seizures occur). Epileptogenesis results from damage to nerve cells precipitated by an initial insult (e.g., status epilepticus).

[0178] Status epilepticus (SE) Status epilepticus (SE) includes, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive seizure states and may include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by a persistent seizure state despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by a persistent seizure state despite first-line and second-line therapies, and general anesthetics are generally administered. Super-refractory status epilepticus is characterized by a persistent seizure state despite first-line therapy, second-line therapy, and treatment with general anesthetics for 24 hours or more.

[0179] Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus, generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0180] Seizure A seizure is a change in physical findings or behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is the rapid and uncontrollable shaking of a person's body. During a convulsion, a person's muscles contract and relax repeatedly.

[0181] Based on the type of action and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or local). Classifying the type of seizure helps a doctor diagnose whether a patient has epilepsy.

[0182] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that causes the seizure is sometimes called the focus.

[0183] There are six types of generalized seizures. The most common and dramatic, and thus the most well-known, is the generalized convulsion also called the grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls. After the loss of consciousness, there is a 30- to 60-second period of generalized stiffness (called the "tonic" phase of the seizure), followed by a 30- to 60-second period of violent jerking (the "clonic" phase), after which the patient enters a deep sleep (the "postictal" or post-seizure phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence may occur.

[0184] Absence seizures cause a short loss of consciousness (only a few seconds) with little or no symptoms. The patient is most often a child and typically interrupts an activity and stares blankly. These seizures start and end suddenly and may occur several times a day. The patient usually does not recognize that a seizure is occurring but may recognize that they are "losing time."

[0185] Myoclonic seizures usually consist of sporadic jerks on both sides of the body. The patient may describe the jerks as short electrical shocks. In severe cases, these seizures can cause the patient to drop an object or involuntarily throw something.

[0186] Clonic seizures are repetitive and rhythmic jerks that involve both sides of the body simultaneously.

[0187] Tonic seizures are characterized by muscle rigidity.

[0188] Atonic seizures consist particularly of a sudden general loss of muscle tone, often causing a fall.

[0189] Seizures described herein include: epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; discontinuous seizures; prolonged seizures; recurrent seizures; seizures in status epilepticus, for example, refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized seizures; infantile convulsions; jacksonian seizures; massive bilateral myoclonic seizures; multiple seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures, sylvian seizures; visual reflex seizures; or drop seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0190] Sterol synthesis disorder In one embodiment, a method for treating a sterol synthesis disorder is described herein. Cholesterol has essential regulations in growth and development. Cholesterol is a membrane lipid and is a precursor of many molecules that play important roles in cell growth and differentiation, protein glycosylation, and signal transduction pathways. The biosynthesis of cholesterol involves several enzymes and intermediates. Disorders resulting from deficiencies in any of the enzymes involved in cholesterol biosynthesis lead to the accumulation of intermediates and imbalances in biomolecules, which result in disorders including congenital skeletal malformations, dysmorphic facial features, psychomotor developmental delay, and growth disorders. In one embodiment, a sterol synthesis disorder or symptoms of a sterol synthesis disorder can be treated by administering to a subject suffering from the sterol synthesis disorder a compound described herein, for example, an NMDA receptor modulating compound described herein. Additional disorders are described below.

[0191] Smith-Lemli-Opitz syndrome In one embodiment, a method for treating Smith-Lemli-Opitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency) is described herein. SLOS is a congenital cholesterol synthesis disorder. In addition to microcephaly, moderate to severe intellectual disability, sensory hypersensitivity, stereotyped behavior, dysmorphic facial features, and syndactyly of the second / third toes, the characteristics of the disease are reduced cerebrosterol (24(S)-hydroxycholesterol) levels. SLOS is an autosomal recessive genetic condition resulting from a deficiency in the last enzyme in the cholesterol synthesis pathway, causing low plasma cholesterol levels or low normal plasma cholesterol levels, and increased levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Current common therapies include dietary cholesterol supplementation, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors, also known as statins), and treatment with agents that enhance cholesterol production and / or adhesion, and reduction of the accumulation of 7DHC and 8DHC, which are potentially toxic precursors of cholesterol.

[0192] Desmosterolosis Desmosterolosis is a deficiency in desmosterol reductase and has a phenotype similar to SLOS. In one embodiment, methods for treating desmosterolosis with the compounds described herein are described herein.

[0193] Sitosterolemia Sitosterolemia is a rare autosomal recessive disorder caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia enhances the intestinal absorption of plant sterols and cholesterol. Patients typically present with tendon and tuberous xanthomas, as well as premature coronary artery disease. In one embodiment, methods for treating sitosterolemia with the compounds described herein are described herein.

[0194] Cerebrotendinous xanthomatosis (CTX) In one embodiment, methods for treating cerebrotendinous xanthomatosis (also referred to as cerebral cholesterosis or Van Bogaert-Scherer-Epstein syndrome) with the compounds described herein are described herein. CTX can be caused by mutations in the CYP27A1 gene that produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid) that are important in the absorption of dietary fat. Enzyme dysfunction can lead to cholesterol accumulation in tissues. CTX is characterized by childhood diarrhea, cataracts, tendon xanthomas, reduced mental ability, and abnormal movements in adults.

[0195] Mevalonate kinase deficiency syndrome (MKD) Mevalonate kinase deficiency (also known as mevalonic aciduria (more severe form of MKD), or hyper IgD syndrome (HIDS or hyperglobulinemia D) and periodic fever syndrome (more benign form of MKD)) results in the accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can lead to developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and overall growth impairment. Mevalonic aciduria is characterized by delays in physical and mental development, growth impairment, recurrent episodes of fever with vomiting and diarrhea, hepatomegaly, splenomegaly and lymphadenopathy, microcephaly (small head size), cataracts, hypotonia, hyporeflexia, characteristic facial features, ataxia, and anemia. HIDS is characterized by recurrent episodes of fever associated with lymphadenopathy, joint pain, gastrointestinal problems, and rashes. In one embodiment, methods for treating MKD with the compounds described herein are described herein.

[0196] SC4MOL gene mutation (SMO deficiency) SC4MOL gene deficiency is a hereditary disorder in the cholesterol biosynthesis pathway (e.g., mutations in the SC4MOL gene encoding a novel sterol oxidase). SC4MOL deficiency is characterized by the accumulation of dimethyl and monomethyl sterols that can be detected in blood, dandruff, or primary skin fibroblasts. In one embodiment, methods for treating SMO deficiency with the compounds described herein are described herein.

[0197] Niemann-Pick disease Niemann-Pick disease is a lysosomal storage disorder resulting from gene mutations that affect metabolism. Niemann-Pick disease results in the abnormal accumulation of cholesterol and other fatty substances (lipids) due to the body's inability to transport substances. The accumulation damages the affected areas.

[0198] Autism In one embodiment, a method for treating autism spectrum disorder or autism is described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is typically characterized, for example, by difficulties in social interaction, such as difficulties in verbal and non-verbal communication. Repetitive behaviors are also often found in individuals with autism. Autism may be associated with intellectual disability, motor coordination and attention difficulties, as well as physical health problems, such as sleep and gastrointestinal disorders. Individuals with autism may also excel in visual skills, music, mathematics, and art. Autism may refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Autism may also refer to autism of single etiology, such as synaptic degeneration, such as Rett syndrome, fragile X syndrome, Angelman syndrome.

[0199] Disorders associated with phenylketonuria In one embodiment, a method for treating a disorder associated with phenylketonuria (e.g., a cognitive disorder) with a compound described herein is described herein. Phenylketonuria can lead to hypocholesterolemia and reduced vitamin D status. Total and low-density cholesterol and 25-hydroxyvitamin D have been found to be decreased in subjects with phenylketonuria compared to subjects without phenylketonuria (Clin. Chim. Acta 2013, 416:54-59). 24S-hydroxy cholesterol and 27S-hydroxy cholesterol, as well as 7α-hydroxy cholesterol (e.g., representing peripheral and hepatic cholesterol elimination, respectively), have been shown to be significantly decreased in subjects with phenylketonuria, while 7β-hydroxy cholesterol (e.g., reflecting oxidative stress) has been significantly increased in subjects with phenylketonuria. Changes in the levels of 24S-OHC and 7β-hydroxy cholesterol correlate with phenylalanine levels, and 27S-hydroxy cholesterol levels may correlate with 25-hydroxyvitamin D levels in subjects with phenylketonuria.

[0200] Method for Preparing Crystal Forms In one aspect, the present disclosure provides a method for preparing a crystal form of Compound 1 disclosed herein.

[0201] In some embodiments, the present disclosure provides a method for preparing a crystal form of Compound 1, comprising: a) dissolving Compound 1 in at least one solvent to form a solution; b) adding an anti-solvent until a precipitate is formed; and c) isolating the precipitate. In some embodiments, the solvent is selected from the group consisting of THF, 1,4-dioxane, and MEK. In some embodiments, the anti-solvent is selected from the group consisting of H2O and ACN.

[0202] In some embodiments, the present disclosure provides a method for preparing a crystal form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at room temperature to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of DME, acetone, nBuOH, EtOAc, IPAc, BuOAc, diethyl ether, and ACN.

[0203] In some embodiments, the present disclosure provides a method for preparing a crystal form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at about 40 °C to precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of IPAc, BuOAc, ACN, and n-heptane.

[0204] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a volatile solvent to form a mixture; b) aging the mixture at room temperature to allow the volatile solvent vapor to interact with Compound 1 and precipitate a solid; and c) isolating the solid. In some embodiments, the solvent is selected from the group consisting of DME, MEK, diethyl ether, and t-BuOH.

[0205] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a solution; b) adding the solution to a poor solvent; c) aging the mixture at room temperature to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is BuOH. In some embodiments, the poor solvent is n-heptane.

[0206] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) filtering the mixture to provide a filtrate; c) aging the filtrate at room temperature; d) precipitating a solid; and e) isolating the solid. In some embodiments, the solvent is selected from the group consisting of IPAc and t-BuOH.

[0207] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) heating the mixture to about 50°C; c) filtering the mixture to provide a filtrate; d) cooling the filtrate to about -20°C; e) precipitating a solid; and f) isolating the solid. In some embodiments, the solvent is acetone.

[0208] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) heating Compound 1 to about 205 °C; b) cooling the heated Compound 1 to about 25 °C to provide a solid; and c) isolating the solid. In some embodiments, the cooling in step b) is at a rate selected from the group consisting of 2 °C / min, 10 °C / min, and 50 °C / min.

[0209] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) aging the mixture at about 90 °C to precipitate a solid; and d) isolating the solid. In some embodiments, the solvent is n-heptane.

[0210] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Compound 1 to a solvent to form a mixture; b) grinding the mixture to provide a solid; and d) isolating the solid. In some embodiments, the solvent is acetone / MIBK.

[0211] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Form E of Compound 1 to a first solvent to form a mixture; b) concentrating the mixture by distillation at atmospheric pressure; c) cooling the mixture to about 80-85 °C; d) adding a second solvent to the mixture and maintaining the temperature of the mixture at about 80-85 °C for at least 1 hour; e) concentrating the mixture by distillation at atmospheric pressure; f) cooling the mixture to about 20 °C to precipitate a solid; and g) isolating the solid. In some embodiments, the first solvent is heptane. In some embodiments, the second solvent is n-BuOH.

[0212] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Form E of Compound 1 to heptane to form a mixture; b) concentrating the mixture by distillation at atmospheric pressure; c) cooling the mixture to about 80 - 85 °C; d) adding n-BuOH to the mixture and maintaining the temperature of the mixture at about 80 - 85 °C for at least 1 hour; e) concentrating the mixture by distillation at atmospheric pressure; f) cooling the mixture to about 20 °C to precipitate a solid; and g) isolating the solid.

[0213] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Form E of Compound 1 to a solvent to form a mixture; b) heating the mixture to about 50 °C; c) adding a poor solvent; d) adding a seed of Form X of Compound 1 and aging the mixture at about 50 °C; e) cooling the mixture to about 20 °C over at least 3 hours and holding the mixture at 20 °C (with optional wet milling) to precipitate a solid; and f) isolating the solid. In some embodiments, the solvent is acetone. In some embodiments, the poor solvent is acetone / water. In some embodiments, the poor solvent is acetone / water (1:1 v / v).

[0214] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding Form E of Compound 1 to acetone to form a mixture; b) heating the mixture to about 50 °C; c) adding an acetone / water poor solvent (1:1 v / v); d) adding a seed of Form X of Compound 1 and aging the mixture at about 50 °C; e) adding an acetone / water poor solvent; f) cooling the mixture to about 20 °C over at least 3 hours and holding the mixture at 20 °C (with optional wet milling) to precipitate a solid; and g) isolating the solid.

[0215] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding crude Compound 1 to a solvent to form a mixture and heating the mixture to about 80°C; b) concentrating the mixture via distillation; c) adding a solvent to the mixture; d) adjusting the temperature of the mixture to about 80°C; e) adding a seed of Form E of Compound 1; f) cooling the mixture to about 15 - 25°C; g) aging the mixture at about 15 - 25°C for about 4 - 18 hours to precipitate a solid; and h) isolating the solid. In some embodiments, the solvent is n-BuOH.

[0216] In some embodiments, the present disclosure provides a method for preparing a crystalline form of Compound 1, comprising: a) adding crude Compound 1 to n-BuOH to form a mixture and heating the mixture to about 80°C; b) concentrating the mixture via distillation; c) adding n-BuOH to the mixture; d) adjusting the temperature of the mixture to about 80°C; e) adding a seed of Form E of Compound 1; f) cooling the mixture to about 15 - 25°C; g) aging the mixture at about 15 - 25°C for about 4 - 18 hours to precipitate a solid; and h) isolating the solid.

Examples

[0217] The following examples are described so that the invention described herein can be more fully understood. The examples are provided to illustrate the crystalline solid forms provided herein and should not be construed as limiting their scope in any way.

[0218] Example 1. Means and Methodology A. X-Ray Powder Diffraction (XRPD) The X-ray diffraction patterns described herein were collected using a PANalytical Empyrean X-ray powder diffractometer. The diffraction peak positions were calibrated using a PANalytical Si reference standard disk. The XRPD parameters used are listed in Table 1.

Table 1

[0219] B. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA data were collected using a TA Discovery 550 / Q500 TGA from TA Instruments. DSC was performed using a TA Q2000 DSC from TA Instruments. The DSC was calibrated with an indium reference standard, and the TGA was calibrated using a nickel reference standard. The detailed parameters are shown in Table 2.

Table 2

[0220] C. Polarizing Microscope (PLM) and Hot Stage Polarizing microscope photographs were taken with a Nikon DS-Fi2 upright microscope at room temperature. The hot stage was performed with Linkam.

[0221] D. Chemical Purity Determination (HPLC) As detailed in Table 3, purity analysis and stoichiometry were performed using an Agilent 1100 HPLC.

Table 3

[0222] E. Dynamic Vapor Sorption (DVS): DVS was measured using an SMS (Surface Measurement System) DVS Intrinsic. The relative humidity at 25 °C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters used in the DVS test are shown in Table 4.

Table 4

[0223] F. Nuclear Magnetic Resonance (NMR) The solution NMR spectrum was collected using a Bruker 400M NMR spectrometer. The sample was prepared in DMSO-d6.

[0224] Example 2. Abbreviations The abbreviations of the solvents are shown in Table 5. [Table 5]

[0225] Example 3. Polymorph Screening Polymorph screening experiments were conducted using different crystallization or solid transition methods. The methods used and the identified crystal forms are summarized in Table 6. [Table 6]

[0226] A. Poor Solvent Addition Approximately 15 mg of the starting material (Compound 1) was dissolved in 0.1 - 0.9 mL of a solvent to obtain a clear solution. The solution was magnetically stirred, and 0.2 mL of the poor solvent was added stepwise until a precipitate appeared or the total amount of the poor solvent reached 15.0 mL. The results in Table 7 (below) showed the forms obtained. [Table 7]

[0227] B. Slurry at Room Temperature Slurry conversion experiments were conducted at room temperature in different solvent systems. Approximately 15 mg of the starting material (Compound 1) was suspended in 0.2 mL of a solvent in a glass vial. The suspension was magnetically stirred at room temperature for 7 days, and then the remaining solid was isolated. The results are summarized in Table 8 below. [Table 8]

[0228] C. Slurry at 40 °C The slurry conversion experiments were also carried out at 40 °C in different solvent systems. Approximately 10 mg of the starting material (Compound 1) was suspended in 0.3 mL of solvent in a glass vial. The suspension was stirred at 40 °C for about 7 days, and then the remaining solid was isolated. The results are summarized in Table 9.

Table 9

[0229] D. Solid Vapor Diffusion Solid vapor diffusion experiments were carried out using different solvents. Approximately 10 mg of the starting material (Compound 1) was weighed into a 3 mL vial, which was then placed into a 20 mL vial containing 2 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature for 7 days to allow the solvent vapor to interact with the sample. The results are summarized in Table 10.

Table 10

[0230] E. Liquid Vapor Diffusion Approximately 15 mg of the starting material (Compound 1) was dissolved in a suitable solvent in a 3 mL vial to obtain a clear solution. This solution was then placed into a 20 mL vial containing 3 mL of a volatile solvent. The 20 mL vial was sealed with a cap and kept at room temperature to allow sufficient time for the organic vapor to interact with the solution. The results are summarized in Table 11.

Table 11

[0231] F. Gentle Evaporation Briefly, 15 mg of the starting material (Compound 1) was dissolved in 0.5 - 1.5 mL of solvent in a 3 mL glass vial. If dissolution was not achieved, the suspension was filtered using a PTFE membrane (pore size 0.20 μm), and the filtrate was used in subsequent steps. The visually clear solution was covered with Parafilm® having six pinholes and evaporated at room temperature. The results are summarized in Table 12.

Table 12

[0232] G. Gentle Cooling Approximately 20 mg of the starting material (Compound 1) was suspended in 0.5 - 1.0 mL of a solvent in a 3 mL glass vial at room temperature. The suspension was then heated to 50 °C, equilibrated for about 2 hours, and filtered using a PTFE membrane (pore size 0.22 μm). The filtrate was gently cooled to 5 °C at a rate of 0.1 °C / min. No solid was obtained for any of the systems, and the solution was then transferred to -20 °C. If no precipitation was observed, the solution was evaporated at room temperature. The results are summarized in Table 13. [Table 13]

[0233] H. Heating Experiment Approximately 10 mg of the starting material (Compound 1) was weighed into a DSC pan. The sample was heated to 205 °C at 30 °C / min and cooled to 25 °C at different rates (2, 10, 50 °C / min). The heated sample was tested by XRPD. The results are summarized in Table 14. [Table 14]

[0234] I. High - Temperature Slurry High - temperature slurry conversion experiments were carried out at 90 °C in different solvent systems. Approximately 100 mg of the starting material (Compound 1) was suspended in 0.3 mL of a solvent in a glass vial. The suspension was magnetically stirred at 90 °C for 24 hours, and the remaining solid was isolated for XRPD analysis. The results are summarized in Table 15. [Table 15]

[0235] J. Wet Milling Approximately 20 mg of Form A and 0.2 mL of a solvent were added to a mortar and milled for 10 minutes. The remaining solid was tested by XRPD. The results are summarized in Table 16.

Table 16

[0236] Example 4 Several crystalline forms including two anhydrides (Form A and B), two hydrates (Form X and D), and a solvate (Form E) were obtained by screening. The detailed characterization data of the various forms are shown in Table 17.

Table 17

[0237] The XRPD patterns of each form are shown in Figures 1A - 5A. These crystalline forms exhibited suitable properties (e.g., chemical stability, thermal stability, solubility, hygroscopicity, particle size, yield, impurity content during crystallization, drying properties, milling properties, and stability during tabletting) for preparing solid dosage forms.

[0238] Example 5. Preparation and Characterization of Form A Form A was used directly in the polymorph screening. The XRPD pattern of Form A is shown in Figure 1A, and the characteristic peaks are summarized in Table 18. Form A had a chemical purity of approximately 98% as detected by HPLC. The TGA and DSC data of Form A are shown in Figure 1B, showing a weight loss of 0.04% up to a maximum of 190 °C due to melting and an endotherm at 203.0 °C (peak temperature). Considering these results, Form A was considered to be an anhydride.

[0239] The crystals disappeared after heating to 205 °C, suggesting evaporation after melting. See Figure 1C. To examine the stability of the solid form as a function of humidity, the DVS isotherm plot of Form A was collected at 25 °C. The results showed an uptake of 0.05% water at 25 °C / 80%RH and no change in form after the DVS test. See Figures 1D and 1E, which suggest that Form A was non - hygroscopic.

Table 18

[0240] Example 6: Preparation and Characterization of Form B Form B was generated by heating Form X. The XRPD pattern of Form B is shown in Figure 2A, and the characteristic peaks are summarized in Table 19. Form B had a chemical purity of approximately 99% as detected by HPLC. The TGA and DSC data of Form B are shown in Figure 2B, showing a 0.2% weight loss up to 150 °C. The DSC data showed a sharp melting peak at 203.7 °C (peak temperature). Considering these results, Form B was considered to be an anhydrate. [Table 19]

[0241] Example 7: Preparation of Form X Form X was generated via a slurry of Form A in EtOH / H2O (0.927 / 0.073, a w = 0.4) at room temperature.

[0242] Example 8: Preparation and Characterization of Form D Form D was generated via vacuum drying of Form X. The XRPD pattern of Form D is shown in Figure 3A, and the characteristic peaks are summarized in Table 20. Form D had a chemical purity of approximately 98% as detected by HPLC. The TGA and DSC data of Form D are shown in Figure 3B, showing a 13.8% weight loss up to 150 °C and an endothermic desolvation at 127.1 °C (peak temperature) before a possible melting peak at 204.0 °C (peak temperature). After heating to 150 °C, then cooling to room temperature under nitrogen protection and re-exposing to ambient conditions, Form D was converted to Form A (see Figure 3C). [Table 20]

[0243] Example 9: Preparation and Characterization of Form E Form E was generated via liquid diffusion of Form A in BuOH / n-heptane at room temperature. The XRPD pattern of Form E is shown in Figure 4A, and the characteristic peaks are summarized in Table 21. Form E had a chemical purity of approximately 98% as detected by HPLC. The TGA and DSC data of Form E are shown in Figure 4B, showing a 7.2% weight loss up to 100 °C and an endothermic desolvation (peak temperature) at 86.7 °C prior to a possible melting peak (peak temperature) at 203.1 °C. After heating to 140 °C, then cooling to room temperature under nitrogen protection and re-exposure to ambient conditions, Form E was converted to Form B (see Figure 4C). As demonstrated by the presence of n-butanol methylene protons at approximately 3.7 ppm (1.5:1, molar ratio of n-butanol / API) detected by 1 1H NMR, Form E was considered to be an n-butanol solvate.

Table 21

[0244] Example 10: Preparation and Characterization of Form F Form F was generated via the following process: 1.1 Conversion at 80 °C at Different Concentrations Three slurries were set at 50, 100, and 150 g / heptane L of the BuOH solvate of Compound 1 on a 1-2 mL scale. The slurries were placed on a temperature-controlled shaker at 80 °C and stirred overnight at 600 rpm. The wet cakes in the slurries after overnight conditioning were tested by XRPD, and they all gave patterns that were consistent with the target anhydrous Form F.

[0245] The 150 g / L slurry was very thick like a cake, and the 100 g / L and 50 g / L slurries were homogeneous and free-flowing slurries. 100 g / L is a suitable concentration for the slurry conversion process.

[0246] 1.2 Conversion Reaction Rate at 80 °C The conversion reaction rate at 80 °C was investigated from a 2 mL test at approximately 100 g / L (using a temperature-controlled shaker). Samples withdrawn at 1.5 and 3 hours (0.5 mL slurry samples) were centrifuged to isolate the solid, and the wet cake solid was immediately analyzed by XRPD.

[0247] The XRPD results indicated that the conversion process was completed very rapidly (data not shown). At 1.5 hours, the sample had already been converted to the highly crystalline anhydrous form F.

[0248] 1.3 Characterization of the slurry conversion product after drying at 40 °C The wet cake of anhydrous form F from slurry conversion at 60 °C over 4 days was dried overnight in a vacuum oven at 40 °C. The resulting sample was characterized by XRPD, TGA, DSC, PLM, and 1H NMR (see Figures 5A - 5C). The characteristic XRPD peaks are summarized in Table 22.

[0249] The sample after overnight drying gave the same XRPD pattern as the wet cake, indicating the possibility of n - heptane removal in a high - temperature vacuum oven. By TGA and DSC, no residual solvent (either BuOH or n - heptane) was detected in the sample after overnight drying at 40 °C.

Table 22

[0250] Example 11: Preparation and Characterization of Form G XRPD Form G was characterized by XRPD (see Figure 5A and Table 23).

Table 23

Claims

1. Crystal morphology of compound 1 【Chemistry 4】 。

2. The crystalline form of compound 1 is a) Crystal morphology A, wherein morphology A is characterized by an X-ray powder diffraction (XRPD) pattern that includes peaks at 15.3±0.2, 16.6±0.2, and 17.9±0.2 degrees 2θ, b) Crystal morphology B, wherein morphology B is characterized by an XRPD pattern including peaks at 14.4±0.2, 16.8±0.2, and 18.5±0.2 degrees 2θ, c) Crystal morphology D, wherein morphology D is characterized by an XRPD pattern including peaks at 15.2±0.2, 17.4±0.2, and 17.7±0.2 degrees 2θ, d) Crystal morphology E, wherein morphology E is characterized by an XRPD pattern including peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ, e) Crystal morphology F, wherein morphology F is characterized by an XRPD pattern including peaks at 10.8±0.5, 17.1±0.5, 20.5±0.5, and 22.9±0.5 degrees 2θ, and f) The crystal morphology G according to claim 1, wherein the morphology G is selected from the group consisting of crystal morphologies G characterized by an XRPD pattern including peaks at 9.1±0.5, 14.7±0.5, 16.0±0.5, and 17.2±0.5 degrees 2θ.

3. The crystalline form of the compound 1 is a) Crystal morphology A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 14.5±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, and 20.1±0.2 degrees 2θ, b) Crystal morphology B, wherein morphology B is characterized by an XRPD pattern containing peaks at 10.9±0.2, 14.4±0.2, 16.8±0.2, 18.5±0.2, and 19.0±0.2 degrees 2θ, c) Crystal morphology D, characterized by an XRPD pattern including peaks at 15.2±0.2, 16.4±0.2, 17.4±0.2, 17.7±0.2, 18.3±0.2, and 18.9±0.2 degrees 2θ, d) Crystal morphology E, characterized by an XRPD pattern including peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, 17.0±0.2, and 21.4±0.2 degrees 2θ, e) Crystal morphology F, characterized by an XRPD pattern including peaks at 7.6±0.5, 10.8±0.5, 13.6±0.5, 14.9±0.5, 15.4±0.5, 15.9±0.5, 17.1±0.5, 20.5±0.5, 22.8±0.5, and 22.9±0.5 degrees 2θ, and f) The crystal morphology G according to claim 1, wherein the morphology G is selected from the group consisting of crystal morphologies G characterized by an XRPD pattern including peaks at 9.1±0.5, 12.0±0.5, 13.5±0.5, 14.7±0.5, 16.0±0.5, 17.2±0.5, and 17.7±0.5 degrees 2θ.

4. The crystalline form of the compound 1 is a) Crystal morphology A, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 11.3±0.2, 14.5±0.2, 15.3±0.2, 16.6±0.2, 17.7±0.2, 17.9±0.2, and 20.1±0.2 degrees 2θ, b) Crystal morphology B, wherein morphology B is characterized by an XRPD pattern including peaks at 10.9±0.2, 14.4±0.2, 15.4±0.2, 16.8±0.2, 18.5±0.2, and 19.0±0.2 degrees 2θ, c) Crystal morphology D, characterized by an XRPD pattern including peaks at 9.1±0.2, 15.2±0.2, 16.4±0.2, 17.4±0.2, 17.7±0.2, 18.3±0.2, and 18.9±0.2 degrees 2θ, d) Crystal morphology E, characterized by an XRPD pattern including peaks at 4.9±0.2, 8.5±0.2, 12.0±0.2, 12.2±0.2, 14.9±0.2, 15.8±0.2, 17.0±0.2, 18.2±0.2, and 21.4±0.2 degrees 2θ, e) Crystal morphology F, characterized by an XRPD pattern including peaks at 7.6±0.5, 10.8±0.5, 13.6±0.5, 14.9±0.5, 15.4±0.5, 15.9±0.5, 17.1±0.5, 20.5±0.5, 22.8±0.5, and 22.9±0.5 degrees 2θ, and f) The crystal morphology G according to claim 1, wherein the morphology G is selected from the group consisting of crystal morphologies G characterized by an XRPD pattern including peaks at 9.1±0.5, 12.0±0.5, 13.5±0.5, 14.7±0.5, 16.0±0.5, 17.2±0.5, and 17.7±0.5 degrees 2θ.

5. The crystal form according to claim 1, wherein the crystal form is an anhydrous substance.

6. The crystal morphology according to claim 5, wherein the crystal morphology is crystal morphology A characterized by an XRPD pattern including peaks at 15.3±0.2, 16.6±0.2, and 17.9±0.2 degrees 2θ.

7. The crystalline morphology according to claim 6, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 11.3±0.2, 14.5±0.2, 17.7±0.2, and 20.1±0.2 degrees 2θ.

8. The crystal morphology according to claim 7, wherein the crystal morphology is crystal morphology A characterized by an XRPD pattern including peaks at 14.5±0.2, 15.3±0.2, 16.6±0.2, 17.9±0.2, and 20.1±0.2 degrees 2θ.

9. The crystal morphology according to claim 1, wherein the crystal morphology is substantially characterized by the XRPD pattern shown in Figure 1A, namely crystal morphology A.

10. The crystal morphology according to claim 1, wherein the crystal morphology substantially has a thermogravimetric analysis (TGA) thermogram shown in Figure 1B.

11. The crystal morphology according to claim 1, wherein the crystal morphology substantially has a differential scanning calorimetry (DSC) thermogram shown in Figure 1B.

12. The crystal morphology according to claim 11, wherein the DSC thermogram includes an endothermic peak at approximately 203°C.

13. The crystal morphology according to claim 5, wherein the crystal morphology is crystal morphology B characterized by an XRPD pattern including peaks at 14.4±0.2, 16.8±0.2, and 18.5±0.2 degrees 2θ.

14. The crystalline morphology according to claim 13, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 10.9 ± 0.2, 15.4 ± 0.2, and 19.0 ± 0.2 degrees 2θ.

15. The crystal morphology according to claim 14, wherein the crystal morphology is crystal morphology B characterized by an XRPD pattern including peaks at 10.9±0.2, 14.4±0.2, 16.8±0.2, 18.5±0.2, and 19.0±0.2 degrees 2θ.

16. The crystal morphology according to claim 1, wherein the crystal morphology is substantially crystal morphology B characterized by the XRPD pattern shown in Figure 2A.

17. The crystal morphology according to claim 1, wherein the crystal morphology substantially has the TGA thermogram shown in Figure 2B.

18. The crystal morphology according to claim 1, wherein the crystal morphology substantially has a DSC thermogram shown in Figure 2B.

19. The crystalline compound according to claim 18, wherein the DSC thermogram includes an endothermic peak at approximately 204°C.

20. The crystalline form according to claim 1, wherein the crystalline form is a solvate.

21. The crystal form according to claim 20, wherein the crystal form is a hydrate.

22. The crystal form according to claim 21, wherein the crystal form is a monohydrate.

23. The crystal morphology according to claim 1, wherein the crystal morphology is crystal morphology D characterized by an XRPD pattern including peaks at 15.2±0.2, 17.4±0.2, and 17.7±0.2 degrees 2θ.

24. The crystalline morphology according to claim 23, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 9.1±0.2, 16.4±0.2, 18.3±0.2, and 18.9±0.2 degrees 2θ.

25. The crystal morphology according to claim 24, wherein the crystal morphology is crystal morphology D characterized by an XRPD pattern having characteristic peaks at 15.2±0.2, 16.4±0.2, 17.4±0.2, 17.7±0.2, 18.3±0.2, and 18.9±0.2 degrees 2θ.

26. The crystal morphology according to claim 1, wherein the crystal morphology is substantially a crystal morphology D characterized by the XRPD pattern shown in Figure 3A.

27. The crystal morphology according to claim 1, wherein the crystal morphology substantially has the TGA thermogram shown in Figure 3B.

28. The crystal morphology according to claim 1, wherein the crystal morphology substantially has a differential scanning calorimetry (DSC) thermogram as shown in Figure 3B.

29. The crystal morphology according to claim 28, wherein the DSC thermogram includes an endothermic peak at approximately 204°C.

30. The crystal morphology according to claim 28, wherein the DSC thermogram includes an endothermic peak at approximately 127°C.

31. The crystalline form according to claim 20, wherein the crystalline form is an nBuOH solvate.

32. The crystal morphology according to claim 31, wherein the crystal morphology is a crystal morphology E characterized by an XRPD pattern including peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, and 17.0±0.2 degrees 2θ.

33. The crystalline morphology according to claim 32, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 8.5±0.2, 14.9±0.2, 15.8±0.2, 18.2±0.2, and 21.4±0.2 degrees 2θ.

34. The crystal morphology according to claim 32, wherein the crystal morphology E is characterized by having an XRPD pattern having characteristic peaks at 4.9±0.2, 12.0±0.2, 12.2±0.2, 17.0±0.2, and 21.4±0.2 degrees 2θ.

35. The crystal morphology according to claim 1, wherein the crystal morphology is substantially characterized by the XRPD pattern shown in Figure 4A, namely crystal morphology E.

36. The crystal morphology according to claim 1, wherein the crystal morphology substantially has the TGA thermogram shown in Figure 4B.

37. The crystal morphology according to claim 1, wherein the crystal morphology substantially has a differential scanning calorimetry (DSC) thermogram shown in Figure 4B.

38. The crystal morphology according to claim 37, wherein the thermogram includes an endothermic peak at approximately 203°C.

39. The crystal morphology according to claim 37, wherein the DSC thermogram includes an endothermic peak at approximately 87°C.

40. The crystal morphology according to claim 5, wherein the crystal morphology is a crystal morphology F characterized by an XRPD pattern including peaks at 10.8±0.5, 17.1±0.5, 20.5±0.5, and 22.9±0.5 degrees 2θ.

41. The crystalline morphology according to claim 40, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 7.6±0.5, 13.6±0.5, 14.9±0.5, 15.4±0.5, 15.9±0.5, and 22.8±0.5 degrees 2θ.

42. The crystal morphology according to claim 41, wherein the crystal morphology is a crystal morphology F characterized by an XRPD pattern including peaks at 7.6±0.5, 10.8±0.5, 13.6±0.5, 14.9±0.5, 15.4±0.5, 15.9±0.5, 17.1±0.5, 20.5±0.5, 22.8±0.5, and 22.9±0.5 degrees 2θ.

43. The crystal morphology according to claim 1, wherein the crystal morphology is a crystal morphology F characterized substantially by the XRPD pattern shown in Figure 5A.

44. The crystal morphology according to claim 5, wherein the crystal morphology G is characterized by an XRPD pattern including peaks at 9.1±0.5, 14.7±0.5, 16.0±0.5, and 17.2±0.5 degrees 2θ.

45. The crystalline morphology according to claim 44, wherein the XRPD pattern further includes at least one additional peak at a position selected from the group consisting of 12.0 ± 0.5, 13.5 ± 0.5, and 17.7 ± 0.5 degrees 2θ.

46. The crystal morphology according to claim 44, wherein the crystal morphology G is characterized by an XRPD pattern including peaks at 9.1±0.5, 12.0±0.5, 13.5±0.5, 14.7±0.5, 16.0±0.5, 17.2±0.5, and 17.7±0.5 degrees 2θ.

47. The crystal morphology according to claim 1, wherein the crystal morphology is a crystal morphology G characterized substantially by the XRPD pattern shown in Figure 5A.

48. A solid dosage form comprising a crystalline form according to any one of claims 1 to 47 and at least one pharmaceutically acceptable carrier.

49. A composition or solid dosage form for treating a CNS-related condition in a subject, wherein the composition comprises a crystalline form according to any one of claims 1 to 47, and the solid dosage form comprises a crystalline form according to any one of claims 1 to 47 and at least one pharmaceutically acceptable carrier.

50. The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymia), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorder (Shank The composition or solid dosage form according to claim 49, selected from the group consisting of: (including those involving mutations in a group of proteins), neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis), pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (including status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), and tinnitus.

51. A composition or solid dosage form for inducing sedation or anesthesia in a subject, wherein the composition comprises a crystalline form according to any one of claims 1 to 47, and the solid dosage form comprises a crystalline form according to any one of claims 1 to 47 and at least one pharmaceutically acceptable carrier.

52. A method for producing the crystalline form of compound 1, A. a) The step of dissolving compound 1 in at least one solvent to form a solution, b) Adding a poor solvent until a precipitate is formed, c) The step of isolating the precipitate, If necessary, the solvent is selected from the group consisting of THF, 1,4-dioxane, and MEK. If necessary, the poor solvent may be selected from the group consisting of H₂O and ACN, or B. a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at room temperature to precipitate the solid, c) the step of isolating the solid, If necessary, the solvent may be selected from the group consisting of DME, acetone, nBuOH, EtOAc, IPAc, BuOAc, diethyl ether, and ACN, or C. a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at approximately 40°C to precipitate the solid, c) the step of isolating the solid, If necessary, the solvent may be selected from the group consisting of IPAc, BuOAc, ACN, and n-heptane, or D. a) The step of adding compound 1 to a volatile solvent to form a mixture, b) A step of aging the mixture at room temperature to allow the volatile solvent vapor to interact with compound 1 and precipitate the solid, c) the step of isolating the solid, If necessary, the solvent may be selected from the group consisting of DME, MEK, diethyl ether, and t-BuOH, or E. a) The step of adding compound 1 to a solvent to form a solution, b) The step of adding the solution to a poor solvent, c) A step of aging the mixture at room temperature to precipitate the solid, d) a step of isolating the solid, If necessary, the solvent may be BuOH and the poor solvent may be n-heptane, or F. a) The step of adding compound 1 to a solvent to form a mixture, b) A step of filtering the mixture to provide a filtrate, c) A step of aging the filtrate at room temperature, d) A step of precipitating the solid, e) the step of isolating the solid, If necessary, the solvent may be selected from the group consisting of IPAc and t-BuOH, or G. a) The step of adding compound 1 to a solvent to form a mixture, b) The step of heating the mixture to about 50°C, c) The step of filtering the mixture to provide a filtrate, d) A step of cooling the filtrate to approximately -20°C, e) A step of precipitating the solid, f) a step of isolating the solid, If necessary, the solvent may be acetone, or H. a) A step of heating compound 1 to approximately 205°C, b) A step of cooling the heated compound 1 to about 25°C to provide a solid, c) the step of isolating the solid, If necessary, the cooling in step b) may be at a rate selected from the group consisting of approximately 2°C / min, approximately 10°C / min, and approximately 50°C / min, or I. a) The step of adding compound 1 to a solvent to form a mixture, b) A step of aging the mixture at approximately 90°C to precipitate the solid, c) the step of isolating the solid, If necessary, the solvent may be n-heptane, or J. a) The step of adding compound 1 to a solvent to form a mixture, b) The step of grinding the mixture to provide a solid, c) the step of isolating the solid, If necessary, the solvent may be acetone / MIBK, or K. a) The step of adding form E of compound 1 to a first solvent to form a mixture, b) A step of concentrating the mixture by distillation at atmospheric pressure, c) A step of cooling the mixture to about 80 to 85°C, d) Adding a second solvent to the mixture and maintaining the temperature of the mixture at approximately 80-85°C for at least one hour, e) A step of concentrating the mixture by distillation at atmospheric pressure, f) The step of cooling the mixture to about 20°C to precipitate the solid, g) a step of isolating the solid, If necessary, the first solvent may be heptane and the second solvent may be n-BuOH, or L. a) The step of adding form E of compound 1 to a solvent to form a mixture, b) The step of heating the mixture to about 50°C, c) The step of adding a poor solvent, d) Adding seeds of form X of compound 1 and aging the mixture at approximately 50°C, e) The steps of cooling the mixture to about 20°C for at least 3 hours, and holding the mixture at 20°C (any wet milling) to precipitate the solid, f) a step of isolating the solid, If necessary, the solvent may be acetone, and the poor solvent may be acetone / water, M. a) Adding crude compound 1 to a solvent to form a mixture and heating it to approximately 80°C, b) A step of concentrating the mixture by distillation, c) The step of adding a solvent to the mixture, d) The step of adjusting the temperature of the mixture to about 80°C, e) The step of adding a seed of form E of compound 1, f) A step of cooling the mixture to about 15 to 25°C, g) A step of aging the mixture at approximately 15 to 25°C for approximately 4 to 18 hours to precipitate the solid, h) The step of isolating the solid, A method wherein, if necessary, the solvent is n-BuOH.

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